U.S. patent application number 15/002131 was filed with the patent office on 2019-08-08 for matrix metalloprotease-cleavable and serine protease-cleavable substrates and methods of use thereof.
The applicant listed for this patent is CytomX Therapeutics, Inc.. Invention is credited to Daniel Robert Hostetter, Stephen James Moore, Margaret Thy Luu Nguyen, Jason Gary Sagert, Jonathan Alexander Terrett, Olga Vasiljeva, James William West.
Application Number | 20190241652 15/002131 |
Document ID | / |
Family ID | 55358121 |
Filed Date | 2019-08-08 |
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United States Patent
Application |
20190241652 |
Kind Code |
A9 |
Moore; Stephen James ; et
al. |
August 8, 2019 |
MATRIX METALLOPROTEASE-CLEAVABLE AND SERINE PROTEASE-CLEAVABLE
SUBSTRATES AND METHODS OF USE THEREOF
Abstract
The invention relates generally to polypeptides that include at
least a first cleavable moiety (CM1) that is a substrate for at
least one matrix metalloprotease (MMP) and at least a second
cleavable moiety (CM2) that is a substrate for at least one serine
protease (SP), to activatable antibodies and other larger molecules
that include these polypeptides that include at least a CM1 that is
a substrate for at least one MMP protease and at least a CM2 that
is a substrate for at least one SP protease, and to methods of
making and using these polypeptides that include at least a CM1
that is a substrate for at least one MMP protease and at least a
CM2 that is a substrate for at least one SP protease in a variety
of therapeutic, diagnostic and prophylactic indications.
Inventors: |
Moore; Stephen James;
(Danville, CA) ; Nguyen; Margaret Thy Luu; (San
Francisco, CA) ; Hostetter; Daniel Robert; (Palo
Alto, CA) ; Vasiljeva; Olga; (Cupertino, CA) ;
Sagert; Jason Gary; (San Mateo, CA) ; Terrett;
Jonathan Alexander; (Cupertino, CA) ; West; James
William; (Bend, OR) |
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Applicant: |
Name |
City |
State |
Country |
Type |
CytomX Therapeutics, Inc. |
South San Francisco |
CA |
US |
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Prior
Publication: |
|
Document Identifier |
Publication Date |
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US 20160289324 A1 |
October 6, 2016 |
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|
Family ID: |
55358121 |
Appl. No.: |
15/002131 |
Filed: |
January 20, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62105490 |
Jan 20, 2015 |
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62258015 |
Nov 20, 2015 |
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62278713 |
Jan 14, 2016 |
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62277771 |
Jan 12, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/40 20130101;
A61K 47/6849 20170801; C07K 2317/51 20130101; C07K 7/08 20130101;
C07K 2319/74 20130101; A61P 35/00 20180101; A61K 2039/507 20130101;
A61K 49/0058 20130101; C07K 16/2863 20130101; C07K 14/00 20130101;
C07K 2317/515 20130101; C07K 16/28 20130101; C07K 16/2896 20130101;
A61K 38/05 20130101; A61K 2039/505 20130101; C07K 2317/92 20130101;
C07K 2319/50 20130101; A61K 47/6851 20170801 |
International
Class: |
C07K 16/28 20060101
C07K016/28; C07K 14/00 20060101 C07K014/00; C07K 7/08 20060101
C07K007/08; A61K 38/05 20060101 A61K038/05; C07K 16/40 20060101
C07K016/40; A61K 47/48 20060101 A61K047/48; A61K 49/00 20060101
A61K049/00 |
Claims
1. An isolated polypeptide comprising a CM1-CM2 substrate
comprising at least a first cleavable moiety (CM1) that is a
substrate for at least one matrix metalloprotease (MMP) and at
least a second cleavable moiety (CM2) that is a substrate for at
least one serine protease (SP).
2. The isolated polypeptide of claim 1, wherein CM1 and CM2 are
linked via a linking peptide.
3. The isolated polypeptide of claim 1, wherein CM1 and CM2 share
at least one amino acid residue.
4. The isolated polypeptide of claim 1, wherein CM1 and CM2 are
directly linked to each other.
5. The isolated polypeptide of claim 1, wherein the CM1-CM2
substrate comprises an amino acid sequence selected from the group
consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490, 515-522, 555,
and 557.
6. The isolated polypeptide of claim 1, wherein the MMP is MMP2,
MMP9, or MMP14.
7. The isolated polypeptide of claim 1, wherein the SP is uPA or
matriptase.
8. An isolated polypeptide comprising an antibody or antigen
binding fragment thereof (AB) that binds a target, and at least a
first cleavable moiety (CM1) that is a substrate for at least one
matrix metalloprotease (MMP) and at least a second cleavable moiety
(CM2) that is a substrate for at least one serine protease
(SP).
9. The isolated polypeptide of claim 8, wherein CM1 and CM2 are
linked via a linking peptide.
10. The isolated polypeptide of claim 8, wherein CM1 and CM2 share
at least one amino acid residue.
11. The isolated polypeptide of claim 8, wherein CM1 and CM2 are
directly linked to each other.
12. The isolated polypeptide of claim 8, wherein the CM1-CM2
substrate comprises an amino acid sequence selected from the group
consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490, 515-522, 555,
and 557.
13. The isolated polypeptide of claim 8, wherein the MMP, the SP,
or both the MMP and the SP are co-localized in a tissue with the
target.
14. The isolated polypeptide of claim 8, wherein the antigen
binding fragment thereof is selected from the group consisting of a
Fab fragment, a F(ab').sub.2 fragment, a scFv, a scab, a dAb, a
single domain heavy chain antibody, and a single domain light chain
antibody.
15. The isolated polypeptide of claim 8, wherein the AB is linked
to the CM1.
16. The isolated polypeptide of claim 15, wherein the AB is linked
directly to the CM1.
17. The isolated polypeptide of claim 15, wherein the AB is linked
to the CM1 via a linking peptide.
18. The isolated polypeptide of claim 8, wherein the AB is linked
to CM2.
19. The isolated polypeptide of claim 18, wherein the AB is linked
directly to CM2.
20. The isolated polypeptide of claim 18, wherein the AB is linked
to the CM1 via a linking peptide.
21. The isolated polypeptide of claim 8, wherein the MMP is MMP2,
MMP9, or MMP14.
22. The isolated polypeptide of claim 8, wherein the SP is uPA or
matriptase.
23. The isolated polypeptide of claim 8, wherein the isolated
polypeptide comprises a masking moiety (MM).
24. The isolated polypeptide of claim 8, wherein the MM has a
dissociation constant for binding to the AB that is greater than
the dissociation constant of the AB for binding to the target.
25. The isolated polypeptide of claim 23, wherein the MM is a
polypeptide of no more than 40 amino acids in length.
26. The isolated polypeptide of claim 23, wherein the MM is linked
to the CM1 such that the isolated polypeptide in an uncleaved state
comprises the structural arrangement from N-terminus to C-terminus
as follows: MM-CM1-CM2-AB or AB-CM2-CM1-MM.
27. The isolated polypeptide of claim 26, wherein the isolated
polypeptide comprises a linking peptide between the MM and the
CM1.
28. The isolated polypeptide of claim 26, wherein the isolated
polypeptide comprises a linking peptide between CM2 and the AB.
29. The isolated polypeptide of claim 23, wherein the isolated
polypeptide comprises a linking peptide between CM1 and CM2.
30. The isolated polypeptide of claim 23, wherein the MM is linked
to CM2 such that the isolated polypeptide in an uncleaved state
comprises the structural arrangement from N-terminus to C-terminus
as follows: MM-CM2-CM1-AB or AB-CM1-CM2-MM.
31. The isolated polypeptide of claim 30, wherein the isolated
polypeptide comprises a linking peptide between the MM and CM2.
32. The isolated polypeptide of claim 30, wherein the isolated
polypeptide comprises a linking peptide between CM1 and the AB.
33. The isolated polypeptide of claim 30, wherein the isolated
polypeptide comprises a linking peptide between CM1 and CM2.
34. The isolated polypeptide of claim 23, wherein the isolated
polypeptide comprises a first linking peptide (LP1) and a second
linking peptide (LP2), and wherein the isolated polypeptide has the
structural arrangement from N-terminus to C-terminus as follows in
the uncleaved state: MM-LP1-CM1-CM2-LP2-AB, AB-LP2-CM2-CM1-LP1-MM,
MM-LP1-CM2-CM1-LP2-AB, or AB-LP2-CM1-CM2-LP1-MM.
35. The isolated polypeptide of claim 34, wherein the two linking
peptides need not be identical to each other.
36. The isolated polypeptide of claim 34, wherein each of LP1 and
LP2 is a peptide of about 1 to 20 amino acids in length.
37. The isolated polypeptide of claim 34, wherein the isolated
polypeptide comprises a third linking peptide (LP') between CM1 and
CM2.
38. The isolated polypeptide of claim 23, wherein the amino acid
sequence of the MM is different from that of the target and is no
more than 10% identical to the amino acid sequence of a natural
binding partner of the AB.
39. The isolated polypeptide of claim 23, wherein the MM does not
interfere or compete with the AB for binding to the target in a
cleaved state.
40. The isolated polypeptide of claim 8, wherein the isolated
polypeptide comprises a light chain amino acid sequence selected
from the group consisting of SEQ ID NOs: 420, 422, 424, 426, 428,
430, 432, 434, 436, 439, 477, 479, 507-514, 539-546, 561, and 562,
and a heavy chain amino acid sequence comprising SEQ ID NO: 67.
41. The isolated polypeptide of claim 8, wherein the isolated
polypeptide comprises a light chain amino acid sequence selected
from the group consisting of SEQ ID NOs: 449, 451, 453, 455, 457,
459, 461, 463, 465, 467, 472, 474, 499-506, 531-538, 559, and 560,
and a heavy chain amino acid sequence comprising SEQ ID NO:
108.
42. The isolated polypeptide of claim 1, wherein the isolated
polypeptide comprises an amino acid sequence selected from the
group consisting of SEQ ID NOs: 420, 422, 424, 426, 428, 430, 432,
434, 436, 439, 477, 479, 507-514, 539-546, 561, and 562.
43. The isolated polypeptide of claim 1, wherein the isolated
polypeptide comprises an amino acid sequence selected from the
group consisting of SEQ ID NOs: 449, 451, 453, 455, 457, 459, 461,
463, 465, 467, 472, 474, 499-506, 531-538, 559, and 560.
43. (canceled)
44. The isolated polypeptide of claim 23, wherein the SP is uPA or
matriptase.
45. A conjugated activatable antibody comprising the isolated
polypeptide of claim 8 conjugated to an agent.
46. The conjugated activatable antibody of claim 45, wherein the
agent is conjugated to the AB via a linker.
47. The conjugated activatable antibody of claim 46, wherein the
linker is a cleavable linker.
48. The conjugated activatable antibody of claim 46, wherein the
linker is a non-cleavable linker.
49. The conjugated activatable antibody of claim 45, wherein the
agent is a toxin or fragment thereof.
50. The conjugated activatable antibody of claim 45, wherein the
agent is a microtubule inhibitor.
51. The conjugated activatable antibody of claim 45, wherein the
agent is a nucleic acid damaging agent.
52. The conjugated activatable antibody of claim 45, wherein the
agent is selected from the group consisting of a dolastatin or a
derivative thereof, an auristatin or a derivative thereof, a
maytansinoid or a derivative thereof, a duocarmycin or a derivative
thereof, and a calicheamicin or a derivative thereof.
53. The conjugated activatable antibody of claim 52, wherein the
agent is auristatin E or a derivative thereof.
54. The conjugated activatable antibody of claim 52, wherein the
agent is monomethyl auristatin E (MMAE).
55. The conjugated activatable antibody of claim 52, wherein the
agent is monomethyl auristatin D (MMAD).
56. The conjugated activatable antibody of claim 52, wherein the
agent is a maytansinoid selected from the group consisting of DM1
and DM4.
57. The conjugated activatable antibody of claim 45, wherein the
agent is a detectable moiety.
58. The conjugated activatable antibody of claim 57, wherein the
detectable moiety is a diagnostic agent.
59. A pharmaceutical composition comprising the isolated
polypeptide claim 8 and a carrier.
60. The pharmaceutical composition of claim 59 comprising an
additional agent.
61. The pharmaceutical composition of claim 60, wherein the
additional agent is a therapeutic agent.
62. An isolated nucleic acid molecule encoding the isolated
polypeptide of claim 1.
63. A vector comprising the isolated nucleic acid molecule of claim
62.
64. A method of producing an antibody or an activatable antibody by
culturing a cell under conditions that lead to expression of an
isolated polypeptide, wherein the cell comprises the nucleic acid
molecule of claim 62.
65. A method of manufacturing an activatable antibody that, in an
activated state, binds a target, the method comprising: (a)
culturing a cell comprising a nucleic acid construct that encodes
the isolated polypeptide of claim 8; and (b) recovering the
activatable antibody.
66. A method of treating, alleviating a symptom of, or delaying the
progression of a disorder or disease comprising administering to a
subject in need thereof a therapeutically effective amount of the
isolated polypeptide of claim 8.
67. The method of claim 66, wherein the disorder or disease is
cancer.
68. The method of claim 66, wherein the method comprises
administering to the subject an additional agent.
69. The method of claim 68, wherein the additional agent is a
therapeutic agent.
70. The isolated polypeptide of claim 23, wherein the MMP is MMP2,
MMP9, or MMP14.
71. A method of treating, alleviating a symptom of, or delaying the
progression of a disorder or disease comprising administering to
the subject a therapeutically effective amount of the conjugated
activatable antibody of claim 45.
72. A method of treating, alleviating a symptom of, or delaying the
progression of a disorder or disease comprising administering to
the subject a therapeutically effective amount of the
pharmaceutical composition of claim 59.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/105,490, filed Jan. 20, 2015, U.S. Provisional
Application No. 62/258,015, filed Nov. 20, 2015, and U.S.
Provisional Application No. 62/278,713, filed Jan. 14, 2016, the
contents of each of which are incorporated herein by reference in
their entirety.
INCORPORATION OF SEQUENCE LISTING
[0002] The contents of the text file named "CYTM037001US_ST25",
which was created on Jan. 15, 2016 and is 456 KB in size, are
hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0003] The invention relates generally to polypeptides that include
at least a first cleavable moiety (CM1) that is a substrate for at
least one matrix metalloprotease (MMP) and at least a second
cleavable moiety (CM2) that is a substrate for at least one serine
protease (SP), to activatable antibodies and other larger molecules
that include these polypeptides that include at least a CM1 that is
a substrate for at least one MMP protease and a CM2 that is a
substrate for at least one SP protease, and to methods of making
and using these polypeptides that include at least a CM1 that is a
substrate for at least one MMP protease and a CM2 that is a
substrate for at least one SP protease in a variety of therapeutic,
diagnostic and prophylactic indications.
BACKGROUND OF THE INVENTION
[0004] Proteases are enzymes that degrade proteins by cleaving the
peptide bonds between amino acid residues. Proteases occur
naturally in all organisms and are involved in a variety of
physiological reactions from simple degradation to highly regulated
pathways. Some proteases are known to break specific peptide bonds
based on the presence of a particular amino acid sequence within a
protein.
[0005] Accordingly, there exists a need to identify new substrates
for proteases and to use these substrates in a variety of
therapeutic, diagnostic and prophylactic indications.
SUMMARY OF THE INVENTION
[0006] The disclosure provides amino acid sequences that include at
least a first cleavable moiety (CM1) that is a substrate for at
least one matrix metalloprotease (MMP) and at least a second
cleavable moiety (CM2) that is a substrate for at least one serine
protease (SP). These amino acid sequences are collectively referred
to herein as "CM1-CM2 substrates." This term is not intended to
convey any requirement regarding the orientation or other
structural arrangement of the first cleavable moiety (CM1) that is
a substrate for at least one matrix metalloprotease (MMP) and at
least a second cleavable moiety (CM2) that is a substrate for at
least one serine protease (SP). Thus, the term "CM1-CM2 substrates"
encompasses CM1-CM2 substrates having the structural arrangement
from N-terminus to C-terminus as follows: CM1-CM2 or CM2-CM1. The
term "CM1-CM2 substrates" also encompasses substrates where at
least a portion of the CM1 sequence overlaps with at least a
portion of the CM2 sequence.
[0007] The CM1-CM2 substrates described herein are useful in a
variety of therapeutic, diagnostic and prophylactic indications.
For example, these CM1-CM2 substrates are useful in activatable
antibodies that include antibodies or antigen-binding fragments
thereof (AB) that include at least one masking moiety (MM) linked
to at least one antigen- or epitope-binding domain of the AB such
that coupling of the MM reduces the ability of the AB to bind its
target.
[0008] In some embodiments, the activatable antibody includes at
least a first CM (CM1) and a second CM (CM2). In some embodiments,
at least a portion of the CM1 substrate sequence overlaps with at
least a portion of the CM2 sequence. In some embodiments, the CM1
substrate sequence and the CM2 substrate sequence share at least
one amino acid residue in common. In some embodiments, the CM1
substrate sequence and the CM2 substrate sequence share at least
two amino acid residues in common. In some embodiments, the CM1
substrate sequence and the CM2 substrate sequence share at least
three amino acid residues in common. In some embodiments, the CM1
substrate sequence and the CM2 substrate sequence share three or
more amino acid residues in common.
[0009] In some embodiments, CM1 and CM2 are separate polypeptides
that are operably linked together.
[0010] In some embodiments, CM1 and CM2 are separate polypeptides
that are directly linked together, i.e., the N-terminus of one
substrate is linked directly to the C-terminus of the other
substrate polypeptide. In some embodiments, the N-terminus of the
CM1 is linked directly to the C-terminus of the CM2. In some
embodiments, the N-terminus of the CM2 is linked directly to the
C-terminus of the CM1.
[0011] In some embodiments, CM1 and CM2 are separate polypeptides
that are operably linked together via at least one linking
moiety.
[0012] In some embodiments, the first cleavable moiety CM1 and the
second cleavable moiety CM2 in the activatable antibody in the
uncleaved state have the structural arrangement from N-terminus to
C-terminus as follows: MM-CM1-CM2-AB, AB-CM2-CM1-MM, MM-CM2-CM1-AB,
or AB-CM1-CM2-MM.
[0013] In some embodiments, the activatable antibody includes a
linking peptide (LP') between CM1 and CM2. In some embodiments, the
activatable antibody includes a linking peptide (LP'') between the
masking moiety (MM) and CM1. In some embodiments, the activatable
antibody includes a linking peptide (LP''') between CM2 and AB. In
some embodiments, the activatable antibody includes a linking
peptide (LP'') between the MM and CM1 and a linking peptide (LP''')
between CM2 and AB. In some embodiments, the activatable antibody
includes a linking peptide between the MM and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
activatable antibody includes a linking peptide (LP') between CM1
and CM2 and a linking peptide (LP''') between CM2 and AB. In some
embodiments, the activatable antibody includes a linking peptide
(LP'') between the MM and CM1, a linking peptide (LP') between CM1
and CM2, and a linking peptide (LP''') between CM2 and AB.
[0014] In some embodiments, the activatable antibody includes a
linking peptide (LP') between CM1 and CM2. In some embodiments, the
activatable antibody includes a linking peptide (LP'') between the
AB and CM1. In some embodiments, the activatable antibody includes
a linking peptide (LP''') between CM2 and the masking moiety (MM).
In some embodiments, the activatable antibody includes a linking
peptide (LP'') between the AB and CM1 and a linking peptide (LP''')
between CM2 and MM. In some embodiments, the activatable antibody
includes a linking peptide between the AB and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
activatable antibody includes a linking peptide (LP') between CM1
and CM2 and a linking peptide (LP''') between CM2 and MM. In some
embodiments, the activatable antibody includes a linking peptide
(LP'') between the AB and CM1, a linking peptide (LP') between CM1
and CM2, and a linking peptide (LP''') between CM2 and MM.
[0015] In some embodiments, LP' is GG. In some embodiments, LP' is
GGSGGS (SEQ ID NO: 350).
[0016] In some embodiments, CM1 is a substrate for at least one
matrix metalloprotease (MMP). Examples of MMPs include MMP1; MMP2;
MMP3; MMP7; MMP8; MMP9; MMP10; MMP11; MMP12; MMP13; MMP14; MMP15;
MMP16; MMP17; MMP19; MMP20; MMP23; MMP24; MMP26; and MMP27.
[0017] In some embodiments, CM1 is a substrate for MMP2, MMP9,
MMP14, MMP1, MMP3, MMP13, MMP17, MMP11, and/or MMP19. In some
embodiments. CM1 is a substrate for MMP2. In some embodiments, CM1
is a substrate for MMP9. In some embodiments, CM1 is a substrate
for MMP14. In some embodiments, CM1 is a substrate for two or more
MMPs. In some embodiments, CM1 is a substrate for at least MMP9 and
MMP14. In some embodiments, CM1 is a substrate for at least MMP2
and MMP9. In some embodiments, CM1 is a substrate for at least MMP2
and MMP14. In some embodiments, CM1 is a substrate for three or
more MMPs. In some embodiments, CM1 is a substrate for at least
MMP2, MMP9, and MMP14. In some embodiments, the CM1 comprises two
or more substrates for the same MMP. In some embodiments, the CM1
comprises at least two or more MMP2 substrates. In some
embodiments, the CM1 comprises at least two or more MMP9
substrates. In some embodiments, the CM1 comprises at least two or
more MMP14 substrates.
[0018] In some embodiments, CM1 is a substrate for an MMP and
includes at least the sequence ISSGLLSS (SEQ ID NO: 20); QNQALRMA
(SEQ ID NO: 21); AQNLLGMV (SEQ ID NO: 351); STFPFGMF (SEQ ID NO:
352); PVGYTSSL (SEQ ID NO: 353); DWLYWPGI (SEQ ID NO: 354);
MIAPVAYR (SEQ ID NO: 355); RPSPMWAY (SEQ ID NO: 356); WATPRPMR (SEQ
ID NO: 357); FRLLDWQW (SEQ ID NO: 358); LKAAPRWA (SEQ ID NO: 359);
GPSHLVLT (SEQ ID NO: 360); LPGGLSPW (SEQ ID NO: 361); MGLFSEAG (SEQ
ID NO: 362); SPLPLRVP (SEQ ID NO: 363); RMHLRSLG (SEQ ID NO: 364);
LAAPLGLL (SEQ ID NO: 365); AVGLLAPP (SEQ ID NO: 366); LLAPSHRA (SEQ
ID NO: 367); PAGLWLDP (SEQ ID NO: 368); ISSGLSS (SEQ ID NO: 369);
ISSGL (SEQ ID NO: 480); ISSGLLS (SEQ ID NO: 481); ISSGLL (SEQ ID
NO: 482); and/or VHMPLGFLGP (SEQ ID NO: 411).
[0019] In some embodiments, the CM1 comprises the amino acid
sequence ISSGLLSS (SEQ ID NO: 20). In some embodiments, the CM1
comprises the amino acid sequence QNQALRMA (SEQ ID NO: 21). In some
embodiments, the CM1 comprises the amino acid sequence AQNLLGMV
(SEQ ID NO: 351). In some embodiments, the CM1 comprises the amino
acid sequence STFPFGMF (SEQ ID NO: 352). In some embodiments, the
CM1 comprises the amino acid sequence PVGYTSSL (SEQ ID NO: 353). In
some embodiments, the CM1 comprises the amino acid sequence
DWLYWPGI (SEQ ID NO: 354). In some embodiments, the CM1 comprises
the amino acid sequence MIAPVAYR (SEQ ID NO: 355). In some
embodiments, the CM1 comprises the amino acid sequence RPSPMWAY
(SEQ ID NO: 356). In some embodiments, the CM1 comprises the amino
acid sequence WATPRPMR (SEQ ID NO: 357). In some embodiments, the
CM1 comprises the amino acid sequence FRLLDWQW (SEQ ID NO: 358). In
some embodiments, the CM1 comprises the amino acid sequence
LKAAPRWA (SEQ ID NO: 359). In some embodiments, the CM1 comprises
the amino acid sequence GPSHLVLT (SEQ ID NO: 360). In some
embodiments, the CM1 comprises the amino acid sequence LPGGLSPW
(SEQ ID NO: 361). In some embodiments, the CM1 comprises the amino
acid sequence MGLFSEAG (SEQ ID NO: 362). In some embodiments, the
CM1 comprises the amino acid sequence SPLPLRVP (SEQ ID NO: 363). In
some embodiments, the CM1 comprises the amino acid sequence
RMHLRSLG (SEQ ID NO: 364). In some embodiments, the CM1 comprises
the amino acid sequence LAAPLGLL (SEQ ID NO: 365). In some
embodiments, the CM1 comprises the amino acid sequence AVGLLAPP
(SEQ ID NO: 366). In some embodiments, the CM1 comprises the amino
acid sequence LLAPSHRA (SEQ ID NO: 367). In some embodiments, the
CM1 comprises the amino acid sequence PAGLWLDP (SEQ ID NO: 368). In
some embodiments, the CM1 comprises the amino acid sequence ISSGLSS
(SEQ ID NO: 369). In some embodiments, CM1 comprises the amino acid
sequence VHMPLGFLGP (SEQ ID NO: 411). In some embodiments, CM1
comprises the amino acid sequence ISSGL (SEQ ID NO: 480). In some
embodiments, CM1 comprises the amino acid sequence ISSGLLS (SEQ ID
NO: 481). In some embodiments, CM1 comprises the amino acid
sequence ISSGLL (SEQ ID NO: 482).
[0020] In some embodiments, CM2 is a substrate for at least one
serine protease (SP). In some embodiments, the SP is selected from
u-type plasminogen activator (uPA, also referred to as urokinase),
matriptase (also referred to herein as MT-SP1 or MTSP1), and
combinations thereof. Examples of other SP that cleave a CM2
described herein include, by way of non-limiting example, activated
protein C; Cathepsin A; Cathepsin G; Chymase; a coagulation factor
protease such as, e.g., FVIIa, FIXa, FXa, FXIa, FXIIa; Elastase;
Granzyme B; Guanidinobenzoatase; HtrA1; Human Neutrophil Elastase;
Lactoferrin; Marapsin; NS3/4A; PACE4; Plasmin; PSA; tPA; Thrombin;
Tryptase; a Type II Transmembrane Serine Protease (TTSP) such as,
e.g., DESC1, DPP-4, FAP, Hepsin, Matriptase-2, TMPRSS2, TMPRSS3,
and/or TMPRSS4.
[0021] For example, suitable CM2 are cleaved by at least one serine
protease and include the sequence TGRGPSWV (SEQ ID NO: 370);
SARGPSRW (SEQ ID NO: 371); TARGPSFK (SEQ ID NO: 372); LSGRSDNH (SEQ
ID NO: 18); GGWHTGRN (SEQ ID NO: 373); HTGRSGAL (SEQ ID NO: 374);
PLTGRSGG (SEQ ID NO: 375); AARGPAIH (SEQ ID NO: 376); RGPAFNPM (SEQ
ID NO: 377); SSRGPAYL (SEQ ID NO: 378); RGPATPIM (SEQ ID NO: 379);
RGPA (SEQ ID NO: 380); LSGRSGNH (SEQ ID NO: 412); TSTSGRSANPRG (SEQ
ID NO: 413); TSGRSANP (SEQ ID NO: 414); SGRSANPRG (SEQ ID NO: 468);
VAGRSMRP (SEQ ID NO: 415); LSGRSDDH (SEQ ID NO: 547); LSGRSDIH (SEQ
ID NO: 548); LSGRSDQH (SEQ ID NO: 549); LSGRSDTH (SEQ ID NO: 550);
LSGRSDYH (SEQ ID NO: 551); LSGRSDNP (SEQ ID NO: 552); LSGRSANP (SEQ
ID NO: 553); LSGRSANI (SEQ ID NO: 554); and/or LSGRSDNI (SEQ ID NO:
71).
[0022] In some embodiments, CM2 comprises the amino acid sequence
TGRGPSWV (SEQ ID NO: 370). In some embodiments, CM2 comprises the
amino acid sequence SARGPSRW (SEQ ID NO: 371). In some embodiments.
CM2 comprises the amino acid sequence TARGPSFK (SEQ ID NO: 372). In
some embodiments, CM2 comprises the amino acid sequence LSGRSDNH
(SEQ ID NO: 18). In some embodiments, CM2 comprises the amino acid
sequence GGWHTGRN (SEQ ID NO: 373). In some embodiments, CM2
comprises the amino acid sequence HTGRSGAL (SEQ ID NO: 374). In
some embodiments, CM2 comprises the amino acid sequence PLTGRSGG
(SEQ ID NO: 375). In some embodiments, CM2 comprises the amino acid
sequence AARGPAIH (SEQ ID NO: 376). In some embodiments, CM2
comprises the amino acid sequence RGPAFNPM (SEQ ID NO: 377). In
some embodiments, CM2 comprises the amino acid sequence SSRGPAYL
(SEQ ID NO: 378). In some embodiments, CM2 comprises the amino acid
sequence RGPATPIM (SEQ ID NO: 379). In some embodiments, CM2
comprises the amino acid sequence RGPA (SEQ ID NO: 380). In some
embodiments, CM2 comprises the amino acid sequence LSGRSGNH (SEQ ID
NO: 412). In some embodiments, CM2 comprises the amino acid
sequence TSTSGRSANPRG (SEQ ID NO: 413). In some embodiments, the
CM2 comprises the amino acid sequence SGRSANPRG (SEQ ID NO: 468).
In some embodiments, CM2 comprises the amino acid sequence TSGRSANP
(SEQ ID NO: 414). In some embodiments, CM2 comprises the amino acid
sequence VAGRSMRP (SEQ ID NO: 415). In some embodiments, CM2
comprises the amino acid sequence LSGRSDDH (SEQ ID NO: 547). In
some embodiments, CM2 comprises the amino acid sequence LSGRSDIH
(SEQ ID NO: 548). In some embodiments, CM2 comprises the amino acid
sequence LSGRSDQH (SEQ ID NO: 549). In some embodiments, CM2
comprises the amino acid sequence LSGRSDTH (SEQ ID NO: 550). In
some embodiments, CM2 comprises the amino acid sequence LSGRSDYH
(SEQ ID NO: 551). In some embodiments, CM2 comprises the amino acid
sequence LSGRSDNP (SEQ ID NO: 552). In some embodiments, CM2
comprises the amino acid sequence LSGRSANP (SEQ ID NO: 553). In
some embodiments, CM2 comprises the amino acid sequence LSGRSANI
(SEQ ID NO: 554). In some embodiments, CM2 comprises the amino acid
sequence LSGRSDNI (SEQ ID NO: 71).
[0023] In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSDNH (SEQ ID NO: 1); ISSGLLSSGGSGGSLSGRSDNH (SEQ
ID NO: 2); AVGLLAPPGGTSTSGRSANPRG (SEQ ID NO: 3);
TSTSGRSANPRGGGAVGLLAPP (SEQ ID NO: 4); VHMPLGFLGPGGTSTSGRSANPRG
(SEQ ID NO: 5); TSTSGRSANPRGGGVHMPLGFLGP (SEQ ID NO: 6);
AVGLLAPPGGLSGRSDNH (SEQ ID NO: 7); LSGRSDNHGGAVGLLAPP (SEQ ID NO:
8); VHMPLGFLGPGGLSGRSDNH (SEQ ID NO: 9); LSGRSDNHGGVHMPLGFLGP (SEQ
ID NO: 10); LSGRSDNHGGSGGSISSGLLSS (SEQ ID NO: 11);
LSGRSGNHGGSGGSISSGLLSS (SEQ ID NO: 12); ISSGLLSSGGSGGSLSGRSGNH (SEQ
ID NO: 13); LSGRSDNHGGSGGSQNQALRMA (SEQ ID NO: 14);
QNQALRMAGGSGGSLSGRSDNH (SEQ ID NO: 15); LSGRSGNHGGSGGSQNQALRMA (SEQ
ID NO: 16); QNQALRMAGGSGGSLSGRSGNH (SEQ ID NO: 17); ISSGLLSGRSGNH
(SEQ ID NO: 22); ISSGLLSGRSANPRG (SEQ ID NO: 469);
AVGLLAPPTSGRSANPRG (SEQ ID NO: 470); AVGLLAPPSGRSANPRG (SEQ ID NO:
471); ISSGLLSGRSDDH (SEQ ID NO: 483); ISSGLLSGRSDIH (SEQ ID NO:
484); ISSGLLSGRSDQH (SEQ ID NO: 485); ISSGLLSGRSDTH (SEQ ID NO:
486); ISSGLLSGRSDYH (SEQ ID NO: 487); ISSGLLSGRSDNP (SEQ ID NO:
488); ISSGLLSGRSANP (SEQ ID NO: 489); ISSGLLSGRSANI (SEQ ID NO:
490); AVGLLAPPGGLSGRSDDH (SEQ ID NO: 515); AVGLLAPPGGLSGRSDIH (SEQ
ID NO: 516); AVGLLAPPGGLSGRSDQH (SEQ ID NO: 517);
AVGLLAPPGGLSGRSDTH (SEQ ID NO: 518); AVGLLAPPGGLSGRSDYH (SEQ ID NO:
519); AVGLLAPPGGLSGRSDNP (SEQ ID NO: 520); AVGLLAPPGGLSGRSANP (SEQ
ID NO: 521); AVGLLAPPGGLSGRSANI (SEQ ID NO: 522); ISSGLLSGRSDNI
(SEQ ID NO: 555); and/or AVGLLAPPGGLSGRSDNI (SEQ ID NO: 557).
[0024] In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSDNH (SEQ ID NO: 1). In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSSGGSGGSLSGRSDNH (SEQ
ID NO: 2). In some embodiments, the CM1-CM2 substrate includes the
sequence AVGLLAPPGGTSTSGRSANPRG (SEQ ID NO: 3). In some
embodiments, the CM1-CM2 substrate includes the sequence
TSTSGRSANPRGGGAVGLLAPP (SEQ ID NO: 4). In some embodiments, the
CM1-CM2 substrate includes the sequence VHMPLGFLGPGGTSTSGRSANPRG
(SEQ ID NO: 5). In some embodiments, the CM1-CM2 substrate includes
the sequence TSTSGRSANPRGGGVHMPLGFLGP (SEQ ID NO: 6). In some
embodiments, the CM1-CM2 substrate includes the sequence
AVGLLAPPGGLSGRSDNH (SEQ ID NO: 7). In some embodiments, the CM1-CM2
substrate includes the sequence LSGRSDNHGGAVGLLAPP (SEQ ID NO: 8).
In some embodiments, the CM1-CM2 substrate includes the sequence
VHMPLGFLGPGGLSGRSDNH (SEQ ID NO: 9). In some embodiments, the
CM1-CM2 substrate includes the sequence LSGRSDNHGGVHMPLGFLGP (SEQ
ID NO: 10). In some embodiments, the CM1-CM2 substrate includes the
sequence LSGRSDNHGGSGGSISSGLLSS (SEQ ID NO: 11). In some
embodiments, the CM1-CM2 substrate includes the sequence
LSGRSGNHGGSGGSISSGLLSS (SEQ ID NO: 12). In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSSGGSGGSLSGRSGNH (SEQ
ID NO: 13). In some embodiments, the CM1-CM2 substrate includes the
sequence LSGRSDNHGGSGGSQNQALRMA (SEQ ID NO: 14). In some
embodiments, the CM1-CM2 substrate includes the sequence
QNQALRMAGGSGGSLSGRSDNH (SEQ ID NO: 15). In some embodiments, the
CM1-CM2 substrate includes the sequence LSGRSGNHGGSGGSQNQALRMA (SEQ
ID NO: 16). In some embodiments, the CM1-CM2 substrate includes the
sequence QNQALRMAGGSGGSLSGRSGNH (SEQ ID NO: 17). In some
embodiments, the CM1-CM2 substrate includes the sequence
ISSGLLSGRSGNH (SEQ ID NO: 22). In some embodiments, the CM1-CM2
substrate includes the sequence ISSGLLSGRSANPRG (SEQ ID NO: 469).
In some embodiments, the CM1-CM2 substrate includes the sequence
AVGLLAPPTSGRSANPRG (SEQ ID NO: 470). In some embodiments, the
CM1-CM2 substrate includes the sequence AVGLLAPPSGRSANPRG (SEQ ID
NO: 471). In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSDDH (SEQ ID NO: 483). In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSGRSDIH (SEQ ID NO:
484). In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSDQH (SEQ ID NO: 485). In some embodiments, the
CM1-CM2 substrate includes the sequence. In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSGRSDTH (SEQ ID NO:
486). In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSDYH (SEQ ID NO: 487). In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSGRSDNP (SEQ ID NO:
488). In some embodiments, the CM1-CM2 substrate includes the
sequence ISSGLLSGRSANP (SEQ ID NO: 489). In some embodiments, the
CM1-CM2 substrate includes the sequence ISSGLLSGRSANI (SEQ ID NO:
490). In some embodiments, the CM1-CM2 substrate includes the
sequence AVGLLAPPGGLSGRSDDH (SEQ ID NO: 515). In some embodiments,
the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDIH (SEQ
ID NO: 516). In some embodiments, the CM1-CM2 substrate includes
the sequence AVGLLAPPGGLSGRSDQH (SEQ ID NO: 517). In some
embodiments, the CM1-CM2 substrate includes the sequence
AVGLLAPPGGLSGRSDTH (SEQ ID NO: 518). In some embodiments, the
CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSDYH (SEQ ID
NO: 519). In some embodiments, the CM1-CM2 substrate includes the
sequence AVGLLAPPGGLSGRSDNP (SEQ ID NO: 520). In some embodiments,
the CM1-CM2 substrate includes the sequence AVGLLAPPGGLSGRSANP (SEQ
ID NO: 521). In some embodiments, the CM1-CM2 substrate includes
the sequence AVGLLAPPGGLSGRSANI (SEQ ID NO: 522). In some
embodiments, the CM1-CM2 substrate includes the sequence
ISSGLLSGRSDNI (SEQ ID NO: 555). In some embodiments, the CM1-CM2
substrate includes the sequence AVGLLAPPGGLSGRSDNI (SEQ ID NO:
557).
[0025] In some embodiments, the activatable antibody in the
uncleaved state has the structural arrangement from N-terminus to
C-terminus as follows: MM-CM1-CM2-AB, AB-CM2-CM1-MM, MM-CM2-CM1-AB,
or AB-CM1-CM2-MM.
[0026] In some embodiments, the activatable antibody comprises a
first linking peptide (LP1) and a second linking peptide (LP2), and
the antibody in the uncleaved state has the structural arrangement
from N-terminus to C-terminus as follows: MM1-LP1-CM1-CM2-LP2-AB,
AB-LP2-CM2-CM1-LP1-MM, MM1-LP1-CM2-CM1-LP2-AB, or
AB-LP2-CM1-CM2-LP-MM. In some embodiments, each of LP1 and LP2 is a
peptide of about 1 to 20 amino acids in length. In some
embodiments, the two linking peptides need not be identical to each
other.
[0027] In some embodiments, the activatable antibody includes a
linking peptide (LP') between CM1 and CM2. In some embodiments, the
activatable antibody includes a linking peptide (LP'') between the
masking moiety (MM) and CM1. In some embodiments, the activatable
antibody includes a linking peptide (LP''') between CM2 and AB. In
some embodiments, the activatable antibody includes a linking
peptide (LP'') between the MM and CM1 and a linking peptide (LP''')
between CM2 and AB. In some embodiments, the activatable antibody
includes a linking peptide between the MM and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
activatable antibody includes a linking peptide (LP') between CM1
and CM2 and a linking peptide (LP''') between CM2 and AB. In some
embodiments, the activatable antibody includes a linking peptide
(LP'') between the MM and CM1, a linking peptide (LP') between CM1
and CM2, and a linking peptide (LP''') between CM2 and AB.
[0028] In some embodiments, the activatable antibody includes a
linking peptide (LP') between CM1 and CM2. In some embodiments, the
activatable antibody includes a linking peptide (LP'') between the
AB and CM1. In some embodiments, the activatable antibody includes
a linking peptide (LP''') between CM2 and the masking moiety (MM).
In some embodiments, the activatable antibody includes a linking
peptide (LP'') between the AB and CM1 and a linking peptide (LP''')
between CM2 and MM. In some embodiments, the activatable antibody
includes a linking peptide between the AB and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
activatable antibody includes a linking peptide (LP') between CM1
and CM2 and a linking peptide (LP''') between CM2 and MM. In some
embodiments, the activatable antibody includes a linking peptide
(LP'') between the AB and CM1, a linking peptide (LP') between CM1
and CM2, and a linking peptide (LP''') between CM2 and MM.
[0029] In some embodiments, LP' is GG. In some embodiments, LP' is
GGSGGS (SEQ ID NO: 350).
[0030] In some embodiments, at least one of LP1 or LP2 comprises an
amino acid sequence selected from the group consisting of
(GS).sub.n, (GGS).sub.n, (GSGGS).sub.n (SEQ ID NO: 381) and
(GGGS).sub.n (SEQ ID NO: 382), where n is an integer of at least
one.
[0031] In some embodiments, at least one of LP1 or LP2 comprises an
amino acid sequence selected from the group consisting of GGSG (SEQ
ID NO: 383), GGSGG (SEQ ID NO: 384), GSGSG (SEQ ID NO: 385), GSGGG
(SEQ ID NO: 386), GGGSG (SEQ ID NO: 387), and GSSSG (SEQ ID NO:
388).
[0032] In some embodiments, LP1 comprises the amino acid sequence
GSSGGSGGSGGSG (SEQ ID NO: 389), GSSGGSGGSGG (SEQ ID NO: 390),
GSSGGSGGSGGS (SEQ ID NO: 391), GSSGGSGGSGGSGGGS (SEQ ID NO: 392),
GSSGGSGGSG (SEQ ID NO: 393), or GSSGGSGGSGS (SEQ ID NO: 394).
[0033] In some embodiments, LP2 comprises the amino acid sequence
GSS, GGS, GGGS (SEQ ID NO: 395), GSSGT (SEQ ID NO: 396) or GSSG
(SEQ ID NO: 397).
[0034] In some embodiments, the AB has a dissociation constant of
about 100 nM or less for binding to the target.
[0035] In some embodiments, the activatable antibody includes an
antibody or antigen-binding fragment (AB) thereof that specifically
binds a target. In some embodiments, the AB is a full-length
antibody. In some embodiments, the AB is an immunologically active
fragment. In some embodiments, the AB is an antigen-binding
fragment. In some embodiments, the AB is a monoclonal antibody,
domain antibody, single chain, Fab fragment, a F(ab').sub.2
fragment, a scFv, a scab, a dAb, a single domain heavy chain
antibody, or a single domain light chain antibody. In some
embodiments, such an AB is a mouse, other rodent, chimeric,
humanized or fully human monoclonal antibody.
[0036] In some embodiments, the MMP protease is co-localized with
the target in a tissue, and the MMP protease cleaves the CM1 in the
antibody when the antibody is exposed to the protease. In some
embodiments, the SP protease is co-localized with the target in a
tissue, and the SP protease cleaves the CM2 substrate in the
antibody when the antibody is exposed to the protease. In some
embodiments, the MMP protease and/or the SP protease are
co-localized with the target in a tissue, and the MMP protease
and/or the SP protease cleave the CM1-CM2 substrate in the antibody
when the antibody is exposed to the protease. In some embodiments,
the MMP protease and the SP protease are co-localized with the
target in a tissue, and at least one of the MMP protease and the SP
protease cleave the CM1-CM2 substrate in the antibody when the
antibody is exposed to the protease.
[0037] In some embodiments, each of the CM1 substrate sequence and
the CM2 substrate sequence of the CM1-CM2 substrate is
independently a polypeptide of up to 15 amino acids in length.
[0038] In some embodiments, the CM1 substrate sequence of the
CM1-CM2 substrate is a substrate for at least one MMP and comprises
a polypeptide sequence that is not substantially identical to any
polypeptide sequence, e.g., any animal polypeptide sequence, that
is naturally cleaved by the same MMP protease. In some embodiments,
the CM1 substrate sequence of the CM1-CM2 substrate is a substrate
for at least one MMP and comprises a polypeptide sequence that is
not substantially identical to any mammalian polypeptide sequence
that is naturally cleaved by the same MMP protease. In some
embodiments, the CM1 substrate sequence of the CM1-CM2 substrate is
a substrate for at least one MMP and comprises a polypeptide
sequence that is not substantially identical to any human
polypeptide sequence that is naturally cleaved by the same MMP
protease. In some embodiments, the CM1 substrate sequence of the
CM1-CM2 substrate is a substrate for at least one MMP and comprises
a polypeptide sequence that is no more than 90% or more identical
to any polypeptide sequence, e.g., any animal polypeptide sequence,
that is naturally cleaved by the same MMP protease. In some
embodiments, the CM1 substrate sequence of the CM1-CM2 substrate is
a substrate for at least one MMP and comprises a polypeptide
sequence that is no more than 90% or more identical to any
mammalian polypeptide sequence that is naturally cleaved by the
same MMP protease. In some embodiments, the CM1 substrate sequence
of the CM1-CM2 substrate is a substrate for at least one MMP and
comprises a polypeptide sequence that is no more than 90% or more
identical to any human polypeptide sequence that is naturally
cleaved by the same MMP protease.
[0039] In some embodiments, the CM2 substrate sequence of the
CM1-CM2 substrate is a substrate for at least one SP and comprises
a polypeptide sequence that is not substantially identical to any
polypeptide sequence, e.g., any animal polypeptide sequence, that
is naturally cleaved by the same SP protease. In some embodiments,
the CM2 substrate sequence of the CM1-CM2 substrate is a substrate
for at least one SP and comprises a polypeptide sequence that is
not substantially identical to any mammalian polypeptide sequence
that is naturally cleaved by the same SP protease. In some
embodiments, the CM2 substrate sequence of the CM1-CM2 substrate is
a substrate for at least one SP and comprises a polypeptide
sequence that is not substantially identical to any human
polypeptide sequence that is naturally cleaved by the same SP
protease. In some embodiments, the CM2 substrate sequence of the
CM1-CM2 substrate is a substrate for at least one SP and comprises
a polypeptide sequence that is no more than 90% or more identical
to any polypeptide sequence, e.g., any animal polypeptide sequence,
that is naturally cleaved by the same SP protease. In some
embodiments, the CM2 substrate sequence of the CM1-CM2 substrate is
a substrate for at least one SP and comprises a polypeptide
sequence that is no more than 90% or more identical to any
mammalian polypeptide sequence that is naturally cleaved by the
same SP protease. In some embodiments, the CM2 substrate sequence
of the CM1-CM2 substrate is a substrate for at least one SP and
comprises a polypeptide sequence that is no more than 90% or more
identical to any human polypeptide sequence that is naturally
cleaved by the same SP protease.
[0040] In some embodiments, the CM1-CM2 substrate comprises an
amino acid sequence selected from the group consisting of SEQ ID
NOs: 1-17, 22, 469-471, 483-490, 515-522, 555, and 557. In some
embodiments, an activatable antibody comprises a CM1-CM2 substrate
comprising an amino acid sequence selected from the group
consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490, 515-522, 555,
and 557, as well as an antibody or antigen binding fragment thereof
(AB) that binds a target and a masking moiety (MM) that reduces the
ability of the antigen- or epitope-binding domain of the AB to bind
its target.
[0041] In some embodiments, an activatable antibody comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an anti-Jagged antibody comprising an
amino acid sequence of an anti-Jagged antibody disclosed herein. In
some embodiments, an activatable antibody comprises a CM1-CM2
substrate comprising an amino acid sequence selected from the group
consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490, 515-522, 555,
and 557, and an antibody having a light chain comprising amino acid
sequence SEQ ID NO: 162 or SEQ ID NO: 164 and a heavy chain
comprising amino acid sequence SEQ ID NO: 67 or SEQ ID NO: 163.
[0042] In some embodiments, the CM1-CM2 is included in an
activatable antibody having a light chain amino acid sequence
selected from the group consisting of SEQ ID NOs: 420, 422, 424,
426, 428, 430, 432, 434, 436, 439, 477, 479, 507-514, 539-546, 561,
and 562, and a heavy chain amino acid sequence of SEQ ID NO:
67.
[0043] In some embodiments, the CM1-CM2 is included in an
activatable antibody having a light chain amino acid sequence
selected from the group consisting of SEQ ID NOs: 420, 422, 424,
426, 428, 430, 432, 434, 436, 439, 477, 479, 507-514, 539-546, 561,
and 562, and a heavy chain amino acid sequence of SEQ ID NO:
163.
[0044] In some embodiments, an activatable antibody comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an anti-EGFR antibody comprising an
amino acid sequence of an anti-EGFR antibody disclosed herein. In
some embodiments, an activatable antibody comprises a CM1-CM2
substrate comprising an amino acid sequence selected from the group
consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490, 515-522, 555,
and 557, and an antibody having a light chain comprising amino acid
sequence SEQ ID NO: 111 and a heavy chain comprising amino acid
sequence SEQ ID NO: 108, SEQ ID NO: 109, or SEQ ID NO: 110.
[0045] In some embodiments, the CM1-CM2 is included in an
activatable antibody having a light chain amino acid sequence
selected from the group consisting of SEQ ID NOs: 449, 451, 453,
455, 457, 459, 461, 463, 465, 467, 472, 474, 499-506, 531-538, 559,
and 560, and a heavy chain amino acid sequence of SEQ ID NO:
108.
[0046] In some embodiments, the CM1-CM2 is included in an
activatable antibody having a light chain amino acid sequence
selected from the group consisting of SEQ ID NOs: 449, 451, 453,
455, 457, 459, 461, 463, 465, 467, 472, 474, 499-506, 531-538, 559,
and 560, and a heavy chain amino acid sequence of SEQ ID NO:
109.
[0047] In some embodiments, the CM1-CM2 is included in an
activatable antibody having a light chain amino acid sequence
selected from the group consisting of SEQ ID NOs: 449, 451, 453,
455, 457, 459, 461, 463, 465, 467, 472, 474, 499-506, 531-538, 559,
and 560, and a heavy chain amino acid sequence of SEQ ID NO:
110.
[0048] In some embodiments, the CM1-CM2 substrate is also a
substrate for at least one additional protease.
[0049] In some embodiments, the at least one additional protease is
a different MMP protease than the MMP protease that cleaves the
CM1. In some embodiments, the at least one additional protease is
an MMP protease selected from the group consisting of MMP1; MMP2;
MMP3; MMP7; MMP8; MMP9; MMP10; MMP11; MMP12; MMP13; MMP14; MMP15;
MMP16; MMP17; MMP19; MMP20; MMP23; MMP24; MMP26; and MMP27.
[0050] In some embodiments, the at least one additional protease is
a different SP protease than the SP protease that cleaves CM2. In
some embodiments, the at least one additional SP protease is
selected from the group consisting of uPA; matriptase; activated
protein C; Cathepsin A; Cathepsin G; Chymase; a coagulation factor
protease such as, e.g., FVIIa, FIXa, FXa, FXIa, FXIIa; Elastase;
Granzyme B; Guanidinobenzoatase; HtrA1; Human Neutrophil Elastase;
Lactoferrin; Marapsin; NS3/4A; PACE4; Plasmin; PSA; tPA; Thrombin;
Tryptase; a Type II Transmembrane Serine Protease (TTSP) such as,
e.g., DESC1, DPP-4, FAP, Hepsin, Matriptase-2, TMPRSS2, TMPRSS3,
and TMPRSS4.
[0051] In some embodiments, the at least one additional protease is
selected from the group consisting of those shown in Table 6.
TABLE-US-00001 TABLE 6 Exemplary Proteases and/or Enzymes ADAMS,
ADAMTS, e.g. ADAM8 ADAM9 ADAM10 ADAM12 ADAM15 ADAM17/TACE ADAMDEC1
ADAMTS1 ADAMTS4 ADAMTS5 Aspartate proteases, e.g., BACE Renin
Aspartic cathepsins, e.g., Cathepsin D Cathepsin E Caspases, e.g.,
Caspase 1 Caspase 2 Caspase 3 Caspase 4 Caspase 5 Caspase 6 Caspase
7 Caspase 8 Caspase 9 Caspase 10 Caspase 14 Cysteine cathepsins,
e.g., Cathepsin B Cathepsin C Cathepsin K Cathepsin L Cathepsin S
Cathepsin V/L2 Cathepsin X/Z/P Cysteine proteinases, e.g.,
Cruzipain Legumain Otubain-2 KLKs, e.g., KLK4 KLK5 KLK6 KLK7 KLK8
KLK10 KLK11 KLK13 KLK14 Metallo proteinases, e.g., Meprin
Neprilysin PSMA BMP-1
[0052] The disclosure also provides an antibody includes at least a
first CM1 and a second CM2 and is conjugated to an agent. In some
embodiments, the first CM1 and the second CM2 are each polypeptides
of no more than 15 amino acids long. In some embodiments, the
activatable antibody is a conjugated activatable antibody that, in
the uncleaved state has the structural arrangement from N-terminus
to C-terminus as follows: MM-CM1-CM2-AB-Agent, Agent-AB-CM2-CM1-MM,
MM-CM2-CM1-AB-Agent, or Agent-AB-CM1-CM2-MM. In some embodiments,
the activatable antibody is a conjugated activatable antibody that,
in the uncleaved state has the structural arrangement from
N-terminus to C-terminus as follows: Agent-MM-CM1-CM2-AB,
AB-CM2-CM1-MM-Agent, Agent-MM-CM2-CM1-AB, or AB-CM1-CM2-MM-Agent.
In some embodiments, the activatable antibody is a conjugated
activatable antibody that, in the uncleaved state has the
structural arrangement from N-terminus to C-terminus as follows:
Agent-MM-CM11-CM2-AB-Agent, Agent-AB-CM2-CM11-MM-Agent,
Agent-MM-CM2-CM1-AB-Agent, or Agent-AB-CM1-CM2-MM-Agent.
[0053] In some embodiments, the activatable antibody is a
conjugated activatable antibody that comprises a masking moiety
(MM), a first linking peptide (LP1) and a second linking peptide
(LP2), and the antibody in the uncleaved state has the structural
arrangement from N-terminus to C-terminus as follows:
MM1-LP1-CM1-CM2-LP2-AB-Agent, Agent-AB-LP2-CM2-CM1-LP1-MM,
MM1-LP1-CM2-CM1-LP2-AB-Agent, or Agent-AB-LP2-CM1-CM2-LP1-MM. In
some embodiments, each of LP1 and LP2 is a peptide of about 1 to 20
amino acids in length. In some embodiments, the two linking
peptides need not be identical to each other.
[0054] In some embodiments, the activatable antibody is a
conjugated activatable antibody that comprises a masking moiety
(MM), a first linking peptide (LP1) and a second linking peptide
(LP2), and the antibody in the uncleaved state has the structural
arrangement from N-terminus to C-terminus as follows:
Agent-MM1-LP1-CM1-CM2-LP2-AB, AB-LP2-CM2-CM1-LP I-MM-Agent,
Agent-MM1-LP1-CM2-CM11-LP2-AB, or AB-LP2-CM1-CM2-LP1-MM-Agent. In
some embodiments, each of LP and LP2 is a peptide of about 1 to 20
amino acids in length. In some embodiments, the two linking
peptides need not be identical to each other.
[0055] In some embodiments, the activatable antibody is a
conjugated activatable antibody that comprises a masking moiety
(MM), a first linking peptide (LP1) and a second linking peptide
(LP2), and the antibody in the uncleaved state has the structural
arrangement from N-terminus to C-terminus as follows:
Agent-MM1-LP1-CM1-CM2-LP2-AB-Agent,
Agent-AB-LP2-CM2-CM1-LP1-MM-Agent,
Agent-MM1-LP1-CM2-CM1-LP2-AB-Agent, or
Agent-AB-LP2-CM1-CM2-LP1-MM-Agent. In some embodiments, each of LP1
and LP2 is a peptide of about 1 to 20 amino acids in length. In
some embodiments, the two linking peptides need not be identical to
each other.
[0056] In some embodiments, the conjugated activatable antibody
includes a linking peptide (LP') between CM1 and CM2. In some
embodiments, the conjugated activatable antibody includes a linking
peptide (LP'') between the masking moiety (MM) and CM1. In some
embodiments, the conjugated activatable antibody includes a linking
peptide (LP''') between CM2 and AB. In some embodiments, the
conjugated activatable antibody includes a linking peptide (LP'')
between the MM and CM1 and a linking peptide (LP''') between CM2
and AB. In some embodiments, the conjugated activatable antibody
includes a linking peptide between the MM and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
conjugated activatable antibody includes a linking peptide (LP')
between CM1 and CM2 and a linking peptide (LP''') between CM2 and
AB. In some embodiments, the conjugated activatable antibody
includes a linking peptide (LP'') between the MM and CM1, a linking
peptide (LP') between CM1 and CM2, and a linking peptide (LP''')
between CM2 and AB.
[0057] In some embodiments, the conjugated activatable antibody
includes a linking peptide (LP') between CM1 and CM2. In some
embodiments, the conjugated activatable antibody includes a linking
peptide (LP'') between the AB and CM1. In some embodiments, the
conjugated activatable antibody includes a linking peptide (LP''')
between CM2 and the masking moiety (MM). In some embodiments, the
conjugated activatable antibody includes a linking peptide (LP'')
between the AB and CM1 and a linking peptide (LP''') between CM2
and MM. In some embodiments, the conjugated activatable antibody
includes a linking peptide between the AB and CM1 (LP'') and a
linking peptide between CM1 and CM2 (LP'). In some embodiments, the
conjugated activatable antibody includes a linking peptide (LP')
between CM1 and CM2 and a linking peptide (LP''') between CM2 and
MM. In some embodiments, the conjugated activatable antibody
includes a linking peptide (LP'') between the AB and CM1, a linking
peptide (LP') between CM1 and CM2, and a linking peptide (LP''')
between CM2 and MM.
[0058] In some embodiments, LP' is GG. In some embodiments, LP' is
GGSGGS (SEQ ID NO: 350).
[0059] In some embodiments, at least one of LP1 or LP2 comprises an
amino acid sequence selected from the group consisting of
(GS).sub.n, (GGS).sub.n, (GSGGS).sub.n (SEQ ID NO: 381) and
(GGGS).sub.n (SEQ ID NO: 382), where n is an integer of at least
one.
[0060] In some embodiments, at least one of LP1 or LP2 comprises an
amino acid sequence selected from the group consisting of GGSG (SEQ
ID NO: 383), GGSGG (SEQ ID NO: 384), GSGSG (SEQ ID NO: 385), GSGGG
(SEQ ID NO: 386), GGGSG (SEQ ID NO: 387), and GSSSG (SEQ ID NO:
388).
[0061] In some embodiments, LP1 comprises the amino acid sequence
GSSGGSGGSGGSG (SEQ ID NO: 389), GSSGGSGGSGG (SEQ ID NO: 390),
GSSGGSGGSGGS (SEQ ID NO: 391), GSSGGSGGSGGSGGGS (SEQ ID NO: 392),
GSSGGSGGSG (SEQ ID NO: 393), or GSSGGSGGSGS (SEQ ID NO: 394).
[0062] In some embodiments, LP2 comprises the amino acid sequence
GSS, GGS, GGGS (SEQ ID NO: 395), GSSGT (SEQ ID NO: 396) or GSSG
(SEQ ID NO: 397).
[0063] In some embodiments, the CM1-CM2 substrate is linked or
otherwise attached to an antibody. For example, the CM1-CM2 is used
to link one or more agents to the antibody or antigen binding
fragment thereof (AB) that binds a given target, such that the
CM1-CM2 is cleaved when exposed to the MMP and/or the SP, and the
agent is released from the AB. Exemplary targets include, but are
not limited to the targets shown in Table 1. Exemplary ABs include,
but are not limited to, the antibodies shown in Table 2.
[0064] In some embodiments, the AB has a dissociation constant of
about 100 nM or less for binding to the target.
[0065] In some embodiments, the antibody includes an antibody or
antigen-binding fragment thereof that specifically binds a target.
In some embodiments, the antibody or immunologically active
fragment thereof that binds the target is a monoclonal antibody,
domain antibody, single chain, Fab fragment, a F(ab').sub.2
fragment, a scFv, a scab, a dAb, a single domain heavy chain
antibody, or a single domain light chain antibody. In some
embodiments, such an antibody or immunologically active fragment
thereof that binds the target is a mouse, other rodent, chimeric,
humanized or fully human monoclonal antibody.
[0066] In some embodiments, the MM has a dissociation constant for
binding to the AB that is no more than the dissociation constant of
the AB to the target.
[0067] In some embodiments, the MM does not interfere or compete
with the AB for binding to the target in a cleaved state.
[0068] In some embodiments, the MM is a polypeptide of about 2 to
40 amino acids in length. For example, the MM is a polypeptide of
up to about 40 amino acids in length.
[0069] In some embodiments, the MM polypeptide sequence is
different from that of any natural binding partner of the AB. In
some embodiments, the MM polypeptide sequence is no more than 50%
identical to any natural binding partner of the AB. In some
embodiments, the MM polypeptide sequence is no more than 40%, 30%,
25%, 20%, 15%, or 10% identical to any natural binding partner of
the AB.
[0070] In some embodiments, the agent conjugated to the AB or the
AB of an activatable antibody is a therapeutic agent. In some
embodiments, the agent is an antineoplastic agent. In some
embodiments, the agent is a toxin or fragment thereof. As used
herein, a fragment of a toxin is a fragment that retains toxic
activity. In some embodiments, the agent is conjugated to the AB
via a cleavable linker. In some embodiments, the agent is
conjugated to the AB via a linker that includes at least one
CM1-CM2 substrate sequence. In some embodiments, the agent is
conjugated to the AB via a noncleavable linker. In some
embodiments, the agent is a microtubule inhibitor. In some
embodiments, the agent is a nucleic acid damaging agent, such as a
DNA alkylator or DNA intercalator, or other DNA damaging agent. In
some embodiments, the agent is an agent selected from the group
listed in Table 3. In some embodiments, the agent is a dolastatin.
In some embodiments, the agent is an auristatin or derivative
thereof. In some embodiments, the agent is auristatin E or a
derivative thereof. In some embodiments, the agent is monomethyl
auristatin E (MMAE). In some embodiments, the agent is monomethyl
auristatin D (MMAD). In some embodiments, the agent is a
maytansinoid or maytansinoid derivative. In some embodiments, the
agent is DM1 or DM4. In some embodiments, the agent is a
duocarmycin or derivative thereof. In some embodiments, the agent
is a calicheamicin or derivative thereof. In some embodiments, the
agent is a pyrrolobenzodiazepine. In some embodiments, the agent is
a pyrrolobenzodiazepine dimer.
[0071] In some embodiments, the agent is an anti-inflammatory
agent.
[0072] In some embodiments, the antibody and/or activatable
antibody also includes a detectable moiety. In some embodiments,
the detectable moiety is a diagnostic agent.
[0073] In some embodiments, the conjugated antibody and/or
conjugated activatable antibody includes a detectable label. In
some embodiments, the detectable label includes an imaging agent, a
contrasting agent, an enzyme, a fluorescent label, a chromophore, a
dye, one or more metal ions, or a ligand-based label. In some
embodiments, the imaging agent comprises a radioisotope. In some
embodiments, the radioisotope is indium or technetium. In some
embodiments, the contrasting agent comprises iodine, gadolinium or
iron oxide. In some embodiments, the enzyme comprises horseradish
peroxidase, alkaline phosphatase, or 3-galactosidase. In some
embodiments, the fluorescent label comprises yellow fluorescent
protein (YFP), cyan fluorescent protein (CFP), green fluorescent
protein (GFP), modified red fluorescent protein (mRFP), red
fluorescent protein tdimer2 (RFP tdimer2), HCRED, or a europium
derivative. In some embodiments, the luminescent label comprises an
N-methylacrydium derivative. In some embodiments, the label
comprises an Alexa Fluor label, such as Alex Fluor.RTM. 680 or
Alexa Fluor.RTM. 750. In some embodiments, the ligand-based label
comprises biotin, avidin, streptavidin or one or more haptens.
[0074] In some embodiments, the antibody and/or the AB of the
activatable antibody naturally contains one or more disulfide
bonds. In some embodiments, the AB can be engineered to include one
or more disulfide bonds.
[0075] In some embodiments, the antibody and/or conjugated antibody
is monospecific. In some embodiments, the antibody and/or
conjugated antibody is multispecific, referred to herein as
multispecific antibodies and/or conjugated multispecific
antibodies. In some embodiments, the multispecific antibody and/or
conjugated multispecific antibody is bispecific or trifunctional.
In some embodiments, the antibody and/or conjugated antibody is
formulated as part of a pro-Bispecific T Cell Engager (pro-BITE)
molecule. In some embodiments, the antibody and/or conjugated
antibody is formulated as part of a pro-Chimeric Antigen Receptor
(pro-CAR) modified T cell or other engineered receptor or other
immune effector cell, such as a CAR modified NK cell. In some
embodiments, the activatable antibody and/or conjugated activatable
antibody is formulated as part of a pro-Chimeric Antigen Receptor
(CAR) modified T cell. In some embodiments, the activatable
antibody and/or conjugated activatable antibody is formulated as
part of a pro-Chimeric Antigen Receptor (CAR) modified NK cell.
[0076] In some embodiments, the activatable antibody and/or
conjugated activatable antibody is monospecific. In some
embodiments, the activatable antibody and/or conjugated activatable
antibody is multispecific, referred to herein as multispecific
activatable antibodies and/or conjugated multispecific activatable
antibodies. As used herein, terms such as "activatable antibody"
and all grammatical variations thereof, unless otherwise noted, are
intended to encompass, but are not limited to embodiments where the
activatable antibody is a multispecific activatable antibody of the
disclosure. As used herein, terms such as "conjugated activatable
antibody" and all grammatical variations thereof, unless otherwise
noted, are intended to encompass, but are not limited to
embodiments where the conjugated activatable antibody is a
conjugated multispecific activatable antibody of the disclosure. In
some embodiments, the multispecific activatable antibody and/or
conjugated multispecific activatable antibody is bispecific or
trifunctional. In some embodiments, the activatable antibody and/or
conjugated activatable antibody is formulated as part of a
pro-Bispecific T Cell Engager (pro-BITE) molecule. In some
embodiments, the activatable antibody and/or conjugated activatable
antibody is formulated as part of a pro-Chimeric Antigen Receptor
(pro-CAR) modified T cell or other engineered receptor.
[0077] In some embodiments, the antibodies, antibody conjugates,
activatable antibodies, conjugated activatable antibodies,
multispecific activatable antibodies, and/or conjugated
multispecific activatable antibodies described herein are used in
conjunction with one or more additional agents or a combination of
additional agents. Suitable additional agents include current
pharmaceutical and/or surgical therapies for an intended
application, such as, for example, cancer. For example, the
activatable antibodies, conjugated activatable antibodies,
multispecific activatable antibodies, and/or conjugated
multispecific activatable antibodies can be used in conjunction
with an additional chemotherapeutic or anti-neoplastic agent.
[0078] In some embodiments, the activatable antibody is a
multispecific activatable antibody. The multispecific activatable
antibodies provided herein are multispecific antibodies that
recognize two or more different antigens or epitopes and that
include at least one masking moiety (MM) linked to at least one
antigen- or epitope-binding domain of the multispecific antibody
such that coupling of the MM reduces the ability of the antigen- or
epitope-binding domain to bind its target. In some embodiments, the
MM is coupled to the antigen- or epitope-binding domain of the
multispecific antibody via a CM11-CM2 substrate that functions as a
substrate for at least one MMP protease and at least one SP
protease. The activatable multispecific antibodies provided herein
are stable in circulation, activated at intended sites of therapy
and/or diagnosis but not in normal, i.e., healthy tissue, and, when
activated, exhibit binding to a target that is at least comparable
to the corresponding, unmodified multispecific antibody.
[0079] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VH CDR1 sequence, a
VH CDR2 sequence, and a VH CDR3 sequence, wherein at least one of
the VH CDR1 sequence, the VH CDR2 sequence, and the VH CDR3
sequence is selected from a VH CDR1 that sequence includes at least
the amino acid sequence SYAMS (SEQ ID NO: 398); a VH CD2 sequence
that includes at least the amino acid sequence SIDPEGRQTYYADSVKG
(SEQ ID NO: 399); a VH CDR3 sequence that includes at least the
amino acid sequence DIGGRSAFDY (SEQ ID NO: 400), and combinations
thereof.
[0080] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VL CDR1 sequence, a
VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one of
the VL CDR1 sequence, the VL CDR2 sequence, and the VL CDR3
sequence is selected from a VL CDR1 sequence that includes at least
the amino acid sequence RASQSISSY (SEQ ID NO: 401); a VL CDR2
sequence that includes at least the amino acid sequence AASSLQS
(SEQ ID NO: 402); a VL CDR3 sequence that includes at least the
amino acid sequence QQTVVAPPL (SEQ ID NO: 403), and combinations
thereof.
[0081] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VH CDR1 sequence, a
VH CDR2 sequence, and a VH CDR3 sequence, wherein at least one of
the VH CDR1 sequence, the VH CDR2 sequence, and the VH CDR3
sequence is selected from a VH CDR1 sequence that includes a
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% or more identical to the amino acid sequence SYAMS (SEQ ID
NO: 398); a VH CD2 sequence that includes a sequence that is at
least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%0 or more
identical to the amino acid sequence SIDPEGRQTYYADSVKG (SEQ ID NO:
399); a VH CDR3 sequence that includes a sequence that is at least
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical
to the amino acid sequence DIGGRSAFDY (SEQ ID NO: 400), and
combinations thereof.
[0082] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VL CDR1 sequence, a
VL CDR2 sequence, and a VL CDR3 sequence, wherein at least one of
the VL CDR1 sequence, the VL CDR2 sequence, and the VL CDR3
sequence is selected from a VL CDR1 sequence that includes a
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% or more identical to the amino acid sequence RASQSISSY
(SEQ ID NO: 401); a VL CDR2 sequence that includes a sequence that
is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or
more identical to the amino acid sequence AASSLQS (SEQ ID NO: 402);
and a VL CDR3 sequence that includes a sequence that is at least
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical
to the amino acid sequence QQTVVAPPL (SEQ ID NO: 403), and
combinations thereof.
[0083] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VH CDR1 sequence, a
VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2
sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence
includes at least the amino acid sequence SYAMS (SEQ ID NO: 398);
the VH CD2 sequence includes at least the amino acid sequence
SIDPEGRQTYYADSVKG (SEQ ID NO: 399); the VH CDR3 sequence includes
at least the amino acid sequence DIGGRSAFDY (SEQ ID NO: 400); the
VL CDR1 sequence includes at least the amino acid sequence
RASQSISSY (SEQ ID NO: 401); the VL CDR2 sequence includes at least
the amino acid sequence AASSLQS (SEQ ID NO: 402); and the VL CDR3
sequence includes at least the amino acid sequence QQTVVAPPL (SEQ
ID NO: 403).
[0084] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds a Jagged target, e.g., Jagged 1 and/or
Jagged 2, and that contains a combination of a VH CDR1 sequence, a
VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1 sequence, a VL CDR2
sequence, and a VL CDR3 sequence, wherein the VH CDR1 sequence
includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99% or more identical to the amino acid sequence
SYAMS (SEQ ID NO: 398); the VH CD2 sequence includes a sequence
that is at least 90%, 91%, 92%, 93%, 94%, 95%6, 96%, 97%, 98%, 99%
or more identical to the amino acid sequence SIDPEGRQTYYADSVKG (SEQ
ID NO: 399); the VH CDR3 sequence includes a sequence that is at
least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more
identical to the amino acid sequence DIGGRSAFDY (SEQ ID NO: 400);
the VL CDR1 sequence includes a sequence that is at least 90%, 91%,
920%, 93%, 94%, 95%, 96%, 97%, 98%, 990% or more identical to the
amino acid sequence RASQSISSY (SEQ ID NO: 401); the VL CDR2
sequence includes a sequence that is at least 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid
sequence AASSLQS (SEQ ID NO: 402); and the VL CDR3 sequence
includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99% or more identical to the amino acid sequence
QQTVVAPPL (SEQ ID NO: 403).
[0085] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds Epidermal Growth Factor Receptor (EGFR) and
that contains a combination of a VH CDR1 sequence, a VH CDR2
sequence, and a VH CDR3 sequence, wherein at least one of the VH
CDR1 sequence, the VH CDR2 sequence, and the VH CDR3 sequence is
selected from a VH CDR1 sequence that includes at least the amino
acid sequence NYGVH (SEQ ID NO: 404); a VH CD2 sequence that
includes at least the amino acid sequence VIWSGGNTDYNTPFTS (SEQ ID
NO: 405); a VH CDR3 sequence that includes at least the amino acid
sequence ALTYYDYEFAY (SEQ ID NO: 406); and combinations
thereof.
[0086] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds EGFR and that contains a combination of a
VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence,
wherein at least one of the VL CDR1 sequence, the VL CDR2 sequence,
and the VL CDR3 sequence is selected from a VL CDR1 sequence that
includes at least the amino acid sequence RASQSIGTNIH (SEQ ID NO:
407); a VL CDR2 sequence that includes at least the amino acid
sequence KYASESIS (SEQ ID NO: 408); and a VL CDR3 sequence that
includes at least the amino acid sequence QQNNNWPTT (SEQ ID NO:
409), and combinations thereof.
[0087] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds EGFR and that contains a combination of a
VH CDR1 sequence, a VH CDR2 sequence, and a VH CDR3 sequence,
wherein at least one of the VH CDR1 sequence, the VH CDR2 sequence,
and the VH CDR3 sequence is selected from a VH CDR1 sequence that
includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99% or more identical to the amino acid sequence
NYGVH (SEQ ID NO: 404); a VH CD2 sequence that includes a sequence
that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%
or more identical to the amino acid sequence VIWSGGNTDYNTPFTS (SEQ
ID NO: 405); a VH CDR3 sequence that includes a sequence that is at
least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more
identical to the amino acid sequence ALTYYDYEFAY (SEQ ID NO: 406);
and combinations thereof.
[0088] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds EGFR and that contains a combination of a
VL CDR1 sequence, a VL CDR2 sequence, and a VL CDR3 sequence,
wherein at least one of the VL CDR1 sequence, the VL CDR2 sequence,
and the VL CDR3 sequence is selected from a VL CDR1 sequence that
includes a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99% or more identical to the amino acid sequence
RASQSIGTNIH (SEQ ID NO: 407); a VL CDR2 sequence that includes a
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 960%, 97%,
98%, 99% or more identical to the amino acid sequence KYASESIS (SEQ
ID NO: 408); and a VL CDR3 sequence that includes a sequence that
is at least 90%, 910%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or
more identical to the amino acid sequence QQNNNWPTT (SEQ ID NO:
409), and combinations thereof.
[0089] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds EGFR and that contains a combination of a
VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1
sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the
VH CDR1 sequence includes at least the amino acid sequence NYGVH
(SEQ ID NO: 404); the VH CD2 sequence includes at least the amino
acid sequence VIWSGGNTDYNTPFTS (SEQ ID NO: 405); the VH CDR3
sequence includes at least the amino acid sequence ALTYYDYEFAY (SEQ
ID NO: 406); the VL CDR1 sequence includes at least the amino acid
sequence RASQSIGTNIH (SEQ ID NO: 407); the VL CDR2 sequence
includes at least the amino acid sequence KYASESIS (SEQ ID NO:
408); and the VL CDR3 sequence includes at least the amino acid
sequence QQNNNWPTT (SEQ ID NO: 409).
[0090] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a first antibody or antigen binding fragment thereof (AB1)
that specifically binds EGFR and that contains a combination of a
VH CDR1 sequence, a VH CDR2 sequence, a VH CDR3 sequence, a VL CDR1
sequence, a VL CDR2 sequence, and a VL CDR3 sequence, wherein the
VH CDR1 sequence includes a sequence that is at least 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the
amino acid sequence NYGVH (SEQ ID NO: 404); the VH CD2 sequence
includes a sequence that is at least 900%, 91%, 92%, 93%, 94%, 95%,
96%, 97%, 98%, 99% or more identical to the amino acid sequence
VIWSGGNTDYNTPFTS (SEQ ID NO: 405); the VH CDR3 sequence includes a
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% or more identical to the amino acid sequence ALTYYDYEFAY
(SEQ ID NO: 406); the VL CDR1 sequence includes a sequence that is
at least 900%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more
identical to the amino acid sequence RASQSIGTNIH (SEQ ID NO: 407);
the VL CDR2 sequence includes a sequence that is at least 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the
amino acid sequence KYASESIS (SEQ ID NO: 408); and the VL CDR3
sequence includes a sequence that is at least 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%, 98%, 99% or more identical to the amino acid
sequence QQNNNWPTT (SEQ ID NO: 409).
[0091] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an anti-Jagged antibody comprising an
amino acid sequence of an anti-Jagged antibody disclosed herein. In
some embodiments, the activatable antibody and/or conjugated
activatable antibody provided herein, including but not limited to
a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an antibody having a light chain
comprising amino acid sequence SEQ ID NO: 162 or SEQ ID NO: 164 and
a heavy chain comprising amino acid sequence SEQ ID NO: 67 or SEQ
ID NO: 163.
[0092] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a heavy chain amino acid sequence of SEQ ID NO: 67 and a
light chain amino acid sequence selected from the group consisting
of SEQ ID NOs: 420, 422, 424, 426, 428, 430, 432, 434, 436, 439,
477, 479, 507-514, 539-546, 561, and 562.
[0093] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an anti-EGFR antibody comprising an
amino acid sequence of an anti-EGFR antibody disclosed herein. In
some embodiments, the activatable antibody and/or conjugated
activatable antibody provided herein, including but not limited to
a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, comprises a
CM1-CM2 substrate comprising an amino acid sequence selected from
the group consisting of SEQ ID NOs: 1-17, 22, 469-471, 483-490,
515-522, 555, and 557, and an antibody having a light chain
comprising amino acid sequence SEQ ID NO: 111 and a heavy chain
comprising amino acid sequence SEQ ID NO: 108, SEQ ID NO: 109, or
SEQ ID NO: 110.
[0094] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a heavy chain amino acid sequence of SEQ ID NO: 108 and a
light chain amino acid sequence selected from the group consisting
of SEQ ID NOs: 449, 451, 453, 455, 457, 459, 461, 463, 465, 467,
472, 474, 499-506, 531-538, 559, and 560.
[0095] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a heavy chain amino acid sequence that is at least 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the
amino acid sequence of SEQ ID NO: 67 and a light chain amino acid
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% or more identical to an amino acid sequence selected from
the group consisting of SEQ ID NOs: 420, 422, 424, 426, 428, 430,
432, 434, 436, 439, 477, 479, 507-514, 539-546, 561, and 562.
[0096] In some embodiments, the activatable antibody and/or
conjugated activatable antibody provided herein, including but not
limited to a multispecific activatable antibody and/or conjugated
multispecific activatable antibody of the disclosure, includes at
least a heavy chain amino acid sequence that is at least 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to the
amino acid sequence of SEQ ID NO: 108 and a light chain amino acid
sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% or more identical to an amino acid sequence selected from
the group consisting of SEQ ID NOs: 449, 451, 453, 455, 457, 459,
461, 463, 465, 467, 472, 474, 499-506, 531-538, 559, and 560.
[0097] In some embodiments, the activatable antibody also includes
an agent conjugated to the AB. In some embodiments, the agent is a
therapeutic agent. In some embodiments, the agent is an
antineoplastic agent. In some embodiments, the agent is a toxin or
a fragment thereof. In some embodiments, the agent is conjugated to
the AB via a linker. In some embodiments, the linker is a cleavable
linker. In some embodiments, the agent is a microtubule inhibitor.
In some embodiments, the agent is a nucleic acid damaging agent,
such as a DNA alkylator or DNA intercalator, or other DNA damaging
agent. In some embodiments, the linker is a cleavable linker. In
some embodiments, the agent is conjugated to the AB via a linker
that includes at least one CM1-CM2 substrate sequence. In some
embodiments, the agent is an agent selected from the group listed
in Table 3. In some embodiments, the agent is a dolastatin. In some
embodiments, the agent is an auristatin or derivative thereof. In
some embodiments, the agent is auristatin E or a derivative
thereof. In some embodiments, the agent is monomethyl auristatin E
(MMAE). In some embodiments, the agent is monomethyl auristatin D
(MMAD). In some embodiments, the agent is a maytansinoid or
maytansinoid derivative. In some embodiments, the agent is DM1 or
DM4. In some embodiments, the agent is a duocarmycin or derivative
thereof. In some embodiments, the agent is a calicheamicin or
derivative thereof. In some embodiments, the agent is a
pyrrolobenzodiazepine. In some embodiments, the agent is a
pyrrolobenzodiazepine dimer.
[0098] In some embodiments, the agent is an anti-inflammatory
agent.
[0099] In some embodiments, the activatable antibody also includes
a detectable moiety. In some embodiments, the detectable moiety is
a diagnostic agent.
[0100] In some embodiments, the conjugated antibody includes a
detectable label. In some embodiments, the detectable label
includes an imaging agent, a contrasting agent, an enzyme, a
fluorescent label, a chromophore, a dye, one or more metal ions, or
a ligand-based label. In some embodiments, the imaging agent
comprises a radioisotope. In some embodiments, the radioisotope is
indium or technetium. In some embodiments, the contrasting agent
comprises iodine, gadolinium or iron oxide. In some embodiments,
the enzyme comprises horseradish peroxidase, alkaline phosphatase,
or 3-galactosidase. In some embodiments, the fluorescent label
comprises yellow fluorescent protein (YFP), cyan fluorescent
protein (CFP), green fluorescent protein (GFP), modified red
fluorescent protein (mRFP), red fluorescent protein tdimer2 (RFP
tdimer2), HCRED, or a europium derivative. In some embodiments, the
luminescent label comprises an N-methylacrydium derivative. In some
embodiments, the label comprises an Alexa Fluor.RTM. label, such as
Alex Fluor.RTM. 680 or Alexa Fluor.RTM. 750. In some embodiments,
the ligand-based label comprises biotin, avidin, streptavidin or
one or more haptens.
[0101] In some embodiments, the activatable antibody also includes
a signal peptide. In some embodiments, the signal peptide is
conjugated to the activatable antibody via a spacer. In some
embodiments, the spacer is conjugated to the activatable antibody
in the absence of a signal peptide. In some embodiments, the spacer
is joined directly to the MM of the activatable antibody. In some
embodiments, the spacer is joined directly to the MM of the
activatable antibody in the structural arrangement from N-terminus
to C-terminus of spacer-MM-CM1-CM2 substrate-AB. An example of a
spacer joined directly to the N-terminus of MM of the activatable
antibody is an amino acid sequence selected from the group
consisting of QGQSGQ (SEQ ID NO: 410), GQSGQ (SEQ ID NO: 416), QSGQ
(SEQ ID NO: 417), SGQ (SEQ ID NO: 418), GQ, and Q. In some
embodiments, the spacer includes at least the amino acid sequence
QGQSGQ (SEQ ID NO: 410). In some embodiments, the spacer includes
at least the amino acid sequence GQSGQ (SEQ ID NO: 416). In some
embodiments, the spacer includes at least the amino acid sequence
QSGQ (SEQ ID NO: 417). In some embodiments, the spacer includes at
least the amino acid sequence SGQ (SEQ ID NO: 418). In some
embodiments, the spacer includes at least the amino acid sequence
GQ. In some embodiments, the spacer includes at least the amino
acid sequence Q.
[0102] In some embodiments, the AB of the activatable antibody
naturally contains one or more disulfide bonds. In some
embodiments, the AB can be engineered to include one or more
disulfide bonds.
[0103] In some embodiments, the serum half-life of the activatable
antibody is longer than that of the corresponding antibody; e.g.,
the pK of the activatable antibody is longer than that of the
corresponding antibody. In some embodiments, the serum half-life of
the activatable antibody is similar to that of the corresponding
antibody. In some embodiments, the serum half-life of the
activatable antibody is at least 15 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 12 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 11 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 10 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 9 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 8 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 7 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 6 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 5 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 4 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 3 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 2 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 24 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 20 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 18 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 16 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 14 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 12 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 10 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 8 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 6 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 4 hours when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 3 hours when administered to an
organism.
[0104] The disclosure also provides compositions and methods that
include an activatable antibody that includes an antibody or
antibody fragment (AB) that specifically binds a given target,
where the AB is coupled to a masking moiety (MM) that decreases the
ability of the AB to bind its target. In some embodiments, the
activatable antibody further includes a CM1-CM2 substrate that is a
substrate for at least one MMP and at least one SP. The
compositions and methods provided herein enable the attachment of
one or more agents to one or more cysteine residues in the AB
without compromising the activity (e.g., the masking, activating or
binding activity) of the activatable antibody. In some embodiments,
the compositions and methods provided herein enable the attachment
of one or more agents to one or more cysteine residues in the AB
without reducing or otherwise disturbing one or more disulfide
bonds within the MM. The compositions and methods provided herein
produce an activatable antibody that is conjugated to one or more
agents, e.g., any of a variety of therapeutic, diagnostic and/or
prophylactic agents, for example, in some embodiments, without any
of the agent(s) being conjugated to the MM of the activatable
antibody. The compositions and methods provided herein produce
conjugated activatable antibodies in which the MM retains the
ability to effectively and efficiently mask the AB of the
activatable antibody in an uncleaved state. The compositions and
methods provided herein produce conjugated activatable antibodies
in which the activatable antibody is still activated, i.e.,
cleaved, in the presence of a MMP that can cleave the CM1-CM2
substrate.
[0105] The activatable antibodies have at least one point of
conjugation for an agent, but in the methods and compositions
provided herein less than all possible points of conjugation are
available for conjugation to an agent. In some embodiments, the one
or more points of conjugation are sulfur atoms involved in
disulfide bonds. In some embodiments, the one or more points of
conjugation are sulfur atoms involved in interchain disulfide
bonds. In some embodiments, the one or more points of conjugation
are sulfur atoms involved in interchain sulfide bonds, but not
sulfur atoms involved in intrachain disulfide bonds. In some
embodiments, the one or more points of conjugation are sulfur atoms
of cysteine or other amino acid residues containing a sulfur atom.
Such residues may occur naturally in the antibody structure or may
be incorporated into the antibody by site-directed mutagenesis,
chemical conversion, or mis-incorporation of non-natural amino
acids.
[0106] Also provided are methods of preparing a conjugate of an
activatable antibody having one or more interchain disulfide bonds
in the AB and one or more intrachain disulfide bonds in the MM, and
a drug reactive with free thiols is provided. The method generally
includes partially reducing interchain disulfide bonds in the
activatable antibody with a reducing agent, such as, for example,
TCEP; and conjugating the drug reactive with free thiols to the
partially reduced activatable antibody. As used herein, the term
partial reduction refers to situations where an activatable
antibody is contacted with a reducing agent and less than all
disulfide bonds, e.g., less than all possible sites of conjugation
are reduced. In some embodiments, less than 99%, 98%, 97%, 96%,
95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%,
30%, 25%, 20%, 15%, 10% or less than 5% of all possible sites of
conjugation are reduced.
[0107] In some embodiments, a method of reducing and conjugating an
agent, e.g., a drug, to an activatable antibody resulting in
selectivity in the placement of the agent is provided. The method
generally includes partially reducing the activatable antibody with
a reducing agent such that any conjugation sites in the masking
moiety or other non-AB portion of the activatable antibody are not
reduced, and conjugating the agent to interchain thiols in the AB.
The conjugation site(s) are selected so as to allow desired
placement of an agent to allow conjugation to occur at a desired
site. The reducing agent is, for example, TCEP. The reduction
reaction conditions such as, for example, the ratio of reducing
agent to activatable antibody, the length of incubation, the
temperature during the incubation, the pH of the reducing reaction
solution, etc., are determined by identifying the conditions that
produce a conjugated activatable antibody in which the MM retains
the ability to effectively and efficiently mask the AB of the
activatable antibody in an uncleaved state. The ratio of reduction
agent to activatable antibody will vary depending on the
activatable antibody. In some embodiments, the ratio of reducing
agent to activatable antibody will be in a range from about 20:1 to
1:1, from about 10:1 to 1:1, from about 9:1 to 1:1, from about 8:1
to 1:1, from about 7:1 to 1:1, from about 6:1 to 1:1, from about
5:1 to 1:1, from about 4:1 to 1:1, from about 3:1 to 1:1, from
about 2:1 to 1:1, from about 20:1 to 1:1.5, from about 10:1 to
1:1.5, from about 9:1 to 1:1.5, from about 8:1 to 1:1.5, from about
7:1 to 1:1.5, from about 6:1 to 1:1.5, from about 5:1 to 1:1.5,
from about 4:1 to 1:1.5, from about 3:1 to 1:1.5, from about 2:1 to
1:1.5, from about 1.5:1 to 1:1.5, or from about 1:1 to 1:1.5. In
some embodiments, the ratio is in a range of from about 5:1 to 1:1.
In some embodiments, the ratio is in a range of from about 5:1 to
1.5:1. In some embodiments, the ratio is in a range of from about
4:1 to 1:1. In some embodiments, the ratio is in a range from about
4:1 to 1.5:1. In some embodiments, the ratio is in a range from
about 8:1 to about 1:1. In some embodiments, the ratio is in a
range of from about 2.5:1 to 1:1.
[0108] In some embodiments, a method of reducing interchain
disulfide bonds in the AB of an activatable antibody and
conjugating an agent, e.g., a thiol-containing agent such as a
drug, to the resulting interchain thiols to selectively locate
agent(s) on the AB is provided. The method generally includes
partially reducing the AB with a reducing agent to form at least
two interchain thiols without forming all possible interchain
thiols in the activatable antibody; and conjugating the agent to
the interchain thiols of the partially reduced AB. For example, the
AB of the activatable antibody is partially reduced for about 1
hour at about 37.degree. C. at a desired ratio of reducing
agent:activatable antibody. In some embodiments, the ratio of
reducing agent to activatable antibody will be in a range from
about 20:1 to 1:1, from about 10:1 to 1:1, from about 9:1 to 1:1,
from about 8:1 to 1:1, from about 7:1 to 1:1, from about 6:1 to
1:1, from about 5:1 to 1:1, from about 4:1 to 1:1, from about 3:1
to 1:1, from about 2:1 to 1:1, from about 20:1 to 1:1.5, from about
10:1 to 1:1.5, from about 9:1 to 1:1.5, from about 8:1 to 1:1.5,
from about 7:1 to 1:1.5, from about 6:1 to 1:1.5, from about 5:1 to
1:1.5, from about 4:1 to 1:1.5, from about 3:1 to 1:1.5, from about
2:1 to 1:1.5, from about 1.5:1 to 1:1.5, or from about 1:1 to
1:1.5. In some embodiments, the ratio is in a range of from about
5:1 to 1:1. In some embodiments, the ratio is in a range of from
about 5:1 to 1.5:1. In some embodiments, the ratio is in a range of
from about 4:1 to 1:1. In some embodiments, the ratio is in a range
from about 4:1 to 1.5:1. In some embodiments, the ratio is in a
range from about 8:1 to about 1:1. In some embodiments, the ratio
is in a range of from about 2.5:1 to 1:1.
[0109] The thiol-containing reagent can be, for example, cysteine
or N-acetyl cysteine. The reducing agent can be, for example, TCEP.
In some embodiments, the reduced activatable antibody can be
purified prior to conjugation, using for example, column
chromatography, dialysis, or diafiltration. In some embodiments,
the reduced antibody is not purified after partial reduction and
prior to conjugation.
[0110] The disclosure also provides partially reduced activatable
antibodies in which at least one interchain disulfide bond in the
activatable antibody has been reduced with a reducing agent without
disturbing any intrachain disulfide bonds in the activatable
antibody, wherein the activatable antibody includes an antibody or
an antigen binding fragment thereof (AB) that specifically binds to
the target, a masking moiety (MM) that inhibits the binding of the
AB of the activatable antibody in an uncleaved state to the target,
and a CM1-CM2 substrate coupled to the AB, wherein the CM1-CM2
substrate is a polypeptide that functions as a substrate for at
least one MMP and one SP. In some embodiments, the MM is coupled to
the AB via the CM1-CM2 substrate. In some embodiments, one or more
intrachain disulfide bond(s) of the activatable antibody is not
disturbed by the reducing agent. In some embodiments, one or more
intrachain disulfide bond(s) of the MM within the activatable
antibody is not disturbed by the reducing agent. In some
embodiments, the activatable antibody in the uncleaved state has
the structural arrangement from N-terminus to C-terminus as
follows: MM-CM1-CM2 substrate-AB or AB-CM1-CM2 substrate-MM. In
some embodiments, the reducing agent is TCEP.
[0111] The disclosure also provides partially reduced activatable
antibodies, including but not limited to multispecific activatable
antibodies of the disclosure, in which at least one interchain
disulfide bond in the activatable antibody has been reduced with a
reducing agent without disturbing or otherwise compromising the
activity and/or efficacy of the activatable antibody, wherein the
activatable antibody includes an antibody or an antigen binding
fragment thereof (AB) that specifically binds to a target, a
masking moiety (MM) that inhibits the binding of the AB of the
activatable antibody in an uncleaved state to the target, and a
CM1-CM2 substrate coupled to the AB, and the CM1-CM2 substrate is a
polypeptide that functions as a substrate for a protease. The
activity and/or efficacy of the activatable antibody is, by way of
nonlimiting example, masking activity, activation of the
activatable antibody, and/or binding activity of the activated
activatable antibody. In some embodiments, one or more intrachain
disulfide bond(s) of the activatable antibody is not disturbed by
the reducing agent. In some embodiments, one or more intrachain
disulfide bond(s) of the MM within the activatable antibody is not
disturbed by the reducing agent. In some embodiments, the
activatable antibody in the uncleaved state has the structural
arrangement from N-terminus to C-terminus as follows: MM-CM1-CM2
substrate-AB or AB-CM1-CM2 substrate-MM. In some embodiments, the
reducing agent is TCEP.
[0112] The disclosure also provides conjugated activatable
antibodies that include an activatable antibody linked to
monomethyl auristatin D (MMAD) payload, wherein the activatable
antibody includes an antibody or an antigen binding fragment
thereof (AB) that specifically binds to a target, a masking moiety
(MM) that inhibits the binding of the AB of the activatable
antibody in an uncleaved state to the target, and CM1-CM2 substrate
coupled to the AB, and the CM1-CM2 substrate is a polypeptide that
functions as a substrate for at least one MMP protease and at least
one SP protease.
[0113] In some embodiments, the MMAD-conjugated activatable
antibody can be conjugated using any of several methods for
attaching agents to ABs: (a) attachment to the carbohydrate
moieties of the AB, or (b) attachment to sulfhydryl groups of the
AB, or (c) attachment to amino groups of the AB, or (d) attachment
to carboxylate groups of the AB.
[0114] In some embodiments, the MMAD payload is conjugated to the
AB via a linker. In some embodiments, the MMAD payload is
conjugated to a cysteine in the AB via a linker. In some
embodiments, the MMAD payload is conjugated to a lysine in the AB
via a linker. In some embodiments, the MMAD payload is conjugated
to another residue of the AB via a linker, such as those residues
disclosed herein. In some embodiments, the linker is a
thiol-containing linker. In some embodiments, the linker is a
cleavable linker. In some embodiments, the linker is a
non-cleavable linker. In some embodiments, the linker is selected
from the group consisting of the linkers shown in Tables 5 and 6.
In some embodiments, the activatable antibody and the MMAD payload
are linked via a maleimide caproyl-valine-citrulline linker. In
some embodiments, the activatable antibody and the MMAD payload are
linked via a maleimide PEG-valine-citrulline linker. In some
embodiments, the activatable antibody and the MMAD payload are
linked via a maleimide
caproyl-valine-citrulline-para-aminobenzyloxycarbonyl linker. In
some embodiments, the activatable antibody and the MMAD payload are
linked via a maleimide
PEG-valine-citrulline-para-aminobenzyloxycarbonyl linker. In some
embodiments, the MMAD payload is conjugated to the AB using the
partial reduction and conjugation technology disclosed herein.
[0115] The disclosure also provides polypeptides and other larger
molecules that include one or more of the CM1-CM2 substrate
sequences presented herein. By way of non-limiting example, the
CM1-CM2 substrate sequences presented herein are useful in prodrug
compositions and methods of use thereof. These CM1-CM2 substrate
sequences presented herein are also useful in probes and other
detection agents and methods of use thereof. For example, the
CM1-CM2 substrate sequences presented herein can be used in
conjunction with fluors and other quenchers to produce detection
agents, such as imaging agents and/or other diagnostic agents.
Those of ordinary skill in the art will appreciate that the CM1-CM2
substrate sequences presented herein are useful in any composition
and/or method in the art that would use a substrate that is
cleavable by at least one MMP and at least one SP.
[0116] The disclosure also provides an isolated nucleic acid
molecule encoding an antibody and/or an activatable antibody
described herein, as well as vectors that include these isolated
nucleic acid sequences. The disclosure provides methods of
producing an antibody and/or activatable antibody by culturing a
cell under conditions that lead to expression of the antibody
and/or activatable antibody, wherein the cell comprises such a
vector.
[0117] The disclosure provides a method of manufacturing a
conjugated antibody of the disclosure that bind a given target by
(a) culturing a cell comprising a nucleic acid construct that
encodes the antibody under conditions that lead to expression of
the antibody, (i) wherein the antibody includes a CM1-CM2
substrate, and (ii) wherein the CM1-CM2 substrate is a polypeptide
that functions as a substrate for a matrix metalloprotease and a
serine protease; (b) recovering the antibody; and (c) conjugating
the recovered antibody to one or more additional agents.
[0118] The disclosure also provides a method of manufacturing the
activatable antibodies of the disclosure that bind in an activated
state a given target by (a) culturing a cell comprising a nucleic
acid construct that encodes the activatable antibody under
conditions that lead to expression of the activatable antibody,
wherein the activatable antibody comprises a masking moiety (MM), a
CM1-CM2 substrate, and an antibody or an antigen binding fragment
thereof (AB) that specifically binds the target, (i) wherein the
CM1-CM2 substrate is a polypeptide that functions as a substrate
for a MMP and a SP: and (ii) wherein the CM1-CM2 substrate is
positioned in the activatable antibody such that, in an uncleaved
state, the MM interferes with specific binding of the AB to the
target and in a cleaved state the MM does not interfere or compete
with specific binding of the AB to the target; and (b) recovering
the activatable antibody.
[0119] The disclosure also provides a method of manufacturing the
conjugated activatable antibodies of the disclosure that bind in an
activated state a given target by (a) culturing a cell comprising a
nucleic acid construct that encodes the activatable antibody under
conditions that lead to expression of the activatable antibody,
wherein the activatable antibody comprises a masking moiety (MM), a
CM1-CM2 substrate, and an antibody or an antigen binding fragment
thereof (AB) that specifically binds the target, (i) wherein the
CM1-CM2 substrate is a polypeptide that functions as a substrate
for a MMP and a SP; and (ii) wherein the CM1-CM2 substrate is
positioned in the activatable antibody such that, in an uncleaved
state, the MM interferes with specific binding of the AB to the
target and in a cleaved state the MM does not interfere or compete
with specific binding of the AB to the target; (b) recovering the
activatable antibody; and (c) conjugating the recovered antibody to
one or more additional agents.
[0120] The disclosure provides methods of preventing, delaying the
progression of, treating, alleviating a symptom of, or otherwise
ameliorating a target-related disease in a subject by administering
a therapeutically effective amount of a conjugated antibody, an
activatable antibody and/or a conjugated activatable antibody
described herein to a subject in need thereof.
[0121] The disclosure provides methods of preventing, delaying the
progression of, treating, alleviating a symptom of, or otherwise
ameliorating inflammation and/or an inflammatory disorder in a
subject by administering a therapeutically effective amount of a
conjugated antibody, an activatable antibody and/or a conjugated
activatable antibody described herein to a subject in need thereof.
The disclosure also provides methods of preventing, delaying the
progression of, treating, alleviating a symptom of, or otherwise
ameliorating cancer in a subject by administering a therapeutically
effective amount of a conjugated antibody, an activatable antibody
and/or a conjugated activatable antibody described herein to a
subject in need thereof. The disclosure also provides methods of
preventing, delaying the progression of, treating, alleviating a
symptom of, or otherwise ameliorating an autoimmune disease in a
subject by administering a therapeutically effective amount a
conjugated antibody, an activatable antibody and/or a conjugated
activatable antibody described herein to a subject in need
thereof.
[0122] A conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody used in any of the embodiments of
these methods and uses can be administered at any stage of the
disease. For example, such a conjugated antibody, activatable
antibody and/or conjugated activatable antibody can be administered
to a patient suffering cancer of any stage, from early to
metastatic. The terms subject and patient are used interchangeably
herein.
[0123] In some embodiments, the subject is a mammal, such as a
human, non-human primate, companion animal (e.g., cat, dog, horse),
farm animal, work animal, or zoo animal. In some embodiments, the
subject is a rodent. In some embodiments, the subject is a human.
In some embodiments, the subject is a companion animal. In some
embodiments, the subject is an animal in the care of a
veterinarian.
[0124] The conjugated antibody, activatable antibody and/or
conjugated activatable antibody and therapeutic formulations
thereof are administered to a subject suffering from or susceptible
to a disease or disorder associated with aberrant target expression
and/or activity. A subject suffering from or susceptible to a
disease or disorder associated with aberrant target expression
and/or activity is identified using any of a variety of methods
known in the art. For example, subjects suffering from cancer or
other neoplastic condition are identified using any of a variety of
clinical and/or laboratory tests such as, physical examination and
blood, urine and/or stool analysis to evaluate health status. For
example, subjects suffering from inflammation and/or an
inflammatory disorder are identified using any of a variety of
clinical and/or laboratory tests such as physical examination
and/or bodily fluid analysis, e.g., blood, urine and/or stool
analysis, to evaluate health status.
[0125] Administration of a conjugated antibody, an activatable
antibody and/or a conjugated activatable antibody to a patient
suffering from a disease or disorder associated with aberrant
target expression and/or activity is considered successful if any
of a variety of laboratory or clinical objectives is achieved. For
example, administration of a conjugated antibody, an activatable
antibody and/or a conjugated activatable antibody to a patient
suffering from a disease or disorder associated with aberrant
target expression and/or activity is considered successful if one
or more of the symptoms associated with the disease or disorder is
alleviated, reduced, inhibited or does not progress to a further,
i.e., worse, state. Administration of a conjugated antibody, an
activatable antibody and/or a conjugated activatable antibody to a
patient suffering from a disease or disorder associated with
aberrant target expression and/or activity is considered successful
if the disease or disorder enters remission or does not progress to
a further, i.e., worse, state.
[0126] In some embodiments, the antibodies, conjugated antibodies,
activatable antibodies, and/or conjugated activatable antibodies
described herein are used in conjunction with one or more
additional agents or a combination of additional agents. Suitable
additional agents include current pharmaceutical and/or surgical
therapies for an intended application, such as, for example,
cancer. For example, the antibodies, conjugated antibodies,
activatable antibodies, and/or conjugated activatable antibodies
can be used in conjunction with an additional chemotherapeutic or
anti-neoplastic agent.
[0127] In some embodiments, the additional agent(s) is a
chemotherapeutic agent, such as a chemotherapeutic agent selected
from the group consisting of docetaxel, paclitaxel, abraxane (i.e.,
albumin-conjugated paclitaxel), doxorubicin, oxaliplatin,
carboplatin, cisplatin, irinotecan, and gemcitabine.
[0128] In some embodiments, the additional agent(s) is a checkpoint
inhibitor, a kinase inhibitor, an agent targeting inhibitors in the
tumor microenvironment, and/or a T cell or NK agonist. In some
embodiments, the additional agent(s) is radiation therapy, alone or
in combination with another additional agent(s) such as a
chemotherapeutic or anti-neoplastic agent. In some embodiments, the
additional agent(s) is a vaccine, an oncovirus, and/or a
DC-activating agent such as, by way of non-limiting example, a
toll-like receptor (TLR) agonist and/or .alpha.-CD40. In some
embodiments, the additional agent(s) is a tumor-targeted antibody
designed to kill the tumor via ADCC or via direct conjugation to a
toxin (e.g., an antibody drug conjugate (ADC).
[0129] In some embodiments, the checkpoint inhibitor is an
inhibitor of a target selected from the group consisting of CTLA-4,
LAG-3, PD-1, PD-1, TIGIT, TIM-3, B7H4, BTLA, and Vista. In some
embodiments, the kinase inhibitor is selected from the group
consisting of B-RAFi, MEKi, and Btk inhibitors, such as ibrutinib.
In some embodiments, the kinase inhibitor is crizotinib. In some
embodiments, the tumor microenvironment inhibitor is selected from
the group consisting of an IDO inhibitor, an .alpha.-CSF1R
inhibitor, an .alpha.-CCR4 inhibitor, a TGF-beta, a myeloid-derived
suppressor cell, or a T-regulatory cell. In some embodiments, the
agonist is selected from the group consisting of Ox40, GITR, CD137,
ICOS, CD27, and HVEM.
[0130] In some embodiments, the inhibitor is a CTLA-4 inhibitor. In
some embodiments, the inhibitor is a LAG-3 inhibitor. In some
embodiments, the inhibitor is a PD-1 inhibitor. In some
embodiments, the inhibitor is a PD-1 inhibitor. In some
embodiments, the inhibitor is a TIGIT inhibitor. In some
embodiments, the inhibitor is a TIM-3 inhibitor. In some
embodiments, the inhibitor is a B7H4 inhibitor. In some
embodiments, the inhibitor is a Vista inhibitor. In some
embodiments, the inhibitor is a B-RAFi inhibitor. In some
embodiments, the inhibitor is a MEKi inhibitor. In some
embodiments, the inhibitor is a Btk inhibitor. In some embodiments,
the inhibitor is ibrutinib. In some embodiments, the inhibitor is
crizotinib. In some embodiments, the inhibitor is an IDO inhibitor.
In some embodiments, the inhibitor is an .alpha.-CSF1R inhibitor.
In some embodiments, the inhibitor is an .alpha.-CCR4 inhibitor. In
some embodiments, the inhibitor is a TGF-beta. In some embodiments,
the inhibitor is a myeloid-derived suppressor cell. In some
embodiments, the inhibitor is a T-regulatory cell.
[0131] In some embodiments, the agonist is Ox40. In some
embodiments, the agonist is GITR. In some embodiments, the agonist
is CD137. In some embodiments, the agonist is ICOS. In some
embodiments, the agonist is CD27. In some embodiments, the agonist
is HVEM.
[0132] In some embodiments, the antibody, conjugated antibody,
activatable antibody, and/or conjugated activatable antibody is
administered during and/or after treatment in combination with one
or more additional agents such as, for example, a chemotherapeutic
agent, an anti-inflammatory agent, and/or an immunosuppressive
agent. In some embodiments, the antibody, conjugated antibody,
activatable antibody, and/or conjugated activatable antibody and
the additional agent are formulated into a single therapeutic
composition, and the antibody, conjugated antibody, activatable
antibody, and/or conjugated activatable antibody and additional
agent are administered simultaneously. Alternatively, the antibody,
conjugated antibody, activatable antibody, and/or conjugated
activatable antibody and additional agent are separate from each
other, e.g., each is formulated into a separate therapeutic
composition, and the antibody, conjugated antibody, activatable
antibody, and/or conjugated activatable antibody and the additional
agent are administered simultaneously, or the antibody, conjugated
antibody, activatable antibody, and/or conjugated activatable
antibody and the additional agent are administered at different
times during a treatment regimen. For example, the antibody,
conjugated antibody, activatable antibody, and/or conjugated
activatable antibody is administered prior to the administration of
the additional agent, the antibody, conjugated antibody,
activatable antibody, and/or conjugated activatable antibody is
administered subsequent to the administration of the additional
agent, or the antibody, conjugated antibody, activatable antibody,
and/or conjugated activatable antibody and the additional agent are
administered in an alternating fashion. As described herein, the
antibody, conjugated antibody, activatable antibody, and/or
conjugated activatable antibody and additional agent are
administered in single doses or in multiple doses.
[0133] In some embodiments, the antibody, conjugated antibody,
activatable antibody, and/or conjugated activatable antibody and
the additional agent(s) are administered simultaneously. For
example, the antibody, conjugated antibody, activatable antibody,
and/or conjugated activatable antibody and the additional agent(s)
can be formulated in a single composition or administered as two or
more separate compositions. In some embodiments, the antibody,
conjugated antibody, activatable antibody, and/or conjugated
activatable antibody and the additional agent(s) are administered
sequentially, or the antibody, conjugated antibody, activatable
antibody, and/or conjugated activatable antibody and the additional
agent are administered at different times during a treatment
regimen.
[0134] In some embodiments, the conjugated antibody, activatable
antibody and/or conjugated activatable antibody is administered
during and/or after treatment in combination with one or more
additional agents such as, by way of non-limiting example, an
anti-inflammatory agent, an immunosuppressive agent, a
chemotherapeutic agent, such as an alkylating agent, an
anti-metabolite, an anti-microtubule agent, a topoisomerase
inhibitor, a cytotoxic antibiotic, and/or any other nucleic acid
damaging agent. In some embodiments, the additional agent is a
taxane, such as paclitaxel (e.g., Abraxane.RTM.). In some
embodiments, the additional agent is an anti-metabolite, such as
gemcitabine. In some embodiments, the additional agent is an
alkylating agent, such as platinum-based chemotherapy, such as
carboplatin or cisplatin. In some embodiments, the additional agent
is a targeted agent, such as a kinase inhibitor, e.g., sorafenib or
erlotinib. In some embodiments, the additional agent is a targeted
agent, such as another antibody, e.g., a monoclonal antibody (e.g.,
bevacizumab), a bispecific antibody, or a multispecific antibody.
In some embodiments, the additional agent is a proteosome
inhibitor, such as bortezomib or carfilzomib. In some embodiments,
the additional agent is an immune modulating agent, such as
lenolidominde or IL-2. In some embodiments, the additional agent is
radiation. In some embodiments, the additional agent is an agent
considered standard of care by those skilled in the art. In some
embodiments, the additional agent is a chemotherapeutic agent well
known to those skilled in the art.
[0135] In some embodiments, the additional agent is an antibody,
another conjugated antibody, another activatable antibody and/or
another conjugated activatable antibody. In some embodiments the
additional agent is an antibody, another conjugated antibody,
another activatable antibody and/or another conjugated activatable
antibody against the same target as the first conjugated antibody,
activatable antibody and/or a conjugated activatable antibody. In
some embodiments the additional agent is an antibody, another
conjugated antibody, another activatable antibody and/or another
conjugated activatable antibody against a target different than the
target of the first conjugated antibody, activatable antibody
and/or a conjugated activatable antibody.
[0136] In some embodiments, the conjugated antibody, activatable
antibody and/or conjugated activatable antibody and the additional
agent(s) are administered simultaneously. For example, the
conjugated antibody, activatable antibody and/or conjugated
activatable antibody and the additional agent(s) can be formulated
in a single composition or administered as two or more separate
compositions. In some embodiments, the conjugated antibody,
activatable antibody and/or conjugated activatable antibody and the
additional agent(s) are administered sequentially, or the antibody
and/or conjugated antibodies and the additional agent are
administered at different times during a treatment regimen. For
example, the antibody and/or conjugated antibodies is administered
prior to the administration of the additional agent, the antibody
and/or conjugated antibodies is administered subsequent to the
administration of the additional agent, or the antibody and/or
conjugated antibodies and the additional agent are administered in
an alternating fashion. As described herein, the antibody and/or
conjugated antibodies and additional agent are in single doses or
in multiple doses.
[0137] The disclosure also provides methods and kits for using the
conjugated antibodies, activatable antibodies and/or conjugated
activatable antibodies in a variety of diagnostic and/or
prophylactic indications.
[0138] Pharmaceutical compositions according to the disclosure can
include an antibody, conjugated antibody, activatable antibody
and/or a conjugated activatable antibody of the disclosure and a
carrier. These pharmaceutical compositions can be included in kits,
such as, for example, diagnostic kits.
BRIEF DESCRIPTION OF THE DRAWINGS
[0139] FIGS. 1A and 1B are a series of graphs depicting the results
of human Jagged 1 binding ELISA assays that demonstrate the binding
of the anti-Jagged antibody and the masked and activated
activatable antibodies. Both the (A) 2001 and (B) 1001/LP'/0001
substrate-containing activatable antibodies were activated by uPA
(a serine protease), MMP14 (an MMP), and uPA in combination with
MMP14. The activated activatable antibodies showed binding
equivalent to the anti-Jagged antibody.
[0140] FIG. 2 is a graph depicting human IgG serum concentrations
for anti-Jagged antibody and the 1001/LP'/0001 and 2001 activatable
antibodies following a single 5 mg/kg intravenous dose. The
anti-Jagged antibody is rapidly cleared due to target-mediated
clearance. In contrast, the anti-Jagged activatable antibodies
remain masked in circulation.
[0141] FIG. 3 is a graph depicting HCC1806 tumor volume (group
mean.+-.SEM n=8) plotted vs time post initial dose. Groups were
dosed on day 1 and day 8 of the study. The anti-Jagged-SPDB-DM4
antibody and anti-Jagged 2001 activatable antibody-SPDB-DM4 groups
both showed tumor regression while the isotype-SPDB-DM4 group did
not show tumor growth inhibition.
[0142] FIG. 4 is a graph depicting percent initial body weight
(group mean n=8) plotted vs time post initial dose. Groups were
dosed on day 1 and day 8 of the study. Animals in the
anti-Jagged-SPDB-DM4 ADC treated group showed significant body
weight loss, whereas the PBS, Isotype-SPDB-DM4 ADC, and anti-Jagged
2001 activatable antibody-SPDB-DM4 treated animals showed no
significant weight loss.
[0143] FIG. 5 is a graph depicting in vivo activation of EGFR
activatable antibodies measured in plasma 8 days post-dose of 12.5
mg/kg of such EGFR activatable antibodies in H292 xenograft
tumor-bearing mice.
[0144] FIG. 6 is a graph depicting in vivo efficacy of EGFR
activatable antibodies in H292 xenograft tumor-bearing mice.
[0145] FIG. 7 is a graph depicting in situ evaluation of EGFR
activatable antibody activation in a H292 xenograft tumor
microenvironment.
[0146] FIGS. 8A, 8B, 8C, 8D, 8E, and 8F are a series of graphs
depicting the tumor volume of H292 xenograft tumors in nu/nu mice
at various time points following administration with a control
intravenous immunoglobulin (IVIG, FIG. 8A), the anti-EGFR antibody
cetuximab (FIG. 8B), the anti-EGFR activatable antibody referred to
herein as anti-EGFR 2001 activatable antibody, which includes the
heavy chain sequence of SEQ ID NO: 108, and the light chain
sequence of SEQ ID NO: 449 (FIG. 8C); the anti-EGFR activatable
antibody referred to herein as anti-EGFR 2003 activatable antibody,
which includes the heavy chain sequence of SEQ ID NO: 108, and the
light chain sequence of SEQ ID NO: 472 (FIG. 8D); or the anti-EGFR
activatable antibody referred to herein as anti-EGFR 2005
activatable antibody, which includes the heavy chain sequence of
SEQ ID NO: 108, and the light chain sequence of SEQ ID NO: 474
(FIG. 8E). For the data shown in FIGS. 8C and 8D, each group lost
one animal each due to body weight loss. FIG. 8F is a graph that
plots and compares the data presented in FIGS. 8A-8E in a single
graph.
[0147] FIG. 9 is a graph depicting toxicity as measured by body
weight (BW) loss following administration with an isotype control
intravenous immunoglobulin (IVIG), a 20 mg/kg dose of the
anti-Jagged antibody referred to herein as 4D11, which includes the
heavy chain sequence of SEQ ID NO: 67 and the light chain sequence
of SEQ ID NO: 162, a 10 mg/kg dose of the 4D11 antibody, a 5 mg/kg
dose of the 4D11 antibody, the anti-Jagged activatable antibody
referred to herein as anti-Jagged 2001 activatable antibody, which
includes the heavy chain sequence of SEQ ID NO: 67, and the light
chain sequence of SEQ ID NO: 420, the anti-Jagged activatable
antibody referred to herein as anti-Jagged 1004/LP'/0001
activatable antibody, which includes the heavy chain sequence of
SEQ ID NO: 67, and the light chain sequence of SEQ ID NO: 432, the
anti-Jagged activatable antibody referred to herein as anti-Jagged
2003 activatable antibody, which includes the heavy chain sequence
of SEQ ID NO: 67, and the light chain sequence of SEQ ID NO: 477,
and the anti-Jagged activatable antibody referred to herein as
anti-Jagged 2005 activatable antibody, which includes the heavy
chain sequence of SEQ ID NO: 67, and the light chain sequence of
SEQ ID NO: 479. The results are shown as relative body weight (BW)
change percent (%) at various time points during the study.
[0148] FIG. 10 is a graph depicting toxicity as measured by body
weight (BW) loss following administration with an isotype control
intravenous immunoglobulin (IVIG), a 20 mg/kg dose of the
anti-Jagged antibody referred to herein as 4D11, which includes the
heavy chain sequence of SEQ ID NO: 67 and the light chain sequence
of SEQ ID NO: 162, a 10 mg/kg dose of the 4D11 antibody, a 5 mg/kg
dose of the 4D11 antibody, the anti-Jagged activatable antibody
referred to herein as anti-Jagged 2001 activatable antibody
("2001"), which includes the heavy chain sequence of SEQ ID NO: 67,
and the light chain sequence of SEQ ID NO: 420, the anti-Jagged
activatable antibody referred to herein as anti-Jagged
1004/LP'/0001 activatable antibody, which includes the heavy chain
sequence of SEQ ID NO: 67, and the light chain sequence of SEQ ID
NO: 432, and the anti-Jagged activatable antibody referred to
herein as anti-Jagged 1004/LP'/0003 activatable antibody, which
includes the heavy chain sequence of SEQ ID NO: 67, and the light
chain sequence of SEQ ID NO: 424. The results are shown as relative
body weight (BW) change percent (%) at various time points during
the study.
[0149] FIGS. 11A, 11B, 11C, 11D, 11E, 11F, 11G, and 11H and FIG. 12
are a series of graphs depicting the efficacy of various substrates
of the disclosure when incorporated in activatable anti-EGFR
antibodies of the disclosure. Efficacy of the substrates was
evaluated by measuring tumor volume (TV mm.sup.3) at various time
points post-administration.
[0150] FIG. 13 is a graph depicting toxicity as measured as a
function of body weight (BW) loss in DBA/1 mice following
administration with a control intravenous immunoglobulin (IVIG),
with anti-Jagged antibodies of the disclosure, and with activatable
anti-Jagged antibodies of the disclosure that include various
substrates of the disclosure.
[0151] FIG. 14 is a graph depicting 3D reconstruction of
FLIT-.mu.CT imaging data for cetuximab and two EGFR activatable
antibodies containing tandem substrates in H292 (open arrows) and
FaDu (filled arrows) co-implanted xenograft tumor model.
DETAILED DESCRIPTION OF THE INVENTION
[0152] The disclosure provides amino acid sequences that include at
least a first cleavable moiety (CM1) that is a substrate for at
least one matrix metalloprotease (MMP) and at least a second
cleavable moiety (CM2) that is a substrate for at least one serine
protease (SP). These CM1-CM2 substrates are useful in a variety of
therapeutic, diagnostic and prophylactic indications. For example,
these CM1-CM2 substrates are useful in activatable antibodies that
include antibodies or antigen-binding fragments thereof (AB) that
include at least one masking moiety (MM) linked to at least one
antigen- or epitope-binding domain of the AB such that coupling of
the MM reduces the ability of the AB to bind its target.
[0153] The working examples provided herein demonstrate that these
CM1-CM2 substrates exhibit a number of desirable cleavage
characteristics when exposed to at least one MMP protease and/or at
least one SP protease under specified conditions.
[0154] The disclosure also provides antibodies that include one or
more of these CM1-CM2 substrates. For example, these CM1-CM2
substrates are useful when conjugating antibodies to one or more
additional agents to produce conjugated antibodies. These CM1-CM2
substrates are also useful in activatable antibodies and/or
activatable antibody conjugates.
[0155] The conjugated antibodies, activatable antibodies, and/or
conjugated activatable antibodies include an antibody or
antigen-binding fragment thereof (AB) that specifically binds a
target. Exemplary classes of targets of an AB include, but are not
necessarily limited to, cell surface receptors and secreted binding
proteins (e.g., growth factors), soluble enzymes, structural
proteins (e.g. collagen, fibronectin) and the like. In some
embodiments, conjugated antibodies and/or activatable antibodies
have an AB that binds an extracellular target, usually an
extracellular protein target. In some embodiments, conjugated
antibodies and/or activatable antibodies are designed for cellular
uptake and are switchable inside a cell.
[0156] As a non-limiting example, the AB is a binding partner for
any target listed in Table 1.
TABLE-US-00002 TABLE 1 Exemplary Targets 1-92-LFA-3 Alpha-4
integrin Alpha-V integrin alpha4beta1 integrin alpha4beta7 integrin
AGR2 Anti-Lewis-Y Apelin J receptor APRIL B7-H4 BAFF BTLA C5
complement C-242 CA9 CA19-9 (Lewis a) Carbonic anhydrase 9 CD2 CD3
CD6 CD9 CD11a CD19 CD20 CD22 CD24 CD25 CD27 CD28 CD30 CD33 CD38
CD40 CD40L CD41 CD44 CD44v6 CD47 CD51 CD52 CD56 CD64 CD70 CD71 CD74
CD80 CD81 CD86 CD95 CD117 CD125 CD132 (IL-2RG) CD133 CD137 CD138
CD166 CD172A CD248 CDH6 CEACAM5 (CEA) CEACAM6 (NCA-90) CLAUDIN-3
CLAUDIN-4 cMet Collagen Cripto CSFR CSFR-1 CTLA-4 CTGF CXCL10
CXCL13 CXCR1 CXCR2 CXCR4 CYR61 DL44 DLK1 DLL4 DPP-4 DSG1 EGFR
EGFRviii Endothelin B receptor (ETBR) ENPP3 EpCAM EPHA2 EPHB2 ERBB3
F protein of RSV FAP FGF-2 FGF8 FGFR1 FGFR2 FGFR3 FGFR4 Folate
receptor GAL3ST1 G-CSF G-CSFR GD2 GITR GLUT1 GLUT4 GM-CSF GM-CSFR
GP IIb/IIIa receptors Gp130 GPIIB/IIIA GPNMB GRP78 HER2/neu HGF hGH
HVEM Hyaluronidase ICOS IFNalpha IFNbeta IFNgamma IgE IgE Receptor
(FceRI) IGF IGF1R IL1B IL1R IL2 IL11 IL12 IL12p40 IL-12R,
IL-12Rbeta1 IL13 IL13R IL15 IL17 IL18 IL21 IL23 IL23R IL27/IL27R
(wsx1) IL29 IL-31R IL31/IL31R IL2R IL4 IL4R IL6, IL6R Insulin
Receptor Jagged Ligands Jagged 1 Jagged 2 LAG-3 LIF-R Lewis X LIGHT
LRP4 LRRC26 MCSP Mesothelin MRP4 MUC1 Mucin-16 (MUC16, CA-125) Na/K
ATPase Neutrophil elastase NGF Nicastrin Notch Receptors Notch 1
Notch 2 Notch 3 Notch 4 NOV OSM-R OX-40 PAR2 PDGF-AA PDGF-BB
PDGFRalpha PDGFRbeta PD-1 PD-L1 PD-L2 Phosphatidyl-serine P1GF PSCA
PSMA RAAG12 RAGE SLC44A4 Sphingosine 1 Phosphate STEAP1 STEAP2
TAG-72 TAPA1 TGFbeta TIGIT TIM-3 TLR2 TLR4 TLR6 TLR7 TLR8 TLR9
TMEM31 TNFalpha TNFR TNFRS12A TRAIL-R1 TRAIL-R2 Transferrin
Transferrin receptor TRK-A TRK-B uPAR VAP1 VCAM-1 VEGF VEGF-A
VEGF-B VEGF-C VEGF-D VEGFR1 VEGFR2 VEGFR3 VISTA WISP-1 WISP-2
WISP-3
[0157] As a non-limiting example, the AB is or is derived from an
antibody listed in Table 2.
TABLE-US-00003 TABLE 2 Exemplary sources for Abs Antibody Trade
Name (antibody name) Target Avastin .TM. (bevacizumab) VEGF
Lucentis .TM. (ranibizumab) VEGF Erbitux .TM. (cetuximab) EGFR
Vectibix .TM. (panitumumab) EGFR Remicade .TM. (infliximab)
TNF.alpha. Humira .TM. (adalimumab) TNF.alpha. Tysabri .TM.
(natalizumab) Integrin.alpha.4 Simulect .TM. (basiliximab) IL2R
Soliris .TM. (eculizumab) Complement C5 Raptiva .TM. (efalizumab)
CD11a Bexxar .TM. (tositumomab) CD20 Zevalin .TM. (ibritumomab
tiuxetan) CD20 Rituxan .TM. (rituximab) CD20 Ocerlizumab CD20
Arzerra .TM. (ofatumumab) CD20 Gazyva .TM. (Obinutuzumab) CD20
Zenapax .TM. (daclizumab) CD25 Adcetris .TM. (brentuximab vedotin)
CD30 Myelotarg .TM. (gemtuzumab) CD33 Mylotarg .TM. (gemtuzumab
ozogamicin) CD33 Campath .TM. (alemtuzumab) CD52 ReoPro .TM.
(abiciximab) Glycoprotein receptor IIb/IIIa Xolair .TM.
(omalizumab) IgE Herceptin .TM. (trastuzumab) Her2 Kadcyla .TM.
(trastuzumab emtansine) Her2 Synagis .TM. (palivizumab) F protein
of RSV (ipilimumab) CTLA-4 (tremelimumab) CTLA-4 Hu5c8 CD40L
(pertuzumab) Her2-neu (ertumaxomab) CD3/Her2-neu Orencia .TM.
(abatacept) CTLA-4 (tanezumab) NGF (bavituximab) Phosphatidylserine
(zalutumumab) EGFR (mapatumumab) EGFR (matuzumab) EGFR
(nimotuzumab) EGFR ICR62 EGFR mAb 528 EGFR CH806 EGFR MDX-447
EGFR/CD64 (edrecolomab) EpCAM RAV12 RAAG12 huJ591 PSMA Enbrel .TM.
(etanercept) TNF-R Amevive .TM. (alefacept) 1-92-LFA-3 Antril .TM.,
Kineret .TM. (ankinra) IL-1Ra GC1008 TGFbeta Notch, e.g., Notch 1
Jagged 1 or Jagged 2 (adecatumumab) EpCAM (figitumumab) IGF1R
(tocilizumab) IL-6 receptor Stelara .TM. (ustekinumab) IL-12/IL-23
Prolia .TM. (denosumab) RANKL
[0158] Exemplary conjugated antibodies, activatable antibodies
and/or conjugated activatable antibodies of the disclosure include,
for example, antibodies that bind interleukin 6 receptor (IL-6R)
and that include a heavy chain and a light chain that are, or are
derived from, the antibody referred to herein as the "Av1"
antibody, which binds interleukin-6 receptor (IL-6R). The amino
acid sequences for the Av1 heavy chain and the Av1 light chain are
shown below in SEQ ID NO: 100 and SEQ ID NO: 101, respectively.
TABLE-US-00004 Av1 Antibody Heavy Chain Amino Acid Sequence: (SEQ
ID NO: 100) QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIG
YISYSGITTYNPSLKSRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARSL
ARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVYTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Av1 Antibody
Light Chain Amino Acid Sequence: (SEQ ID NO: 101)
DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYY
TSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQ
GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC
[0159] Exemplary activatable antibodies and/or conjugated
activatable antibodies of the disclosure include, for example,
antibodies that bind interleukin 6 receptor (IL-6R) and that
include a heavy chain and a light chain that are, or are derived
from, the Av1 antibody and a masking moiety. Exemplary activatable
antibodies and/or conjugated activatable antibodies of the
disclosure include an amino acid sequence attached to the
N-terminus of the AV1 light chain. These N-terminal amino acid
sequences include, for example, YGSCSWNYVHIFMDC (SEQ ID NO: 102);
QGDFDIPFPAHWVPIT (SEQ ID NO: 103); MGVPAGCVWNYAHIFMDC (SEQ ID NO:
104); QGQSGQYGSCSWNYVHIFMDC (SEQ ID NO: 105); QGQSGQGDFDIPFPAHWVPIT
(SEQ ID NO: 106); or QGQSGQMGVPAGCVWNYAHIFMDC (SEQ ID NO: 107). It
is also to be appreciated that such amino acid sequences can be
attached to the N-terminus of the AV1 heavy chain or to the
C-terminus of the AV1 heavy or light chain.
[0160] Exemplary activatable antibodies of the disclosure include,
for example, antibodies that bind Epidermal Growth Factor Receptor
(EGFR) and that include a heavy chain and a light chain that are,
or are derived from, an antibody selected from the group consisting
of the antibody referred to herein as the "c225v5" antibody (also
referred to herein as the C225v5 antibody), the antibody referred
to herein as the "c225v4" antibody (also referred to herein as the
C225v4 antibody), and the antibody referred to herein as the
"c225v6" antibody (also referred to herein as the C225v6 antibody),
each of which binds EGFR. The c225v5 antibody, the c225v4 antibody,
and the c225v6 antibody share the same light chain sequence,
referred to herein as "c225 light chain." The amino acid sequences
for the c225v5 heavy chain, the c225v4 antibody, the c225v6
antibody, and the c225 light chain are shown below.
TABLE-US-00005 C225v5 Antibody Heavy Chain Amino Acid Sequence:
(SEQ ID NO: 108) QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV
IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALT
YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K C225v4 Antibody
Heavy Chain Amino Acid Sequence: (SEQ ID NO: 109)
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV
IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALT
YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK C225v6 Antibody
Heavy Chain Amino Acid Sequence: (SEQ ID NO: 110)
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV
IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALT
YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK C225 Antibody
Light Chain Amino Acid Sequence: (SEQ ID NO: 111)
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY
ASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGA
GTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC
[0161] Exemplary conjugated antibodies and/or activatable
antibodies of the disclosure include, for example, antibodies that
bind a Jagged target, e.g., Jagged-1, Jagged-2 and/or both Jagged-1
and Jagged-2, and that include a combination of a variable heavy
chain region and a variable light chain region that are, or are
derived from, the variable heavy chain and variable light chain
sequences shown below.
TABLE-US-00006 Variable Light Chain Amino Sequence Lc4 (SEQ ID NO:
112) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc4 (SEQ ID NO: 113)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc5 (SEQ ID
NO: 114) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc5 (SEQ ID NO: 115)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PYHGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc7 (SEQ ID
NO: 116) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc7 (SEQ ID NO: 117)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PFFGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc8 (SEQ ID
NO: 118) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc8 (SEQ ID NO: 119)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHI
GRTNPFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc13 (SEQ
ID NO: 120) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc13 (SEQ ID NO: 121)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable Light Chain Amino Sequence Lc16 (SEQ ID NO: 122)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc16 (SEQ ID NO: 123)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PYYGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc19 (SEQ
ID NO: 124) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc19 (SEQ ID NO: 125)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PFFGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc21 (SEQ
ID NO: 126) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc21 (SEQ ID NO: 127)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc24 (SEQ
ID NO: 128) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc24 (SEQ ID NO: 129)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEEMGWQTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable Light Chain Amino Sequence Lc26 (SEQ ID NO: 130)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc26 (SEQ ID NO: 131)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc27 (SEQ
ID NO: 132) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc27 (SEQ ID NO: 133)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PFYGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc28 (SEQ
ID NO: 134) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc28 (SEQ ID NO: 135)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PFFGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc30 (SEQ
ID NO: 136) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc30 (SEQ ID NO: 137)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEEMGWQTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYAKSAA AFDYWGQGTLVTVSS
Variable Light Chain Amino Sequence Lc31 (SEQ ID NO: 138)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc31 (SEQ ID NO: 139)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc32 (SEQ
ID NO: 140) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc32 (SEQ ID NO: 141)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDPEGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable Light Chain Amino Sequence Lc37 (SEQ ID NO: 142)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc37 (SEQ ID NO: 143)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PHNGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc39 (SEQ
ID NO: 144) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc39 (SEQ ID NO: 145)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable Light Chain Amino Sequence Lc40 (SEQ ID NO: 146)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR Heavy
Chain Amino Sequence Hc40 (SEQ ID NO: 147)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSP
PFFGQFDYWGQGTLVTVSS Variable Light Chain Amino Sequence Lc47 (SEQ
ID NO: 148) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQ GTKVEIKR
Variable Heavy Chain Amino Sequence Hc47 (SEQ ID NO: 149)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDEMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable 4B2 Light Chain (SEQ ID NO: 150)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTLDAPPQFGQ GTKVEIKR
Variable 4B2 Heavy Chain (SEQ ID NO: 151)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable 4D11 Light Chain (SEQ ID NO: 152)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQ GTKVEIKR
Variable 4D11 Heavy Chain (SEQ ID NO: 153)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable 4E7 Light Chain (SEQ ID NO: 154)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLVAPLTFGQ GTKVEIKR
Variable 4E7 Heavy Chain (SEQ ID NO: 155)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEEMGWQTKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable 4E11 Light Chain (SEQ ID NO: 156)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALDAPLMFGQ GTKVEIKR
Variable 4E11 Heavy Chain (SEQ ID NO: 157)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IEPMGQLTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSS Variable 6B7 Light Chain (SEQ ID NO: 158)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALVAPLTFGQ GTKVEIKR
Variable 6B7 Heavy Chain (SEQ ID NO: 159)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDEMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA AAFDYWGQGTLVTVSS
Variable 6F8 Light Chain (SEQ ID NO: 160)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALVAPLTFGQ GTKVEIKR
Variable 6F8 Heavy Chain (SEQ ID NO: 161)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDEMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSA
AAFDYWGQGTLVTVSS
[0162] Exemplary conjugated antibodies, activatable antibodies
and/or conjugated activatable antibodies of the disclosure include,
for example, antibodies that bind a Jagged target, e.g., Jagged-1,
Jagged-2 and/or both Jagged-1 and Jagged-2, and that include a
combination of a heavy chain region and a light chain region that
are, or are derived from, the heavy chain and light chain sequences
shown below.
TABLE-US-00007 4D11 Light Chain sequence: (SEQ ID NO: 162)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQ
GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC
4D11 Heavy Chain sequence: (SEQ ID NO: 67)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4D11v2 Heavy
Chain sequence (SEQ ID NO: 163)
EVHLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSS
IDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDI
GGRSAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4D11v2 Light
Chain Sequence (SEQ ID NO: 164)
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA
ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQ
GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLXKADYEKHKVYACEVTHQG
LSSPVTKSFNRGEC
[0163] The activatable antibodies and activatable antibody
compositions provided herein contain at least an antibody or
antibody fragment thereof (collectively referred to as AB
throughout the disclosure) that specifically binds a target, e.g.,
a human target, wherein the AB is modified by a masking moiety
(MM).
[0164] In some embodiments, the masking moiety is selected for use
with a specific antibody or antibody fragment. For example,
suitable masking moieties for use with antibodies that bind EGFR
include MMs that include the sequence CISPRG (SEQ ID NO: 165). By
way of non-limiting examples, the MM can include a sequence such as
CISPRGC (SEQ ID NO: 166); CISPRGCG (SEQ ID NO: 167);
CISPRGCPDGPYVMY (SEQ ID NO: 168); CISPRGCPDGPYVM (SEQ ID NO: 169),
CISPRGCEPGTYVPT (SEQ ID NO: 170) and CISPRGCPGQIWHPP (SEQ ID NO:
171). Other suitable masking moieties include any of the
EGFR-specific masks disclosed in PCT Publication No. WO
2010/081173, such as, by way of non-limiting example,
GSHCLIPINMGAPSC (SEQ ID NO: 172); CISPRGCGGSSASQSGQGSHCLIPINMGAPSC
(SEQ ID NO: 173); CNHHYFYTCGCISPRGCPG (SEQ ID NO: 174);
ADHVFWGSYGCISPRGCPG (SEQ ID NO: 175); CHHVYWGHCGCISPRGCPG (SEQ ID
NO: 176); CPHFTTTSCGCISPRGCPG (SEQ ID NO: 177); CNHHYHYYCGCISPRGCPG
(SEQ ID NO: 178); CPHVSFGSCGCISPRGCPG (SEQ ID NO: 179);
CPYYTLSYCGCISPRGCPG (SEQ ID NO: 180); CNHVYFGTCGCISPRGCPG (SEQ ID
NO: 181); CNHFTLTTCGCISPRGCPG (SEQ ID NO: 182); CHHFTLTTCGCISPRGCPG
(SEQ ID NO: 183); YNPCATPMCCISPRGCPG (SEQ ID NO: 184);
CNHHYFYTCGCISPRGCG (SEQ ID NO: 185); CNHHYHYYCGCISPRGCG (SEQ ID NO:
186); CNHVYFGTCGCISPRGCG (SEQ ID NO: 187); CHHVYWGHCGCISPRGCG (SEQ
ID NO: 188); CPHFTTTSCGCISPRGCG (SEQ ID NO: 189);
CNHFTLTTCGCISPRGCG (SEQ ID NO: 190); CHHFTLTTCGCISPRGCG (SEQ ID NO:
191); CPYYTLSYCGCISPRGCG (SEQ ID NO: 192); CPHVSFGSCGCISPRGCG (SEQ
ID NO: 193); ADHVFWGSYGCISPRGCG (SEQ ID NO: 194); YNPCATPMCCISPRGCG
(SEQ ID NO: 195); CHHVYWGHCGCISPRGCG (SEQ ID NO: 196);
C(N/P)H(H/V/FXY/TXF/W/T/L)(Y/G/T/SXT/S/Y/H)CGCISPRGCG (SEQ ID NO:
197); CISPRGCGQPIPSVK (SEQ ID NO: 198); CISPRGCTQPYHVSR (SEQ ID NO:
199); and/or CISPRGCNAVSGLGS (SEQ ID NO: 200).
[0165] Suitable masking moieties for use with antibodies that bind
a Jagged target, e.g., Jagged 1 and/or Jagged 2, include, by way of
non-limiting example, masking moieties that include a sequence such
as QGQSGQCNIWLVGGDCRGWQG (SEQ ID NO: 201);
QGQSGQGQQQWCNIWINGGDCRGWNG (SEQ ID NO: 202); PWCMQRQDFLRCPQP (SEQ
ID NO: 203); QLGLPAYMCTFECLR (SEQ ID NO: 204); CNLWVSGGDCGGLQG (SEQ
ID NO: 205); SCSLWTSGSCLPHSP (SEQ ID NO: 206); YCLQLPHYMQAMCGR (SEQ
ID NO: 207); CFLYSCTDVSYWNNT (SEQ ID NO: 208); PWCMQRQDYLRCPQP (SEQ
ID NO: 209); CNLWISGGDCRGLAG (SEQ ID NO: 210); CNLWVSGGDCRGVQG (SEQ
ID NO: 211); CNLWVSGGDCRGLRG (SEQ ID NO: 212); CNLWISGGDCRGLPG (SEQ
ID NO: 213); CNLWVSGGDCRDAPW (SEQ ID NO: 214); CNLWVSGGDCRDLLG (SEQ
ID NO: 215); CNLWVSGGDCRGLQG (SEQ ID NO: 216); CNLWLHGGDCRGWQG (SEQ
ID NO: 217); CNIWLVGGDCRGWQG (SEQ ID NO: 218); CTTWFCGGDCGVMRG (SEQ
ID NO: 219); CNIWGPSVDCGALLG (SEQ ID NO: 220); CNIWVNGGDCRSFEG (SEQ
ID NO: 221); YCLNLPRYMQDMCWA (SEQ ID NO: 222); YCLALPHYMQADCAR (SEQ
ID NO: 223); CFLYSCGDVSYWGSA (SEQ ID NO: 224); CYLYSCTDSAFWNNR (SEQ
ID NO: 225); CYLYSCNDVSYWSNT (SEQ ID NO: 226); CFLYSCTDVSYW (SEQ ID
NO: 227); CFLYSCTDVAYWNSA (SEQ ID NO: 228); CFLYSCTDVSYWGDT (SEQ ID
NO: 229); CFLYSCTDVSYWGNS (SEQ ID NO: 230); CFLYSCTDVAYWNNT (SEQ ID
NO: 231); CFLYSCGDVSYWGNPGLS (SEQ ID NO: 232); CFLYSCTDVAYWSGL (SEQ
ID NO: 233); CYLYSCTDGSYWNST (SEQ ID NO: 234); CFLYSCSDVSYWGNI (SEQ
ID NO: 235); CFLYSCTDVAYW (SEQ ID NO: 236); CFLYSCTDVSYWGST (SEQ ID
NO: 237); CFLYSCTDVAYWGDT (SEQ ID NO: 238); GCNIWLNGGDCRGWVDPLQG
(SEQ ID NO: 239); GCNIWLVGGDCRGWIGDTNG (SEQ ID NO: 240);
GCNIWLVGGDCRGWIEDSNG (SEQ ID NO: 241); GCNIWANGGDCRGWIDNIDG (SEQ ID
NO: 242); GCNIWLVGGDCRGWLGEAVG (SEQ ID NO: 243);
GCNIWLVGGDCRGWLEEAVG (SEQ ID NO: 244); GGPALCNIWLNGGDCRGWSG (SEQ ID
NO: 245); GAPVFCNIWLNGGDCRGWMG (SEQ ID NO: 246);
GQQQWCNIWINGGDCRGWNG (SEQ ID NO: 247); GKSEFCNIWLNGGDCRGWIG (SEQ ID
NO: 248); GTPGGCNIWANGGDCRGWEG (SEQ ID NO: 249);
GASQYCNLWINGGDCRGWRG (SEQ ID NO: 250); GCNIWLVGGDCRPWVEGG (SEQ ID
NO: 251); GCNIWAVGGDCRPFVDGG (SEQ ID NO: 252); GCNIWLNGGDCRAWVDTG
(SEQ ID NO: 253); GCNIWIVGGDCRPFINDG (SEQ ID NO: 254);
GCNIWLNGGDCRPVVFGG (SEQ ID NO: 255); GCNIWLSGGDCRMFMNEG (SEQ ID NO:
256); GCNIWVNGGDCRSFVYSG (SEQ ID NO: 257); GCNIWLNGGDCRGWEASG (SEQ
ID NO: 258); GCNIWAHGGDCRGFIEPG (SEQ ID NO: 259);
GCNIWLNGGDCRTFVASG (SEQ ID NO: 260); GCNIWAHGGDCRGFIEPG (SEQ ID NO:
261); GFLENCNIWLNGGDCRTG (SEQ ID NO: 262); GIYENCNIWLNGGDCRMG (SEQ
ID NO: 263); and/or GIPDNCNIWINGGDCRYG (SEQ ID NO: 264).
[0166] Suitable masking moieties for use with antibodies that bind
an interleukin 6 target, e.g., interleukin 6 receptor (IL-6R),
include, by way of non-limiting example, masking moieties that
include a sequence such as QGQSGQYGSCSWNYVHIFMDC (SEQ ID NO: 265);
QGQSGQGDFDIPFPAHWVPIT (SEQ ID NO: 266); QGQSGQMGVPAGCVWNYAHIFMDC
(SEQ ID NO: 267); YRSCNWNYVSIFLDC (SEQ ID NO: 268);
PGAFDIPFPAHWVPNT (SEQ ID NO: 269); ESSCVWNYVHIYMDC (SEQ ID NO:
270); YPGCKWNYDRIFLDC (SEQ ID NO: 271); YRTCSWNYVGIFLDC (SEQ ID NO:
272); YGSCSWNYVHIFMDC (SEQ ID NO: 273); YGSCSWNYVHIFLDC (SEQ ID NO:
274); YGSCNWNYVHIFLDC (SEQ ID NO: 275); YTSCNWNYVHIFMDC (SEQ ID NO:
276); YPGCKWNYDRIFLDC (SEQ ID NO: 277); WRSCNWNYAHIFLDC (SEQ ID NO:
278); WSNCHWNYVHIFLDC (SEQ ID NO: 279); DRSCTWNYVRISYDC (SEQ ID NO:
280); SGSCKWDYVHIFLDC (SEQ ID NO: 281); SRSCIWNYAHIHLDC (SEQ ID NO:
282); SMSCYWQYERIFLDC (SEQ ID NO: 283); YRSCNWNYVSIFLDC (SEQ ID NO:
284); SGSCKWDYVHIFLDC (SEQ ID NO: 285); YKSCHWDYVHIFLDC (SEQ ID NO:
286); YGSCTWNYVHIFMEC (SEQ ID NO: 287); FSSCNWNYVHIFLDC (SEQ ID NO:
288); WRSCNWNYAHIFLDC (SEQ ID NO: 289); YGSCQWNYVHIFLDC (SEQ ID NO:
290); YRSCNWNYVHIFLDC (SEQ ID NO: 291); NMSCHWDYVHIFLDC (SEQ ID NO:
292); FGPCTWNYARISWDC (SEQ ID NO: 293); XXsCXWXYvhIfXdC (SEQ ID NO:
294); MGVPAGCVWNYAHIFMDC (SEQ ID NO: 295); RDTGGQCRWDYVHIFMDC (SEQ
ID NO: 296); AGVPAGCTWNYVHIFMEC (SEQ ID NO: 297);
VGVPNGCVWNYAHIFMEC (SEQ ID NO: 298); DGGPAGCSWNYVHIFMEC (SEQ ID NO:
299); AVGPAGCWWNYVHIFMEC (SEQ ID NO: 300); CTWNYVHIFMDCGEGEGP (SEQ
ID NO: 301); GGVPEGCTWNYAHIFMEC (SEQ ID NO: 302);
AEVPAGCWWNYVHIFMEC (SEQ ID NO: 303); AGVPAGCTWNYVHIFMEC (SEQ ID NO:
304); SGASGGCKWNYVHIFMDC (SEQ ID NO: 305); TPGCRWNYVHIFMECEAL (SEQ
ID NO: 306); VGVPNGCVWNYAHIFMEC (SEQ ID NO: 307); PGAFDIPFPAHWVPNT
(SEQ ID NO: 308); RGACDIPFPAHWIPNT (SEQ ID NO: 309);
QGDFDIPFPAHWVPIT (SEQ ID NO: 310); XGafDIPFPAHWvPnT (SEQ ID NO:
311); RGDGNDSDIPFPAHWVPRT (SEQ ID NO: 312); SGVGRDRDIPFPAHWVPRT
(SEQ ID NO: 313); WAGGNDCDIPFPAHWIPNT (SEQ ID NO: 314);
WGDGMDVDIPFPAHWVPVT (SEQ ID NO: 315); AGSGNDSDIPFPAHWVPRT (SEQ ID
NO: 316); ESRSGYADIPFPAHWVPRT (SEQ ID NO: 317); and/or
RECGRCGDIPFPAHWVPRT (SEQ ID NO: 318).
[0167] When the AB is modified with a MM and is in the presence of
the target, specific binding of the AB to its target is reduced or
inhibited, as compared to the specific binding of the AB not
modified with an MM or the specific binding of the parental AB to
the target.
[0168] The K.sub.d of the AB modified with a MM towards the target
is at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000,
10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000,
50,000,000 or greater, or between 5-10, 10-100, 10-1,000,
10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000,
100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000,
1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000,
10,000-100,000, 10,000-1,000,000, 10,000-10,000,000,
100,000-1,000,000, or 100,000-10,000,000 times greater than the
K.sub.d of the AB not modified with an MM or of the parental AB
towards the target. Conversely, the binding affinity of the AB
modified with a MM towards the target is at least 2, 3, 4, 5, 10,
20, 25, 40, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000,
100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or
greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000,
10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000,
100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000,
1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000,
10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times
lower than the binding affinity of the AB not modified with an MM
or of the parental AB towards the target.
[0169] The dissociation constant (K.sub.d) of the MM towards the AB
is generally greater than the K.sub.d of the AB towards the target.
The K.sub.d of the MM towards the AB can be at least 5, 10, 25, 50,
100, 250, 500, 1,000, 2,500, 5,000, 10,000, 100,000, 1,000,000 or
even 10,000,000 times greater than the K.sub.d of the AB towards
the target. Conversely, the binding affinity of the MM towards the
AB is generally lower than the binding affinity of the AB towards
the target. The binding affinity of MM towards the AB can be at
least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000,
100,000, 1,000,000 or even 10,000,000 times lower than the binding
affinity of the AB towards the target.
[0170] When the AB is modified with a MM and is in the presence of
the target specific binding of the AB to its target is reduced or
inhibited, as compared to the specific binding of the AB not
modified with an MM or the specific binding of the parental AB to
the target. When compared to the binding of the AB not modified
with an MM or the binding of the parental AB to the target the AB's
ability to bind the target when modified with an MM can be reduced
by at least 50%, 60%, 70%, 80%, 90%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, 99% and even 100% for at least 2, 4, 6, 8, 12, 28, 24, 30, 36,
48, 60, 72, 84, or 96 hours, or 5, 10, 15, 30, 45, 60, 90, 120,
150, or 180 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
months or more when measured in vivo or in an in vitro assay.
[0171] The MM inhibits the binding of the AB to the target. The MM
binds the antigen binding domain of the AB and inhibits binding of
the AB to the target. The MM can sterically inhibit the binding of
the AB to the target. The MM can allosterically inhibit the binding
of the AB to its target. In these embodiments when the AB is
modified or coupled to a MM and in the presence of target there is
no binding or substantially no binding of the AB to the target, or
no more than 0.001%, 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,
9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% binding of the AB to
the target, as compared to the binding of the AB not modified with
an MM, the parental AB, or the AB not coupled to an MM to the
target, for at least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72,
84, or 96 hours, or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180
days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer
when measured in vivo or in an in vitro assay.
[0172] When an AB is coupled to or modified by a MM, the MM `masks`
or reduces or otherwise inhibits the specific binding of the AB to
the target. When an AB is coupled to or modified by a MM, such
coupling or modification can effect a structural change that
reduces or inhibits the ability of the AB to specifically bind its
target.
[0173] An AB coupled to or modified with an MM can be represented
by the following formulae (in order from an amino (N) terminal
region to carboxyl (C) terminal region: [0174] (MM)-(AB) [0175]
(AB)-(MM) [0176] (MM)-L-(AB) [0177] (AB)-L-(MM) where MM is a
masking moiety, the AB is an antibody or antibody fragment thereof,
and the L is a linker. In many embodiments, it may be desirable to
insert one or more linkers, e.g., flexible linkers, into the
composition so as to provide for flexibility.
[0178] In certain embodiments, the MM is not a natural binding
partner of the AB. In some embodiments, the MM contains no or
substantially no homology to any natural binding partner of the AB.
In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% similar to
any natural binding partner of the AB. In some embodiments, the MM
is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, or 80% identical to any natural binding
partner of the AB. In some embodiments, the MM is no more than 25%
identical to any natural binding partner of the AB. In some
embodiments, the MM is no more than 50% identical to any natural
binding partner of the AB. In some embodiments, the MM is no more
than 20% identical to any natural binding partner of the AB. In
some embodiments, the MM is no more than 10% identical to any
natural binding partner of the AB.
[0179] In some embodiments, the activatable antibodies include an
AB that is modified by an MM and also includes at least one
cleavable moiety (CM1) that is a substrate for at least one matrix
metalloprotease (MMP) and at least a second cleavable moiety (CM2)
that is a subject for at least one serine protease (SP). Such
activatable antibodies exhibit activatable/switchable binding, to
the AB's target. Activatable antibodies generally include an
antibody or antibody fragment (AB), modified by or coupled to a
masking moiety (MM) and a CM1-CM2 substrate.
[0180] The elements of the activatable antibodies are arranged so
that the MM and CM1-CM2 substrate are positioned such that in a
cleaved (or relatively active) state and in the presence of a
target, the AB binds a target while in an uncleaved (or relatively
inactive) state in the presence of the target, specific binding of
the AB to its target is reduced or inhibited. The specific binding
of the AB to its target can be reduced due to the inhibition or
masking of the AB's ability to specifically bind its target by the
MM.
[0181] The K.sub.d of the AB modified with a MM and a CM1-CM2
substrate towards the target is at least 5, 10, 20, 25, 40, 50,
100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000, 100,000,
500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or greater,
or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000,
10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000,
100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000,
1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000,
10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times
greater than the K.sub.d of the AB not modified with an MM and a
CM1-CM2 substrate or of the parental AB towards the target.
Conversely, the binding affinity of the AB modified with a MM and a
CM1-CM2 substrate towards the target is at least 2, 3, 4, 5, 10,
20, 25, 40, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000, 50,000,
100,000, 500,000, 1,000,000, 5,000,000, 10,000,000, 50,000,000 or
greater, or between 5-10, 10-100, 10-1,000, 10-10,000, 10-100,000,
10-1,000,000, 10-10,000,000, 100-1,000, 100-10,000, 100-100,000,
100-1,000,000, 100-10,000,000, 1,000-10,000, 1,000-100,000,
1,000-1,000,000, 1000-10,000,000, 10,000-100,000, 10,000-1,000,000,
10,000-10,000,000, 100,000-1,000,000, or 100,000-10,000,000 times
lower than the binding affinity of the AB not modified with an MM
and a CM1-CM2 substrate or of the parental AB towards the
target.
[0182] When the AB is modified with a MM and a CM1-CM2 substrate
and is in the presence of the target but not in the presence of a
modifying agent (for example a MMP and a SP), specific binding of
the AB to its target is reduced or inhibited, as compared to the
specific binding of the AB not modified with an MM and a CM1-CM2
substrate or of the parental AB to the target. When compared to the
binding of the parental AB or the binding of an AB not modified
with an MM and a CM1-CM2 substrate to its target, the AB's ability
to bind the target when modified with an MM and a CM1-CM2 substrate
can be reduced by at least 50%, 60%, 70%, 80%, 90%, 92%, 93%, 94%,
95%, 96%, 97%, 98%, 99% and even 100% for at least 2, 4, 6, 8, 12,
28, 24, 30, 36, 48, 60, 72, 84, or 96 hours or 5, 10, 15, 30, 45,
60, 90, 120, 150, or 180 days, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 months or longer when measured in vivo or in an in vitro
assay.
[0183] As used herein, the term cleaved state refers to the
condition of the activatable antibodies following modification,
i.e., cleavage, of the CM1-CM2 substrate by at least one matrix
metalloprotease and/or at least one serine protease. The term
uncleaved state or fully uncleaved, as used herein, refers to the
condition of the activatable antibodies in the absence of cleavage
of the CM1-CM2 substrate by a MMP and/or a SP. As discussed above,
the term "activatable antibodies" is used herein to refer to an
activatable antibody in both its uncleaved (native) state, as well
as in its cleaved state. An activatable antibody in its cleaved
state is also referred to herein as an activated antibody and/or
activated activatable antibody. It will be apparent to the
ordinarily skilled artisan that in some embodiments, a cleaved
activatable antibody may lack an MM due to cleavage of the CM1-CM2
substrate by protease, resulting in release of at least the MM.
[0184] By activatable or switchable is meant that the activatable
antibody exhibits a first level of binding to a target when in a
inhibited, masked or uncleaved state (i.e., a first conformation),
and a second level of binding to the target in the uninhibited,
unmasked and/or cleaved state (i.e., a second conformation), where
the second level of target binding is greater than the first level
of binding. In general, the access of target to the AB of the
activatable antibody is greater in the presence of a cleaving agent
capable of cleaving the CM1-CM2 substrate than in the absence of
such a cleaving agent. Thus, when the activatable antibody is in
the uncleaved state, the AB is inhibited from target binding and
can be masked from target binding (i.e., the first conformation is
such the AB cannot bind the target), and in the cleaved state the
AB is not inhibited or is unmasked to target binding.
[0185] The CM1-CM2 substrate and AB of the activatable antibodies
are selected so that the AB represents a binding moiety for a given
target, and the CM1-CM2 substrate represents a substrate for a MMP
and a SP, where the MMP and/or the SP are co-localized with the
target at a treatment site or diagnostic site in a subject. The
activatable antibodies disclosed herein find particular use where,
for example, a MMP and a SP, each capable of cleaving a site in the
CM1-CM2 substrate, are present at relatively higher levels in
target-containing tissue of a treatment site or diagnostic site
than in tissue of non-treatment sites (for example in healthy
tissue).
[0186] In some embodiments, activatable antibodies provide for
reduced toxicity and/or adverse side effects that could otherwise
result from binding of the AB at non-treatment sites if the AB were
not masked or otherwise inhibited from binding to the target.
[0187] In general, an activatable antibody can be designed by
selecting an AB of interest and constructing the remainder of the
activatable antibody so that, when conformationally constrained,
the MM provides for masking of the AB or reduction of binding of
the AB to its target. Structural design criteria can be to be taken
into account to provide for this functional feature.
[0188] Activatable antibodies exhibiting a switchable phenotype of
a desired dynamic range for target binding in an inhibited versus
an uninhibited conformation are provided. Dynamic range generally
refers to a ratio of (a) a maximum detected level of a parameter
under a first set of conditions to (b) a minimum detected value of
that parameter under a second set of conditions. For example, in
the context of an activatable antibody, the dynamic range refers to
the ratio of (a) a maximum detected level of target protein binding
to an activatable antibody in the presence of a MMP and a SP that
are capable of cleaving the CM1-CM2 substrate of the activatable
antibodies to (b) a minimum detected level of target protein
binding to an activatable antibody in the absence of the protease.
The dynamic range of an activatable antibody can be calculated as
the ratio of the dissociation constant of an activatable antibody
cleaving agent (e.g., enzyme) treatment to the dissociation
constant of the activatable antibodies cleaving agent treatment.
The greater the dynamic range of an activatable antibody, the
better the switchable phenotype of the activatable antibody.
Activatable antibodies having relatively higher dynamic range
values (e.g., greater than 1) exhibit more desirable switching
phenotypes such that target protein binding by the activatable
antibodies occurs to a greater extent (e.g., predominantly occurs)
in the presence of a cleaving agent (e.g., enzyme) capable of
cleaving the CM1-CM2 substrate of the activatable antibodies than
in the absence of a cleaving agent.
[0189] Activatable antibodies can be provided in a variety of
structural configurations. Exemplary formulae for activatable
antibodies are provided below. It is specifically contemplated that
the N- to C-terminal order of the AB, MM and CM1-CM2 substrate may
be reversed within an activatable antibody. It is also specifically
contemplated that the CM and MM may overlap in amino acid sequence,
e.g., such that the CM1-CM2 substrate is at least partially
contained within the MM.
[0190] For example, activatable antibodies can be represented by
the following formula (in order from an amino (N) terminal region
to carboxyl (C) terminal region: [0191] (MM)-(CM1-CM2
substrate)-(AB) [0192] (AB)-(CM1-CM2 substrate)-(MM) where MM is a
masking moiety, the CM1-CM2 substrate is a cleavable moiety, and AB
is an antibody or fragment thereof. As noted above, the term
"CM1-CM2 substrate" is not intended to convey any requirement
regarding the orientation or other structural arrangement of the
first cleavable moiety (CM1) that is a substrate for at least one
matrix metalloprotease (MMP) and at least a second cleavable moiety
(CM2) that is a substrate for at least one serine protease (SP).
Thus, the term "CM1-CM2 substrates" encompasses CM1-CM2 substrates
having the structural arrangement from N-terminus to C-terminus as
follows: CM1-CM2 or CM2-CM1. The term "CM1-CM2 substrates" also
encompasses substrates where at least a portion of the CM1 sequence
overlaps with at least a portion of the CM2 sequence. It should
also be noted that although MM and CM1-CM2 substrate are indicated
as distinct components in the formulae above, in all exemplary
embodiments (including formulae) disclosed herein it is
contemplated that the amino acid sequences of the MM and the
CM1-CM2 substrate could overlap, e.g., such that the CM1-CM2
substrate is completely or partially contained within the MM. In
addition, the formulae above provide for additional amino acid
sequences that may be positioned N-terminal or C-terminal to the
activatable antibodies elements.
[0193] In certain embodiments, the MM is not a natural binding
partner of the AB. In some embodiments, the MM contains no or
substantially no homology to any natural binding partner of the AB.
In some embodiments, the MM is no more than 5%, 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% similar to
any natural binding partner of the AB. In some embodiments, the MM
is no more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75%, or 80% identical to any natural binding
partner of the AB. In some embodiments, the MM is no more than 50%
identical to any natural binding partner of the AB. In some
embodiments, the MM is no more than 25% identical to any natural
binding partner of the AB. In some embodiments, the MM is no more
than 20% identical to any natural binding partner of the AB. In
some embodiments, the MM is no more than 10% identical to any
natural binding partner of the AB.
[0194] In many embodiments, it may be desirable to insert one or
more linkers, e.g., flexible linkers, into the activatable antibody
construct so as to provide for flexibility at one or more of the
MM-CM1-CM2 substrate junction, the CM1-CM2 substrate-AB junction,
or both. For example, the AB, MM, and/or CM1-CM2 substrate may not
contain a sufficient number of residues (e.g., Gly, Ser, Asp, Asn,
especially Gly and Ser, particularly Gly) to provide the desired
flexibility. As such, the switchable phenotype of such activatable
antibody constructs may benefit from introduction of one or more
amino acids to provide for a flexible linker. In addition, as
described below, where the activatable antibody is provided as a
conformationally constrained construct, a flexible linker can be
operably inserted to facilitate formation and maintenance of a
cyclic structure in the uncleaved activatable antibody.
[0195] For example, in certain embodiments, an activatable antibody
comprises one of the following formulae (where the formula below
represent an amino acid sequence in either N- to C-terminal
direction or C- to N-terminal direction): [0196] (MM)-L1-(CM1-CM2
substrate)-(AB) [0197] (MM)-(CM1-CM2 substrate)-L2-(AB) [0198]
(MM)-L1-(CM1-CM2 substrate)-L2-(AB) wherein MM, CM1-CM2 substrate,
and AB are as defined above; wherein L1 and L2 are each
independently and optionally present or absent, are the same or
different flexible linkers that include at least 1 flexible amino
acid (e.g., Gly). In addition, the formulae above provide for
additional amino acid sequences that may be positioned N-terminal
or C-terminal to the activatable antibodies elements. Examples
include, but are not limited to, targeting moieties (e.g., a ligand
for a receptor of a cell present in a target tissue) and serum
half-life extending moieties (e.g., polypeptides that bind serum
proteins, such as immunoglobulin (e.g., IgG) or serum albumin
(e.g., human serum albumin (HAS)).
[0199] The CM1-CM2 substrate is specifically cleaved by at least
one MMP at a rate of about 0.001-1500.times.10.sup.4
M.sup.-1S.sup.-1 or at least 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1,
2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, 100, 125, 150, 200, 250, 500,
750, 1000, 1250, or 1500.times.10.sup.4 M.sup.-1S.sup.-1 and is
specifically cleaved by at least one SP at a rate of about
0.001-1500.times.10.sup.4 M.sup.-1S.sup.-1 or at least 0.001,
0.005, 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5, 7.5, 10, 15, 20, 25, 50,
75, 100, 125, 150, 200, 250, 500, 750, 1000, 1250, or
1500.times.10.sup.4 M.sup.-1S.sup.-1.
[0200] For specific cleavage by an enzyme, contact between the
enzyme and CM1-CM2 substrate is made. When the activatable antibody
comprising an AB coupled to a MM and a CM1-CM2 substrate is in the
presence of target and sufficient enzyme activity, the CM1-CM2
substrate can be cleaved. Sufficient enzyme activity can refer to
the ability of the enzyme to make contact with the CM1-CM2
substrate and effect cleavage. It can readily be envisioned that an
enzyme may be in the vicinity of the CM1-CM2 substrate but unable
to cleave because of other cellular factors or protein modification
of the enzyme.
[0201] Linkers suitable for use in compositions described herein
are generally ones that provide flexibility of the modified AB or
the activatable antibodies to facilitate the inhibition of the
binding of the AB to the target. Such linkers are generally
referred to as flexible linkers. Suitable linkers can be readily
selected and can be of any of a suitable of different lengths, such
as from 1 amino acid (e.g., Gly) to 20 amino acids, from 2 amino
acids to 15 amino acids, from 3 amino acids to 12 amino acids,
including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino
acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino
acids, and may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, or 20 amino acids in length.
[0202] Exemplary flexible linkers include glycine polymers (G)n,
glycine-serine polymers (including, for example, (GS)n, (GSGGS)n
(SEQ ID NO: 381) and (GGGS)n (SEQ ID NO: 382), where n is an
integer of at least one), glycine-alanine polymers, alanine-serine
polymers, and other flexible linkers known in the art. Glycine and
glycine-serine polymers are relatively unstructured, and therefore
may be able to serve as a neutral tether between components.
Glycine accesses significantly more phi-psi space than even
alanine, and is much less restricted than residues with longer side
chains (see Scheraga, Rev. Computational Chem. 11173-142 (1992)).
Exemplary flexible linkers include, but are not limited to
Gly-Gly-Ser-Gly (SEQ ID NO: 383), Gly-Gly-Ser-Gly-Gly (SEQ ID NO:
384, Gly-Ser-Gly-Ser-Gly (SEQ ID NO: 385), Gly-Ser-Gly-Gly-Gly (SEQ
ID NO: 386), Gly-Gly-Gly-Ser-Gly (SEQ ID NO: 387),
Gly-Ser-Ser-Ser-Gly (SEQ ID NO: 388), and the like. The ordinarily
skilled artisan will recognize that design of an activatable
antibodies can include linkers that are all or partially flexible,
such that the linker can include a flexible linker as well as one
or more portions that confer less flexible structure to provide for
a desired activatable antibodies structure.
[0203] In some embodiments, the activatable antibodies described
herein also include an agent conjugated to the activatable
antibody. In some embodiments, the conjugated agent is a
therapeutic agent, such as an anti-inflammatory and/or an
antineoplastic agent. In such embodiments, the agent is conjugated
to a carbohydrate moiety of the activatable antibody, for example,
in some embodiments, where the carbohydrate moiety is located
outside the antigen-binding region of the antibody or
antigen-binding fragment in the activatable antibody. In some
embodiments, the agent is conjugated to a sulfhydryl group of the
antibody or antigen-binding fragment in the activatable
antibody.
[0204] In some embodiments, the agent is a cytotoxic agent such as
a toxin (e.g., an enzymatically active toxin of bacterial, fungal,
plant, or animal origin, or fragments thereof), or a radioactive
isotope (i.e., a radioconjugate).
[0205] In some embodiments, the agent is a detectable moiety such
as, for example, a label or other marker. For example, the agent is
or includes a radiolabeled amino acid, one or more biotinyl
moieties that can be detected by marked avidin (e.g., streptavidin
containing a fluorescent marker or enzymatic activity that can be
detected by optical or calorimetric methods), one or more
radioisotopes or radionuclides, one or more fluorescent labels, one
or more enzymatic labels, and/or one or more chemiluminescent
agents. In some embodiments, detectable moieties are attached by
spacer molecules.
[0206] The disclosure also pertains to immunoconjugates comprising
an antibody conjugated to a cytotoxic agent such as a toxin (e.g.,
an enzymatically active toxin of bacterial, fungal, plant, or
animal origin, or fragments thereof), or a radioactive isotope
(i.e., a radioconjugate). Suitable cytotoxic agents include, for
example, dolastatins and derivatives thereof (e.g. auristatin E,
AFP, MMAF, MMAE, MMAD, DMAF, DMAE). For example, the agent is
monomethyl auristatin E (MMAE) or monomethyl auristatin D (MMAD).
In some embodiments, the agent is an agent selected from the group
listed in Table 3. In some embodiments, the agent is a dolastatin.
In some embodiments, the agent is an auristatin or derivative
thereof. In some embodiments, the agent is auristatin E or a
derivative thereof. In some embodiments, the agent is monomethyl
auristatin E (MMAE). In some embodiments, the agent is monomethyl
auristatin D (MMAD). In some embodiments, the agent is a
maytansinoid or maytansinoid derivative. In some embodiments, the
agent is DM1 or DM4. In some embodiments, the agent is a
duocarmycin or derivative thereof. In some embodiments, the agent
is a calicheamicin or derivative thereof. In some embodiments, the
agent is a pyrrolobenzodiazepine. In some embodiments, the agent is
a pyrrolobenzodiazepine dimer.
[0207] In some embodiments, the agent is linked to the AB using a
maleimide caproyl-valine-citrulline linker or a maleimide
PEG-valine-citrulline linker. In some embodiments, the agent is
linked to the AB using a maleimide caproyl-valine-citrulline
linker. In some embodiments, the agent is linked to the AB using a
maleimide PEG-valine-citrulline linker In some embodiments, the
agent is monomethyl auristatin D (MMAD) linked to the AB using a
maleimide PEG-valine-citrulline-para-aminobenzyloxycarbonyl linker,
and this linker payload construct is referred to herein as
"vc-MMAD." In some embodiments, the agent is monomethyl auristatin
E (MMAE) linked to the AB using a maleimide
PEG-valine-citrulline-para-aminobenzyloxycarbonyl linker, and this
linker payload construct is referred to herein as "vc-MMAE." The
structures of vc-MMAD and vc-MMAE are shown below:
vc-MMAD:
##STR00001##
vc-MMAE:
##STR00002##
[0208] Enzymatically active toxins and fragments thereof that can
be used include diphtheria A chain, nonbinding active fragments of
diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa),
ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin,
Aleurites fordii proteins, dianthin proteins, Phytolaca americana
proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor,
curcin, crotin, sapaonaria officinalis inhibitor, gelonin,
mitogellin, restrictocin, phenomycin, enomycin, and the
tricothecenes. A variety of radionuclides are available for the
production of radioconjugated antibodies. Examples include
.sup.212Bi, .sup.131I, .sup.131In, .sup.90Y, and .sup.186Re.
[0209] Conjugates of the antibody and cytotoxic agent are made
using a variety of bifunctional protein-coupling agents such as
N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP),
iminothiolane (IT), bifunctional derivatives of imidoesters (such
as dimethyl adipimidate HCL), active esters (such as disuccinimidyl
suberate), aldehydes (such as glutareldehyde), bis-azido compounds
(such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium
derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine),
diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active
fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For
example, a ricin immunotoxin can be prepared as described in
Vitetta et al., Science 238: 1098 (1987). Carbon-14-labeled
1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid
(MX-DTPA) is an exemplary chelating agent for conjugation of
radionucleotide to the antibody. (See WO94/11026).
[0210] Table 3 lists some of the exemplary pharmaceutical agents
that may be employed in the herein described disclosure but in no
way is meant to be an exhaustive list.
TABLE-US-00008 TABLE 3 Exemplary Pharmaceutical Agents for
Conjugation CYTOTOXIC AGENTS Auristatins Auristatin E Monomethyl
auristatin D (MMAD) Monomethyl auristatin E (MMAE) Desmethyl
auristatin E (DMAE) Auristatin F Monomethyl auristatin F (MMAF)
Desmethyl auristatin F (DMAF) Auristatin derivatives, e.g., amides
thereof Auristatin tyramine Auristatin quinolone Dolastatins
Dolastatin derivatives Dolastatin 16 DmJ Dolastatin 16 Dpv
Maytansinoids, e.g. DM-1; DM-4 Maytansinoid derivatives Duocarmycin
Duocarmycin derivatives Alpha-amanitin Anthracyclines Doxorubicin
Daunorubicin Bryostatins Camptothecin Camptothecin derivatives
7-substituted Camptothecin 10,11-Difluoromethylenedioxycamptothecin
Combretastatins Debromoaplysiatoxin Kahalalide-F Discodermolide
Ecteinascidins ANTIVIRALS Acyclovir Vira A Symmetrel ANTIFUNGALS
Nystatin ADDITIONAL ANTI-NEOPLASTICS Adriamycin Cerubidine
Bleomycin Alkeran Velban Oncovin Fluorouracil Methotrexate Thiotepa
Bisantrene Novantrone Thioguanine Procarabizine Cytarabine
ANTI-BACTERIALS Aminoglycosides Streptomycin Neomycin Kanamycin
Amikacin Gentamicin Tobramycin Streptomycin B Spectinomycin
Ampicillin Sulfanilamide Polymyxin Chloramphenicol Turbostatin
Phenstatins Hydroxyphenstatin Spongistatin 5 Spongistatin 7
Halistatin 1 Halistatin 2 Halistatin 3 Modified Bryostatins
Halocomstatins Pyrrolobenzimidazoles (PBI) Cibrostatin6 Doxaliform
Anthracyclins analogues Cemadotin analogue (CemCH2-SH) Pseudomonas
toxin A (PE38) variant Pseudomonas toxin A (ZZ-PE38) variant ZJ-101
OSW-1 4-Nitrobenzyloxycarbonyl Derivatives of O6-Benzylguanine
Topoisomerase inhibitors Hemiasterlin Cephalotaxine
Homoharringtonine Pyrrolobenzodiazepine (PBD) Pyrrolobenzodiazepine
(PBD) dimers Functionalized pyrrolobenzodiazepenes Functionalized
pyrrolobenzodiazepene dimers Calicheamicins Podophyllotoxins
Taxanes Vinca alkaloids CONJUGATABLE DETECTION REAGENTS Fluorescein
and derivatives thereof Fluorescein isothiocyanate (FITC)
RADIOPHARMACEUTICALS .sup.125I .sup.131I .sup.89Zr .sup.111In
.sup.123I .sup.131I .sup.99mTc .sup.201Tl .sup.133Xe .sup.11C
.sup.62Cu .sup.18F .sup.68Ga .sup.13N .sup.15O .sup.38K .sup.82Rb
.sup.99mTc (Technetium) HEAVY METALS Barium Gold Platinum
ANTI-MYCOPLASMALS Tylosine Spectinomycin
[0211] Those of ordinary skill in the art will recognize that a
large variety of possible moieties can be coupled to the resultant
antibodies of the disclosure. (See, for example, "Conjugate
Vaccines", Contributions to Microbiology and Immunology, J. M.
Cruse and R. E. Lewis, Jr (eds), Carger Press, New York, (1989),
the entire contents of which are incorporated herein by
reference).
[0212] Coupling may be accomplished by any chemical reaction that
will bind the two molecules so long as the antibody and the other
moiety retain their respective activities. This linkage can include
many chemical mechanisms, for instance covalent binding, affinity
binding, intercalation, coordinate binding and complexation. In
some embodiments, the binding is, however, covalent binding.
Covalent binding can be achieved either by direct condensation of
existing side chains or by the incorporation of external bridging
molecules. Many bivalent or polyvalent linking agents are useful in
coupling protein molecules, such as the antibodies of the present
disclosure, to other molecules. For example, representative
coupling agents can include organic compounds such as thioesters,
carbodiimides, succinimide esters, diisocyanates, glutaraldehyde,
diazobenzenes and hexamethylene diamines. This listing is not
intended to be exhaustive of the various classes of coupling agents
known in the art but, rather, is exemplary of the more common
coupling agents. (See Killen and Lindstrom, Jour. Immun.
133:1335-2549 (1984); Jansen et al., Immunological Reviews
62:185-216 (1982); and Vitetta et al., Science 238:1098 (1987).
[0213] In some embodiments, in addition to the compositions and
methods provided herein, the conjugated activatable antibody can
also be modified for site-specific conjugation through modified
amino acid sequences inserted or otherwise included in the
activatable antibody sequence. These modified amino acid sequences
are designed to allow for controlled placement and/or dosage of the
conjugated agent within a conjugated activatable antibody. For
example, the activatable antibody can be engineered to include
cysteine substitutions at positions on light and heavy chains that
provide reactive thiol groups and do not negatively impact protein
folding and assembly, nor alter antigen binding. In some
embodiments, the activatable antibody can be engineered to include
or otherwise introduce one or more non-natural amino acid residues
within the activatable antibody to provide suitable sites for
conjugation. In some embodiments, the activatable antibody can be
engineered to include or otherwise introduce enzymatically
activatable peptide sequences within the activatable antibody
sequence.
[0214] Suitable linkers are described in the literature. (See, for
example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984)
describing use of MBS (M-maleimidobenzoyl-N-hydroxysuccinimide
ester). See also, U.S. Pat. No. 5,030,719, describing use of
halogenated acetyl hydrazide derivative coupled to an antibody by
way of an oligopeptide linker. In some embodiments, suitable
linkers include: (i) EDC (1-ethyl-3-(3-dimethylamino-propyl)
carbodiimide hydrochloride; (ii) SMPT
(4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pridyl-dithio)-toluene
(Pierce Chem. Co., Cat. (21558G); (iii) SPDP (succinimidyl-6
[3-(2-pyridyldithio) propionamido]hexanoate (Pierce Chem. Co., Cat
#21651G); (iv) Sulfo-LC-SPDP (sulfosuccinimidyl 6
[3-(2-pyridyldithio)-propianamide]hexanoate (Pierce Chem. Co. Cat.
#2165-G); and (v) sulfo-NHS (N-hydroxysulfo-succinimide: Pierce
Chem. Co., Cat. #24510) conjugated to EDC. Additional linkers
include, but are not limited to, SMCC, sulfo-SMCC, SPDB, or
sulfo-SPDB.
[0215] The linkers described above contain components that have
different attributes, thus leading to conjugates with differing
physio-chemical properties. For example, sulfo-NHS esters of alkyl
carboxylates are more stable than sulfo-NHS esters of aromatic
carboxylates. NHS-ester containing linkers are less soluble than
sulfo-NHS esters. Further, the linker SMPT contains a sterically
hindered disulfide bond, and can form conjugates with increased
stability. Disulfide linkages, are in general, less stable than
other linkages because the disulfide linkage is cleaved in vitro,
resulting in less conjugate available. Sulfo-NHS, in particular,
can enhance the stability of carbodimide couplings. Carbodimide
couplings (such as EDC) when used in conjunction with sulfo-NHS,
forms esters that are more resistant to hydrolysis than the
carbodimide coupling reaction alone.
[0216] In some embodiments, the linkers are cleavable. In some
embodiments, the linkers are non-cleavable. In some embodiments,
two or more linkers are present. The two or more linkers are all
the same, i.e., cleavable or non-cleavable, or the two or more
linkers are different, i.e., at least one cleavable and at least
one non-cleavable.
[0217] The present disclosure utilizes several methods for
attaching agents to ABs: (a) attachment to the carbohydrate
moieties of the AB, or (b) attachment to sulfhydryl groups of the
AB, or (c) attachment to amino groups of the AB, or (d) attachment
to carboxylate groups of the AB. According to the disclosure, ABs
may be covalently attached to an agent through an intermediate
linker having at least two reactive groups, one to react with AB
and one to react with the agent. The linker, which may include any
compatible organic compound, can be chosen such that the reaction
with AB (or agent) does not adversely affect AB reactivity and
selectivity. Furthermore, the attachment of linker to agent might
not destroy the activity of the agent. Suitable linkers for
reaction with oxidized antibodies or oxidized antibody fragments
include those containing an amine selected from the group
consisting of primary amine, secondary amine, hydrazine, hydrazide,
hydroxylamine, phenylhydrazine, semicarbazide and thiosemicarbazide
groups. Such reactive functional groups may exist as part of the
structure of the linker, or may be introduced by suitable chemical
modification of linkers not containing such groups.
[0218] According to the present disclosure, suitable linkers for
attachment to reduced ABs include those having certain reactive
groups capable of reaction with a sulfhydryl group of a reduced
antibody or fragment. Such reactive groups include, but are not
limited to: reactive haloalkyl groups (including, for example,
haloacetyl groups), p-mercuribenzoate groups and groups capable of
Michael-type addition reactions (including, for example, maleimides
and groups of the type described by Mitra and Lawton, 1979, J.
Amer. Chem. Soc. 101: 3097-3110).
[0219] According to the present disclosure, suitable linkers for
attachment to neither oxidized nor reduced Abs include those having
certain functional groups capable of reaction with the primary
amino groups present in unmodified lysine residues in the Ab. Such
reactive groups include, but are not limited to, NHS carboxylic or
carbonic esters, sulfo-NHS carboxylic or carbonic esters,
4-nitrophenyl carboxylic or carbonic esters, pentafluorophenyl
carboxylic or carbonic esters, acyl imidazoles, isocyanates, and
isothiocyanates.
[0220] According to the present disclosure, suitable linkers for
attachment to neither oxidized nor reduced Abs include those having
certain functional groups capable of reaction with the carboxylic
acid groups present in aspartate or glutamate residues in the Ab,
which have been activated with suitable reagents. Suitable
activating reagents include EDC, with or without added NHS or
sulfo-NHS, and other dehydrating agents utilized for carboxamide
formation. In these instances, the functional groups present in the
suitable linkers would include primary and secondary amines,
hydrazines, hydroxylamines, and hydrazides.
[0221] The agent may be attached to the linker before or after the
linker is attached to the AB. In certain applications it may be
desirable to first produce an AB-linker intermediate in which the
linker is free of an associated agent. Depending upon the
particular application, a specific agent may then be covalently
attached to the linker. In some embodiments, the AB is first
attached to the MM, CM1-CM2 substrate and associated linkers and
then attached to the linker for conjugation purposes.
[0222] Branched Linkers:
[0223] In specific embodiments, branched linkers that have multiple
sites for attachment of agents are utilized. For multiple site
linkers, a single covalent attachment to an AB would result in an
AB-linker intermediate capable of binding an agent at a number of
sites. The sites may be aldehyde or sulfhydryl groups or any
chemical site to which agents can be attached.
[0224] In some embodiments, higher specific activity (or higher
ratio of agents to AB) can be achieved by attachment of a single
site linker at a plurality of sites on the AB. This plurality of
sites may be introduced into the AB by either of two methods.
First, one may generate multiple aldehyde groups and/or sulfhydryl
groups in the same AB. Second, one may attach to an aldehyde or
sulfhydryl of the AB a "branched linker" having multiple functional
sites for subsequent attachment to linkers. The functional sites of
the branched linker or multiple site linker may be aldehyde or
sulfhydryl groups, or may be any chemical site to which linkers may
be attached. Still higher specific activities may be obtained by
combining these two approaches, that is, attaching multiple site
linkers at several sites on the AB.
[0225] Cleavable Linkers:
[0226] Peptide linkers that are susceptible to cleavage by enzymes
of the complement system, such as but not limited to urokinase,
tissue plasminogen activator, trypsin, plasmin, or another enzyme
having proteolytic activity may be used in one embodiment of the
present disclosure. According to one method of the present
disclosure, an agent is attached via a linker susceptible to
cleavage by complement. The antibody is selected from a class that
can activate complement. The antibody-agent conjugate, thus,
activates the complement cascade and releases the agent at the
target site. According to another method of the present disclosure,
an agent is attached via a linker susceptible to cleavage by
enzymes having a proteolytic activity such as a urokinase, a tissue
plasminogen activator, plasmin, or trypsin. These cleavable linkers
are useful in conjugated activatable antibodies that include an
extracellular toxin, e.g., by way of non-limiting example, any of
the extracellular toxins shown in Table 3.
[0227] Non-limiting examples of cleavable linker sequences are
provided in Table 4.
TABLE-US-00009 TABLE 4 Exemplary Linker Sequences for Conjugation
Types of Cleavable Sequences Amino Acid Sequence Plasmin cleavable
sequences Pro-urokinase PRFKIIGG (SEQ ID NO: 319) PRFRIIGG (SEQ ID
NO: 320) TGF.beta. SSRHRRALD (SEQ ID NO: 321) Plasminogen
RKSSIIIRMRDVVL (SEQ ID NO: 322) Staphylokinase SSSFDKGKYKKGDDA (SEQ
ID NO: 323) SSSFDKGKYKRGDDA (SEQ ID NO: 324) Factor Xa cleavable
sequences IEGR (SEQ ID NO: 325) IDGR (SEQ ID NO: 326) GGSIDGR (SEQ
ID NO: 327) MMP cleavable sequences Gelatinase A PLGLWA (SEQ ID NO:
328) Collagenase cleavable sequences Calf skin collagen
(.alpha.1(I) chain) GPQGIAGQ (SEQ ID NO: 329) Calf skin collagen
(.alpha.2(I) chain) GPQGLLGA (SEQ ID NO: 330) Bovine cartilage
collagen (.alpha.1(III) chain) GIAGQ (SEQ ID NO: 331) Human liver
collagen (.alpha.1(III) chain) GPLGIAGI (SEQ ID NO: 332) Human
.alpha..sub.2M GPEGLRVG (SEQ ID NO: 333) Human PZP YGAGLGVV (SEQ ID
NO: 334) AGLGVVER (SEQ ID NO: 335) AGLGISST (SEQ ID NO: 336) Rat
.alpha..sub.1M EPQALAMS (SEQ ID NO: 337) QALAMSAI (SEQ ID NO: 338)
Rat .alpha..sub.2M AAYHLVSQ (SEQ ID NO: 339) MDAFLESS (SEQ ID NO:
340) Rat .alpha..sub.1I.sub.3(2J) ESLPVVAV (SEQ ID NO: 341) Rat
.alpha..sub.1I.sub.3(27J) SAPAVESE (SEQ ID NO: 342) Human
fibroblast collagenase DVAQFVLT (SEQ ID NO: 343) (autolytic
cleavages) VAQFVLTE (SEQ ID NO: 344) AQFVLTEG (SEQ ID NO: 345)
PVQPIGPQ (SEQ ID NO: 346)
[0228] In addition, agents may be attached via disulfide bonds (for
example, the disulfide bonds on a cysteine molecule) to the AB.
Since many tumors naturally release high levels of glutathione (a
reducing agent) this can reduce the disulfide bonds with subsequent
release of the agent at the site of delivery. In certain specific
embodiments, the reducing agent that would modify a CM1-CM2
substrate would also modify the linker of the conjugated
activatable antibody.
[0229] Spacers and Cleavable Elements:
[0230] In some embodiments, it may be necessary to construct the
linker in such a way as to optimize the spacing between the agent
and the AB of the activatable antibody. This may be accomplished by
use of a linker of the general structure:
W--(CH.sub.2)n-Q
wherein W is either --NH--CH.sub.2-- or --CH.sub.2--; Q is an amino
acid, peptide; and n is an integer from 0 to 20.
[0231] In some embodiments, the linker may comprise a spacer
element and a cleavable element. The spacer element serves to
position the cleavable element away from the core of the AB such
that the cleavable element is more accessible to the enzyme
responsible for cleavage. Certain of the branched linkers described
above may serve as spacer elements.
[0232] Throughout this discussion, it should be understood that the
attachment of linker to agent (or of spacer element to cleavable
element, or cleavable element to agent) need not be particular mode
of attachment or reaction. Any reaction providing a product of
suitable stability and biological compatibility is acceptable.
[0233] Serum Complement and Selection of Linkers:
[0234] According to one method of the present disclosure, when
release of an agent is desired, an AB that is an antibody of a
class that can activate complement is used. The resulting conjugate
retains both the ability to bind antigen and activate the
complement cascade. Thus, according to this embodiment of the
present disclosure, an agent is joined to one end of the cleavable
linker or cleavable element and the other end of the linker group
is attached to a specific site on the AB. For example, if the agent
has an hydroxy group or an amino group, it may be attached to the
carboxy terminus of a peptide, amino acid or other suitably chosen
linker via an ester or amide bond, respectively. For example, such
agents may be attached to the linker peptide via a carbodimide
reaction. If the agent contains functional groups that would
interfere with attachment to the linker, these interfering
functional groups can be blocked before attachment and deblocked
once the product conjugate or intermediate is made. The opposite or
amino terminus of the linker is then used either directly or after
further modification for binding to an AB that is capable of
activating complement.
[0235] Linkers (or spacer elements of linkers) may be of any
desired length, one end of which can be covalently attached to
specific sites on the AB of the activatable antibody. The other end
of the linker or spacer element may be attached to an amino acid or
peptide linker.
[0236] Thus when these conjugates bind to antigen in the presence
of complement the amide or ester bond that attaches the agent to
the linker will be cleaved, resulting in release of the agent in
its active form. These conjugates, when administered to a subject,
will accomplish delivery and release of the agent at the target
site, and are particularly effective for the in vivo delivery of
pharmaceutical agents, antibiotics, antimetabolites,
antiproliferative agents and the like as presented in but not
limited to those in Table 3.
[0237] Linkers for Release without Complement Activation:
[0238] In yet another application of targeted delivery, release of
the agent without complement activation is desired since activation
of the complement cascade will ultimately lyse the target cell.
Hence, this approach is useful when delivery and release of the
agent should be accomplished without killing the target cell. Such
is the goal when delivery of cell mediators such as hormones,
enzymes, corticosteroids, neurotransmitters, genes or enzymes to
target cells is desired. These conjugates may be prepared by
attaching the agent to an AB that is not capable of activating
complement via a linker that is mildly susceptible to cleavage by
serum proteases. When this conjugate is administered to an
individual, antigen-antibody complexes will form quickly whereas
cleavage of the agent will occur slowly, thus resulting in release
of the compound at the target site.
[0239] Biochemical Cross Linkers:
[0240] In some embodiments, the activatable antibody may be
conjugated to one or more therapeutic agents using certain
biochemical cross-linkers. Cross-linking reagents form molecular
bridges that tie together functional groups of two different
molecules. To link two different proteins in a step-wise manner,
hetero-bifunctional cross-linkers can be used that eliminate
unwanted homopolymer formation.
[0241] Peptidyl linkers cleavable by lysosomal proteases are also
useful, for example, Val-Cit, Val-Ala or other dipeptides. In
addition, acid-labile linkers cleavable in the low-pH environment
of the lysosome may be used, for example: bis-sialyl ether. Other
suitable linkers include cathepsin-labile substrates, particularly
those that show optimal function at an acidic pH.
[0242] Exemplary hetero-bifunctional cross-linkers are referenced
in Table 5.
TABLE-US-00010 TABLE 5 Exemplary Hetero-Bifunctional Cross Linkers
HETERO-BIFUNCTIONAL CROSS-LINKERS Spacer Arm Length after
cross-linking Linker Reactive Toward Advantages and Applications
(Angstroms) SMPT Primary amines Greater stability 11.2 .ANG.
Sulfhydryls SPDP Primary amines Thiolation 6.8 .ANG. Sulfhydryls
Cleavable cross-linking LC-SPDP Primary amines Extended spacer arm
15.6 .ANG. Sulfhydryls Sulfo-LC-SPDP Primary amines Extender spacer
arm 15.6 .ANG. Sulfhydryls Water-soluble SMCC Primary amines Stable
maleimide reactive group 11.6 .ANG. Sulfhydryls Enzyme-antibody
conjugation Hapten-carrier protein conjugation Sulfo-SMCC Primary
amines Stable maleimide reactive group 11.6 .ANG. Sulfhydryls
Water-soluble Enzyme-antibody conjugation MBS Primary amines
Enzyme-antibody conjugation 9.9 .ANG. Sulfhydryls Hapten-carrier
protein conjugation Sulfo-MBS Primary amines Water-soluble 9.9
.ANG. Sulfhydryls SIAB Primary amines Enzyme-antibody conjugation
10.6 .ANG. Sulfhydryls Sulfo-SIAB Primary amines Water-soluble 10.6
.ANG. Sulfhydryls SMPB Primary amines Extended spacer arm 14.5
.ANG. Sulfhydryls Enzyme-antibody conjugation Sulfo-SMPB Primary
amines Extended spacer arm 14.5 .ANG. Sulfhydryls Water-soluble
EDE/Sulfo-NHS Primary amines Hapten-Carrier conjugation 0 Carboxyl
groups ABH Carbohydrates Reacts with sugar groups 11.9 .ANG.
Nonselective
[0243] Non-Cleavable Linkers or Direct Attachment:
[0244] In some embodiments of the disclosure, the conjugate may be
designed so that the agent is delivered to the target but not
released. This may be accomplished by attaching an agent to an AB
either directly or via a non-cleavable linker.
[0245] These non-cleavable linkers may include amino acids,
peptides, D-amino acids or other organic compounds that may be
modified to include functional groups that can subsequently be
utilized in attachment to ABs by the methods described herein.
A-general formula for such an organic linker could be
W--(CH.sub.2)n-Q
wherein W is either --NH--CH.sub.2-- or --CH.sub.2--; Q is an amino
acid, peptide; and n is an integer from 0 to 20.
[0246] Non-Cleavable Conjugates:
[0247] In some embodiments, a compound may be attached to ABs that
do not activate complement. When using ABs that are incapable of
complement activation, this attachment may be accomplished using
linkers that are susceptible to cleavage by activated complement or
using linkers that are not susceptible to cleavage by activated
complement.
[0248] The antibodies disclosed herein can also be formulated as
immunoliposomes. Liposomes containing the antibody are prepared by
methods known in the art, such as described in Epstein et al.,
Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc.
Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045
and 4,544,545. Liposomes with enhanced circulation time are
disclosed in U.S. Pat. No. 5,013,556.
[0249] Particularly useful liposomes can be generated by the
reverse-phase evaporation method with a lipid composition
comprising phosphatidylcholine, cholesterol, and PEG-derivatized
phosphatidylethanolamine (PEG-PE). Liposomes are extruded through
filters of defined pore size to yield liposomes with the desired
diameter. Fab' fragments of the antibody of the present disclosure
can be conjugated to the liposomes as described in Martin et al.,
J. Biol. Chem., 257; 286-288 (1982) via a disulfide-interchange
reaction.
DEFINITIONS
[0250] Unless otherwise defined, scientific and technical terms
used in connection with the present disclosure shall have the
meanings that are commonly understood by those of ordinary skill in
the art. The term "a" entity or "an" entity refers to one or more
of that entity. For example, a compound refers to one or more
compounds. As such, the terms "a", "an", "one or more" and "at
least one" can be used interchangeably. Further, unless otherwise
required by context, singular terms shall include pluralities and
plural terms shall include the singular. Generally, nomenclatures
utilized in connection with, and techniques of, cell and tissue
culture, molecular biology, and protein and oligo- or
polynucleotide chemistry and hybridization described herein are
those well-known and commonly used in the art. Standard techniques
are used for recombinant DNA, oligonucleotide synthesis, and tissue
culture and transformation (e.g., electroporation, lipofection).
Enzymatic reactions and purification techniques are performed
according to manufacturer's specifications or as commonly
accomplished in the art or as described herein. The foregoing
techniques and procedures are generally performed according to
conventional methods well known in the art and as described in
various general and more specific references that are cited and
discussed throughout the present specification. See e.g., Sambrook
et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)). The
nomenclatures utilized in connection with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic
organic chemistry, and medicinal and pharmaceutical chemistry
described herein are those well-known and commonly used in the art.
Standard techniques are used for chemical syntheses, chemical
analyses, pharmaceutical preparation, formulation, and delivery,
and treatment of patients.
[0251] As utilized in accordance with the present disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings:
[0252] As used herein, the term "antibody" refers to immunoglobulin
molecules and immunologically active portions of immunoglobulin
(Ig) molecules, i.e., molecules that contain an antigen binding
site that specifically binds (immunoreacts with) an antigen. By
"specifically bind" or "immunoreacts with" or "immunospecifically
bind" is meant that the antibody reacts with one or more antigenic
determinants of the desired antigen and does not react with other
polypeptides or binds at much lower affinity
(K.sub.d>10.sup.-6). Antibodies include, but are not limited to,
polyclonal, monoclonal, chimeric, domain antibody, single chain,
Fab, and F(ab').sub.2 fragments, scFvs, and an Fab expression
library.
[0253] The basic antibody structural unit is known to comprise a
tetramer. Each tetramer is composed of two identical pairs of
polypeptide chains, each pair having one "light" (about 25 kDa) and
one "heavy" chain (about 50-70 kDa). The amino-terminal portion of
each chain includes a variable region of about 100 to 110 or more
amino acids primarily responsible for antigen recognition. The
carboxy-terminal portion of each chain defines a constant region
primarily responsible for effector function. In general, antibody
molecules obtained from humans relate to any of the classes IgG,
IgM, IgA, IgE and IgD, which differ from one another by the nature
of the heavy chain present in the molecule. Certain classes have
subclasses as well, such as IgG.sub.1, IgG.sub.2, and others.
Furthermore, in humans, the light chain may be a kappa chain or a
lambda chain.
[0254] The term "monoclonal antibody" (mAb) or "monoclonal antibody
composition", as used herein, refers to a population of antibody
molecules that contain only one molecular species of antibody
molecule consisting of a unique light chain gene product and a
unique heavy chain gene product. In particular, the complementarity
determining regions (CDRs) of the monoclonal antibody are identical
in all the molecules of the population. MAbs contain an antigen
binding site capable of immunoreacting with a particular epitope of
the antigen characterized by a unique binding affinity for it.
[0255] The term "antigen-binding site" or "binding portion" refers
to the part of the immunoglobulin molecule that participates in
antigen binding. The antigen binding site is formed by amino acid
residues of the N-terminal variable ("V") regions of the heavy
("H") and light ("L") chains. Three highly divergent stretches
within the V regions of the heavy and light chains, referred to as
"hypervariable regions," are interposed between more conserved
flanking stretches known as "framework regions," or "FRs". Thus,
the term "FR" refers to amino acid sequences that are naturally
found between, and adjacent to, hypervariable regions in
immunoglobulins. In an antibody molecule, the three hypervariable
regions of a light chain and the three hypervariable regions of a
heavy chain are disposed relative to each other in three
dimensional space to form an antigen-binding surface. The
antigen-binding surface is complementary to the three-dimensional
surface of a bound antigen, and the three hypervariable regions of
each of the heavy and light chains are referred to as
"complementarity-determining regions," or "CDRs." The assignment of
amino acids to each domain is in accordance with the definitions of
Kabat Sequences of Proteins of Immunological Interest (National
Institutes of Health, Bethesda, Md. (1987 and 1991)), or Chothia
& Lesk J. Mol. Biol. 196:901-917 (1987), Chothia et al. Nature
342:878-883 (1989).
[0256] As used herein, the term "epitope" includes any protein
determinant capable of specific binding to an immunoglobulin, a
scFv, or a T-cell receptor. The term "epitope" includes any protein
determinant capable of specific binding to an immunoglobulin or
T-cell receptor.
[0257] Epitopic determinants usually consist of chemically active
surface groupings of molecules such as amino acids or sugar side
chains and usually have specific three dimensional structural
characteristics, as well as specific charge characteristics. For
example, antibodies may be raised against N-terminal or C-terminal
peptides of a polypeptide. An antibody is said to specifically bind
an antigen when the dissociation constant is .ltoreq.1 .mu.M; in
some embodiments, .ltoreq.100 nM and in some embodiments,
.ltoreq.10 nM.
[0258] As used herein, the terms "specific binding," "immunological
binding," and "immunological binding properties" refer to the
non-covalent interactions of the type that occur between an
immunoglobulin molecule and an antigen for which the immunoglobulin
is specific. The strength, or affinity of immunological binding
interactions can be expressed in terms of the dissociation constant
(K.sub.d) of the interaction, wherein a smaller K.sub.d represents
a greater affinity. Immunological binding properties of selected
polypeptides can be quantified using methods well known in the art.
One such method entails measuring the rates of antigen-binding
site/antigen complex formation and dissociation, wherein those
rates depend on the concentrations of the complex partners, the
affinity of the interaction, and geometric parameters that equally
influence the rate in both directions. Thus, both the "on rate
constant" (K.sub.on) and the "off rate constant" (K.sub.off) can be
determined by calculation of the concentrations and the actual
rates of association and dissociation. (See Nature 361:186-87
(1993)). The ratio of K.sub.off/K.sub.on enables the cancellation
of all parameters not related to affinity, and is equal to the
dissociation constant K.sub.d. (See, generally, Davies et al.
(1990) Annual Rev Biochem 59:439-473). An antibody of the present
disclosure is said to specifically bind to the target, when the
binding constant (K.sub.d) is .ltoreq.1 .mu.M, in some embodiments
.ltoreq.100 nM, in some embodiments .ltoreq.10 nM, and in some
embodiments .ltoreq.100 pM to about 1 pM, as measured by assays
such as radioligand binding assays or similar assays known to those
skilled in the art.
[0259] The term "isolated polynucleotide" as used herein shall mean
a polynucleotide of genomic, cDNA, or synthetic origin or some
combination thereof, which by virtue of its origin the "isolated
polynucleotide" (1) is not associated with all or a portion of a
polynucleotide in which the "isolated polynucleotide" is found in
nature, (2) is operably linked to a polynucleotide that it is not
linked to in nature, or (3) does not occur in nature as part of a
larger sequence. Polynucleotides in accordance with the disclosure
include the nucleic acid molecules encoding the heavy chain
immunoglobulin molecules shown herein, and nucleic acid molecules
encoding the light chain immunoglobulin molecules shown herein.
[0260] The term "isolated protein" referred to herein means a
protein of cDNA, recombinant RNA, or synthetic origin or some
combination thereof, which by virtue of its origin, or source of
derivation, the "isolated protein" (1) is not associated with
proteins found in nature, (2) is free of other proteins from the
same source, e.g., free of murine proteins, (3) is expressed by a
cell from a different species, or (4) does not occur in nature.
[0261] The term "polypeptide" is used herein as a generic term to
refer to native protein, fragments, or analogs of a polypeptide
sequence. Hence, native protein fragments, and analogs are species
of the polypeptide genus. Polypeptides in accordance with the
disclosure comprise the heavy chain immunoglobulin molecules shown
herein, and the light chain immunoglobulin molecules shown herein,
as well as antibody molecules formed by combinations comprising the
heavy chain immunoglobulin molecules with light chain
immunoglobulin molecules, such as kappa light chain immunoglobulin
molecules, and vice versa, as well as fragments and analogs
thereof.
[0262] The term "naturally-occurring" as used herein as applied to
an object refers to the fact that an object can be found in nature.
For example, a polypeptide or polynucleotide sequence that is
present in an organism (including viruses) that can be isolated
from a source in nature and that has not been intentionally
modified by man in the laboratory or otherwise is
naturally-occurring.
[0263] The term "operably linked" as used herein refers to
positions of components so described are in a relationship
permitting them to function in their intended manner. A control
sequence "operably linked" to a coding sequence is ligated in such
a way that expression of the coding sequence is achieved under
conditions compatible with the control sequences.
[0264] The term "control sequence" as used herein refers to
polynucleotide sequences that are necessary to effect the
expression and processing of coding sequences to which they are
ligated. The nature of such control sequences differs depending
upon the host organism in prokaryotes, such control sequences
generally include promoter, ribosomal binding site, and
transcription termination sequence in eukaryotes, generally, such
control sequences include promoters and transcription termination
sequence. The term "control sequences" is intended to include, at a
minimum, all components whose presence is essential for expression
and processing, and can also include additional components whose
presence is advantageous, for example, leader sequences and fusion
partner sequences. The term "polynucleotide" as referred to herein
means nucleotides of at least 10 bases in length, either
ribonucleotides or deoxynucleotides or a modified form of either
type of nucleotide. The term includes single and double stranded
forms of DNA.
[0265] The term oligonucleotide referred to herein includes
naturally occurring, and modified nucleotides linked together by
naturally occurring, and non-naturally occurring oligonucleotide
linkages. Oligonucleotides are a polynucleotide subset generally
comprising a length of 200 bases or fewer. In some embodiments,
oligonucleotides are 10 to 60 bases in length and in some
embodiments, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to 40 bases in
length. Oligonucleotides are usually single stranded, e.g., for
probes, although oligonucleotides may be double stranded, e.g., for
use in the construction of a gene mutant. Oligonucleotides of the
disclosure are either sense or antisense oligonucleotides.
[0266] The term "naturally occurring nucleotides" referred to
herein includes deoxyribonucleotides and ribonucleotides. The term
"modified nucleotides" referred to herein includes nucleotides with
modified or substituted sugar groups and the like. The term
"oligonucleotide linkages" referred to herein includes
oligonucleotide linkages such as phosphorothioate,
phosphorodithioate, phosphoroselerloate, phosphorodiselenoate,
phosphoroanilothioate, phoshoraniladate, phosphoronmidate, and the
like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081 (1986);
Stec et al. J. Am. Chem. Soc. 106:6077 (1984), Stein et al. Nucl.
Acids Res. 16:3209 (1988), Zon et al. Anti Cancer Drug Design 6:539
(1991); Zon et al. Oligonucleotides and Analogues: A Practical
Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University Press,
Oxford England (1991)); Stec et al. U.S. Pat. No. 5,151,510;
Uhlmann and Peyman Chemical Reviews 90:543 (1990). An
oligonucleotide can include a label for detection, if desired.
[0267] As used herein, the twenty conventional amino acids and
their abbreviations follow conventional usage. See Immunology--A
Synthesis (2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer
Associates. Sunderland 7 Mass. (1991)). Stereoisomers (e.g.,
D-amino acids) of the twenty conventional amino acids, unnatural
amino acids such as .alpha.-, .alpha.-disubstituted amino acids,
N-alkyl amino acids, lactic acid, and other unconventional amino
acids may also be suitable components for polypeptides of the
present disclosure. Examples of unconventional amino acids include:
4 hydroxyproline, .gamma.-carboxyglutamate, -N,N,N-trimethyllysine,
-N-acetyllysine, O-phosphoserine, N-acetylserine,
N-formylmethionine, 3-methylhistidine, 5-hydroxylysine,
.sigma.-N-methylarginine, and other similar amino acids and imino
acids (e.g., 4-hydroxyproline). In the polypeptide notation used
herein, the left-hand direction is the amino terminal direction and
the right-hand direction is the carboxy-terminal direction, in
accordance with standard usage and convention.
[0268] Similarly, unless specified otherwise, the left-hand end of
single-stranded polynucleotide sequences is the 5' end the
left-hand direction of double-stranded polynucleotide sequences is
referred to as the 5' direction. The direction of 5' to 3' addition
of nascent RNA transcripts is referred to as the transcription
direction sequence regions on the DNA strand having the same
sequence as the RNA and that are 5' to the 5' end of the RNA
transcript are referred to as "upstream sequences", sequence
regions on the DNA strand having the same sequence as the RNA and
that are 3' to the 3' end of the RNA transcript are referred to as
"downstream sequences".
[0269] As applied to polypeptides, the term "substantial identity"
means that two peptide sequences, when optimally aligned, such as
by the programs GAP or BESTFIT using default gap weights, share at
least 80 percent sequence identity, in some embodiments, at least
90 percent sequence identity, in some embodiments, at least 95
percent sequence identity, and in some embodiments, at least 99
percent sequence identity.
[0270] In some embodiments, residue positions that are not
identical differ by conservative amino acid substitutions.
[0271] As discussed herein, minor variations in the amino acid
sequences of antibodies or immunoglobulin molecules are
contemplated as being encompassed by the present disclosure,
providing that the variations in the amino acid sequence maintain
at least 75%, in some embodiments, at least 80%, 90%, 95%, and in
some embodiments, 99%. In particular, conservative amino acid
replacements are contemplated. Conservative replacements are those
that take place within a family of amino acids that are related in
their side chains. Genetically encoded amino acids are generally
divided into families: (1) acidic amino acids are aspartate,
glutamate; (2) basic amino acids are lysine, arginine, histidine;
(3) non-polar amino acids are alanine, valine, leucine, isoleucine,
proline, phenylalanine, methionine, tryptophan, and (4) uncharged
polar amino acids are glycine, asparagine, glutamine, cysteine,
serine, threonine, tyrosine. The hydrophilic amino acids include
arginine, asparagine, aspartate, glutamine, glutamate, histidine,
lysine, serine, and threonine. The hydrophobic amino acids include
alanine, cysteine, isoleucine, leucine, methionine, phenylalanine,
proline, tryptophan, tyrosine and valine. Other families of amino
acids include (i) serine and threonine, which are the
aliphatic-hydroxy family; (ii) asparagine and glutamine, which are
the amide containing family; (iii) alanine, valine, leucine and
isoleucine, which are the aliphatic family; and (iv) phenylalanine,
tryptophan, and tyrosine, which are the aromatic family. For
example, it is reasonable to expect that an isolated replacement of
a leucine with an isoleucine or valine, an aspartate with a
glutamate, a threonine with a serine, or a similar replacement of
an amino acid with a structurally related amino acid will not have
a major effect on the binding or properties of the resulting
molecule, especially if the replacement does not involve an amino
acid within a framework site. Whether an amino acid change results
in a functional peptide can readily be determined by assaying the
specific activity of the polypeptide derivative. Assays are
described in detail herein. Fragments or analogs of antibodies or
immunoglobulin molecules can be readily prepared by those of
ordinary skill in the art. Suitable amino- and carboxy-termini of
fragments or analogs occur near boundaries of functional domains.
Structural and functional domains can be identified by comparison
of the nucleotide and/or amino acid sequence data to public or
proprietary sequence databases. In some embodiments, computerized
comparison methods are used to identify sequence motifs or
predicted protein conformation domains that occur in other proteins
of known structure and/or function. Methods to identify protein
sequences that fold into a known three-dimensional structure are
known. Bowie et al. Science 253:164 (1991). Thus, the foregoing
examples demonstrate that those of skill in the art can recognize
sequence motifs and structural conformations that may be used to
define structural and functional domains in accordance with the
disclosure.
[0272] Suitable amino acid substitutions are those that: (1) reduce
susceptibility to proteolysis, (2) reduce susceptibility to
oxidation, (3) alter binding affinity for forming protein
complexes, (4) alter binding affinities, and (5) confer or modify
other physicochemical or functional properties of such analogs.
Analogs can include various muteins of a sequence other than the
naturally-occurring peptide sequence. For example, single or
multiple amino acid substitutions (for example, conservative amino
acid substitutions) may be made in the naturally-occurring sequence
(for example, in the portion of the polypeptide outside the
domain(s) forming intermolecular contacts. A conservative amino
acid substitution should not substantially change the structural
characteristics of the parent sequence (e.g., a replacement amino
acid should not tend to break a helix that occurs in the parent
sequence, or disrupt other types of secondary structure that
characterizes the parent sequence). Examples of art-recognized
polypeptide secondary and tertiary structures are described in
Proteins, Structures and Molecular Principles (Creighton, Ed., W.
H. Freeman and Company, New York (1984)); Introduction to Protein
Structure (C. Branden and J. Tooze, eds., Garland Publishing, New
York, N.Y. (1991)); and Thornton et at. Nature 354:105 (1991).
[0273] The term "polypeptide fragment" as used herein refers to a
polypeptide that has an amino terminal and/or carboxy-terminal
deletion and/or one or more internal deletion(s), but where the
remaining amino acid sequence is identical to the corresponding
positions in the naturally-occurring sequence deduced, for example,
from a full length cDNA sequence. Fragments typically are at least
5, 6, 8 or 10 amino acids long, in some embodiments, at least 14
amino acids long, in some embodiments, at least 20 amino acids
long, usually at least 50 amino acids long, and in some
embodiments, at least 70 amino acids long. The term "analog" as
used herein refers to polypeptides that are comprised of a segment
of at least 25 amino acids that has substantial identity to a
portion of a deduced amino acid sequence and that has specific
binding to the target, under suitable binding conditions.
Typically, polypeptide analogs comprise a conservative amino acid
substitution (or addition or deletion) with respect to the
naturally-occurring sequence. Analogs typically are at least 20
amino acids long, in some embodiments, at least 50 amino acids long
or longer, and can often be as long as a full-length
naturally-occurring polypeptide.
[0274] The term "agent" is used herein to denote a chemical
compound, a mixture of chemical compounds, a biological
macromolecule, or an extract made from biological materials.
[0275] As used herein, the terms "label" or "labeled" refers to
incorporation of a detectable marker, e.g., by incorporation of a
radiolabeled amino acid or attachment to a polypeptide of biotinyl
moieties that can be detected by marked avidin (e.g., streptavidin
containing a fluorescent marker or enzymatic activity that can be
detected by optical or calorimetric methods). In certain
situations, the label or marker can also be therapeutic. Various
methods of labeling polypeptides and glycoproteins are known in the
art and may be used. Examples of labels for polypeptides include,
but are not limited to, the following: radioisotopes or
radionuclides (e.g., .sup.3H, .sup.14C, .sup.15N, .sup.35S,
.sup.90Y, .sup.99Tc, .sup.111In, .sup.125I, .sup.131I), fluorescent
labels (e.g., FITC, rhodamine, lanthanide phosphors), enzymatic
labels (e.g., horseradish peroxidase, p-galactosidase, luciferase,
alkaline phosphatase), chemiluminescent, biotinyl groups,
predetermined polypeptide epitopes recognized by a secondary
reporter (e.g., leucine zipper pair sequences, binding sites for
secondary antibodies, metal binding domains, epitope tags). In some
embodiments, labels are attached by spacer arms of various lengths
to reduce potential steric hindrance. The term "pharmaceutical
agent or drug" as used herein refers to a chemical compound or
composition capable of inducing a desired therapeutic effect when
properly administered to a patient.
[0276] Other chemistry terms herein are used according to
conventional usage in the art, as exemplified by The McGraw-Hill
Dictionary of Chemical Terms (Parker, S., Ed., McGraw-Hill, San
Francisco (1985)).
[0277] As used herein, "substantially pure" means an object species
is the predominant species present (i.e., on a molar basis it is
more abundant than any other individual species in the
composition), and in some embodiments, a substantially purified
fraction is a composition wherein the object species comprises at
least about 50 percent (on a molar basis) of all macromolecular
species present.
[0278] Generally, a substantially pure composition will comprise
more than about 80 percent of all macromolecular species present in
the composition, in some embodiments, more than about 85%, 90%,
95%, and 99%. In some embodiments, the object species is purified
to essential homogeneity (contaminant species cannot be detected in
the composition by conventional detection methods) wherein the
composition consists essentially of a single macromolecular
species.
[0279] The term patient includes human and veterinary subjects.
[0280] Activatable antibodies of the disclosure specifically bind a
given target, e.g., a human target protein. Also included in the
disclosure are activatable antibodies that bind to the same epitope
as the activatable antibodies described herein.
[0281] Those skilled in the art will recognize that it is possible
to determine, without undue experimentation, if a monoclonal
antibody (e.g., a murine monoclonal or humanized antibody) has the
same specificity as a monoclonal antibody used in the methods
described herein by ascertaining whether the former prevents the
latter from binding to the target. If the monoclonal antibody being
tested competes with the monoclonal antibody of the disclosure, as
shown by a decrease in binding by the monoclonal antibody of the
disclosure, then the two monoclonal antibodies bind to the same, or
a closely related, epitope. A method for determining whether a
monoclonal antibody has the specificity of a monoclonal antibody of
the disclosure is to pre-incubate the monoclonal antibody of the
disclosure with the target and then add the monoclonal antibody
being tested to determine if the monoclonal antibody being tested
is inhibited in its ability to bind the target. If the monoclonal
antibody being tested is inhibited then, in all likelihood, it has
the same, or functionally equivalent, epitopic specificity as the
monoclonal antibody of the disclosure.
[0282] Multispecific Activatable Antibodies
[0283] The disclosure also provides multispecific activatable
antibodies. The multispecific activatable antibodies provided
herein are multispecific antibodies that recognize two or more
different antigens or epitopes and that include at least one
masking moiety (MM) linked to at least one antigen- or
epitope-binding domain of the multispecific antibody such that
coupling of the MM reduces the ability of the antigen- or
epitope-binding domain to bind its target. In some embodiments, the
MM is coupled to the antigen- or epitope-binding domain of the
multispecific antibody via a CM1-CM2 substrate that functions as a
substrate for at least one MMP protease and at least one SP. The
activatable multispecific antibodies provided herein are stable in
circulation, activated at intended sites of therapy and/or
diagnosis but not in normal, i.e., healthy tissue, and, when
activated, exhibit binding to a target that is at least comparable
to the corresponding, unmodified multispecific antibody.
[0284] In some embodiments, the multispecific activatable
antibodies are designed to engage immune effector cells, also
referred to herein as immune-effector cell engaging multispecific
activatable antibodies. In some embodiments, the multispecific
activatable antibodies are designed to engage leukocytes, also
referred to herein as leukocyte engaging multispecific activatable
antibodies. In some embodiments, the multispecific activatable
antibodies are designed to engage T cells, also referred to herein
as T-cell engaging multispecific activatable antibodies. In some
embodiments, the multispecific activatable antibodies engage a
surface antigen on a leukocyte, such as on a T cell, on a natural
killer (NK) cell, on a myeloid mononuclear cell, on a macrophage,
and/or on another immune effector cell. In some embodiments, the
immune effector cell is a leukocyte. In some embodiments, the
immune effector cell is a T cell. In some embodiments, the immune
effector cell is a NK cell. In some embodiments, the immune
effector cell is a mononuclear cell, such as a myeloid mononuclear
cell. In some embodiments, the multispecific activatable antibodies
are designed to bind or otherwise interact with more than one
target and/or more than one epitope, also referred to herein as
multi-antigen targeting activatable antibodies. As used herein, the
terms "target" and "antigen" are used interchangeably.
[0285] In some embodiments, immune effector cell engaging
multispecific activatable antibodies of the disclosure include a
targeting antibody or antigen-binding fragment thereof and an
immune effector cell engaging antibody or antigen-binding portion
thereof, where at least one of the targeting antibody or
antigen-binding fragment thereof and/or the immune effector cell
engaging antibody or antigen-binding portion thereof is masked. In
some embodiments, the immune effector cell engaging antibody or
antigen binding fragment thereof includes a first antibody or
antigen-binding fragment thereof (AB1) that binds a first, immune
effector cell engaging target, where the AB1 is attached to a
masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind the first target. In some embodiments,
the targeting antibody or antigen-binding fragment thereof includes
a second antibody or fragment thereof that includes a second
antibody or antigen-binding fragment thereof (AB2) that binds a
second target, where the AB2 is attached to a masking moiety (MM2)
such that coupling of the MM2 reduces the ability of the AB2 to
bind the second target. In some embodiments, the immune effector
cell engaging antibody or antigen binding fragment thereof includes
a first antibody or antigen-binding fragment thereof (AB1) that
binds a first, immune effector cell engaging target, where the AB1
is attached to a masking moiety (MM1) such that coupling of the MM1
reduces the ability of the AB1 to bind the first target, and the
targeting antibody or antigen-binding fragment thereof includes a
second antibody or fragment thereof that includes a second antibody
or antigen-binding fragment thereof (AB2) that binds a second
target, where the AB2 is attached to a masking moiety (MM2) such
that coupling of the MM2 reduces the ability of the AB2 to bind the
second target. In some embodiments, the non-immune effector cell
engaging antibody is a cancer targeting antibody. In some
embodiments the non-immune cell effector antibody is an IgG. In
some embodiments the immune effector cell engaging antibody is a
scFv. In some embodiments the targeting antibody (e.g., non-immune
cell effector antibody) is an IgG and the immune effector cell
engaging antibody is a scFv. In some embodiments, the immune
effector cell is a leukocyte. In some embodiments, the immune
effector cell is a T cell. In some embodiments, the immune effector
cell is a NK cell. In some embodiments, the immune effector cell is
a myeloid mononuclear cell.
[0286] In some embodiments, T-cell engaging multispecific
activatable antibodies of the disclosure include a targeting
antibody or antigen-binding fragment thereof and a T-cell engaging
antibody or antigen-binding portion thereof, where at least one of
the targeting antibody or antigen-binding fragment thereof and/or
the T-cell engaging antibody or antigen-binding portion thereof is
masked. In some embodiments, the T-cell engaging antibody or
antigen binding fragment thereof includes a first antibody or
antigen-binding fragment thereof (AB1) that binds a first, T-cell
engaging target, where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind the first target. In some embodiments, the targeting
antibody or antigen-binding fragment thereof includes a second
antibody or fragment thereof that includes a second antibody or
antigen-binding fragment thereof (AB2) that binds a second target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second target. In some embodiments, the T-cell engaging antibody or
antigen binding fragment thereof includes a first antibody or
antigen-binding fragment thereof (AB1) that binds a first, T-cell
engaging target, where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind the first target, and the targeting antibody or
antigen-binding fragment thereof includes a second antibody or
fragment thereof that includes a second antibody or antigen-binding
fragment thereof (AB2) that binds a second target, where the AB2 is
attached to a masking moiety (MM2) such that coupling of the MM2
reduces the ability of the AB2 to bind the second target.
[0287] In some embodiments, the T-cell engaging multispecific
activatable antibodies include a cancer targeting antibody or
antigen-binding fragment thereof and a T-cell engaging antibody or
antigen-binding portion thereof, where at least one of the cancer
targeting antibody or antigen-binding fragment thereof and/or the
T-cell engaging antibody or antigen-binding portion thereof is
masked. In some embodiments, the T-cell engaging antibody or
antigen binding fragment thereof includes a first antibody or
antigen-binding fragment thereof (AB1) that binds a first, T-cell
engaging target, where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind the first target. In some embodiments, the cancer targeting
antibody or antigen-binding fragment thereof includes a second
antibody or fragment thereof that includes a second antibody or
antigen-binding fragment thereof (AB2) that binds a second,
cancer-related target, where the AB2 is attached to a masking
moiety (MM2) such that coupling of the MM2 reduces the ability of
the AB2 to bind the second, cancer-related target. In some
embodiments, the T-cell engaging antibody or antigen binding
fragment thereof includes a first antibody or antigen-binding
fragment thereof (AB1) that binds a first, T-cell engaging target,
where the AB1 is attached to a masking moiety (MM1) such that
coupling of the MM1 reduces the ability of the AB1 to bind the
first target, and the cancer targeting antibody or antigen-binding
fragment thereof includes a second antibody or fragment thereof
that includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second, cancer-related target, where the AB2 is
attached to a masking moiety (MM2) such that coupling of the MM2
reduces the ability of the AB2 to bind the second, cancer-related
target.
[0288] In some embodiments, the T-cell engaging multispecific
activatable antibodies include a cancer targeting IgG antibody or
antigen-binding fragment thereof and a T-cell engaging scFv, where
at least one of the cancer targeting IgG antibody or
antigen-binding fragment thereof and/or the T-cell engaging
antibody or antigen-binding portion thereof is masked. In some
embodiments, the T-cell engaging antibody or antigen binding
fragment thereof includes a first antibody or antigen-binding
fragment thereof (AB1) that binds a first, T-cell engaging target,
where the AB1 is attached to a masking moiety (MM1) such that
coupling of the MM1 reduces the ability of the AB1 to bind the
first target. In some embodiments, the cancer targeting IgG
antibody or antigen-binding fragment thereof includes a second
antibody or fragment thereof that includes a second antibody or
antigen-binding fragment thereof (AB2) that binds a second,
cancer-related target, where the AB2 is attached to a masking
moiety (MM2) such that coupling of the MM2 reduces the ability of
the AB2 to bind the second, cancer-related target. In some
embodiments, the T-cell engaging antibody or antigen binding
fragment thereof includes a first antibody or antigen-binding
fragment thereof (AB1) that binds a first, T-cell engaging target,
where the AB1 is attached to a masking moiety (MM1) such that
coupling of the MM1 reduces the ability of the AB1 to bind the
first target, and the cancer targeting IgG antibody or
antigen-binding fragment thereof includes a second antibody or
fragment thereof that includes a second antibody or antigen-binding
fragment thereof (AB2) that binds a second, cancer-related target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second, cancer-related target.
[0289] In some embodiments of an immune effector cell engaging
multispecific activatable antibody, one antigen is typically an
antigen present on the surface of a tumor cell or other cell type
associated with disease, such as, but not limited to, any target
listed in Table 1, such as, but not limited to, EGFR, erbB2, EpCAM,
Jagged, PD-L, B7H3, or CD71 (transferrin receptor), and another
antigen is typically a stimulatory or inhibitory receptor present
on the surface of a T-cell, natural killer (NK) cell, myeloid
mononuclear cell, macrophage, and/or other immune effector cell,
such as, but not limited to, B7-H4, BTLA, CD3, CD4, CD8, CD16a,
CD25, CD27, CD28, CD32, CD56, CD137, CTLA-4, GITR, HVEM, ICOS,
LAG3, NKG2D, OX40, PD-1, TIGIT, TIM3, or VISTA. In some
embodiments, the antigen is a stimulatory receptor present on the
surface of a T cell or NK cell; examples of such stimulatory
receptors include, but are not limited to, CD3, CD27, CD28, CD137
(also referred to as 4-1BB), GITR, HVEM, ICOS, NKG2D, and OX40. In
some embodiments, the antigen is an inhibitory receptor present on
the surface of a T-cell; examples of such inhibitory receptors
include, but are not limited to, BTLA, CTLA-4, LAG3, PD-1, TIGIT.
TIM3, and NK-expressed KIRs. The antibody domain conferring
specificity to the T-cell surface antigen may also be substituted
by a ligand or ligand domain that binds to a T-cell receptor, a
NK-cell receptor, a macrophage receptor, and/or other immune
effector cell receptor, such as, but not limited to, B7-1, B7-2,
B7H3, PD-L1, PD-L2, or TNFSF9.
[0290] One embodiment of the disclosure is a multispecific
activatable antibody that is activatable in a cancer
microenvironment and that includes an antibody, for example a IgG
or scFv, directed to a tumor target and an agonist antibody, for
example an IgG or scFv, directed to a co-stimulatory receptor
expressed on the surface of an activated T cell or NK cell, wherein
at least one of the cancer target antibody and/or agonist antibody
is masked. Examples of co-stimulatory receptors include, but are
not limited to, CD27, CD137, GITR, HVEM, NKG2D, and OX40. In this
embodiment, the multispecific activatable antibody, once activated
by tumor-associated proteases, would effectively crosslink and
activate the T cell or NK cell expressed co-stimulatory receptors
in a tumor-dependent manner to enhance the activity of T cells that
are responding to any tumor antigen via their endogenous T cell
antigen or NK-activating receptors. The activation-dependent nature
of these T cell or NK cell costimulatory receptors would focus the
activity of the activated multispecific activatable antibody to
tumor-specific T cells, without activating all T cells independent
of their antigen specificity. In one embodiment, at least the
co-stimulatory receptor antibody of the multispecific activatable
antibody is masked to prevent activation of auto-reactive T cells
that may be present in tissues that also express the antigen
recognized by the tumor target-directed antibody in the
multispecific activatable antibody, but whose activity is
restricted by lack of co-receptor engagement.
[0291] One embodiment of the disclosure is a multispecific
activatable antibody that is activatable in a disease characterized
by T cell overstimulation, such as, but not limited to, an
autoimmune disease or inflammatory disease microenvironment. Such a
multispecific activatable antibody includes an antibody, for
example a IgG or scFv, directed to a target comprising a surface
antigen expressed in a tissue targeted by a T cell in autoimmune or
inflammatory disease and an antibody, for example a IgG or scFv,
directed to an inhibitory receptor expressed on the surface of a T
cell or NK cell, wherein at least one of the disease tissue target
antibody and/or T cell inhibitory receptor antibody is masked.
Examples of inhibitory receptors include, but are not limited to,
BTLA, CTLA-4, LAG3, PD-1, TIGIT, TIM3, and NK-expressed KIRs.
Examples of a tissue antigen targeted by T cells in autoimmune
disease include, but are not limited to, a surface antigen
expressed on myelin or nerve cells in multiple sclerosis or a
surface antigen expressed on pancreatic islet cells in Type 1
diabetes. In this embodiment, the multispecific activatable
antibody when localized in the tissue under autoimmune attack or
inflammation is activated and co-engages the T cell or NK cell
inhibitory receptor to suppress the activity of autoreactive T
cells responding to any disease tissue-targeted antigens via their
endogenous TCR or activating receptors. In one embodiment, at least
one or multiple antibodies are masked to prevent suppression of T
cell responses in non-disease tissues where the target antigen may
also be expressed.
[0292] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CD3 epsilon (CD3 , also
referred to herein as CD3 and CD3) scFv and a targeting antibody or
antigen-binding fragment thereof, where at least one of the
anti-CD3 scFv and/or the targeting antibody or antigen-binding
portion thereof is masked. In some embodiments, the CD3 scFv
includes a first antibody or antigen-binding fragment thereof (AB1)
that binds CD3 , where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind CD3 . In some embodiments, the targeting antibody or
antigen-binding fragment thereof includes a second antibody or
fragment thereof that includes a second antibody or antigen-binding
fragment thereof (AB2) that binds a second target, where the AB2 is
attached to a masking moiety (MM2) such that coupling of the MM2
reduces the ability of the AB2 to bind the second target. In some
embodiments, the CD3 scFv includes a first antibody or
antigen-binding fragment thereof (AB1) that binds CD3 , where the
AB1 is attached to a masking moiety (MM1) such that coupling of the
MM1 reduces the ability of the AB1 to bind CD3 , and the targeting
antibody or antigen-binding fragment thereof includes a second
antibody or fragment thereof that includes a second antibody or
antigen-binding fragment thereof (AB2) that binds a second target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second target.
[0293] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CD3 scFv and a cancer
targeting antibody or antigen-binding fragment thereof, where at
least one of the anti-CD3 scFv and/or the cancer targeting antibody
or antigen-binding portion thereof is masked. In some embodiments,
the CD3 scFv includes a first antibody or antigen-binding fragment
thereof (AB1) that binds CD3 , where the AB1 is attached to a
masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CD3 . In some embodiments, the cancer
targeting antibody or antigen-binding fragment thereof includes a
second antibody or fragment thereof that includes a second antibody
or antigen-binding fragment thereof (AB2) that binds a second,
cancer-related target, where the AB2 is attached to a masking
moiety (MM2) such that coupling of the MM2 reduces the ability of
the AB2 to bind the second, cancer-related target. In some
embodiments, the CD3 scFv includes a first antibody or
antigen-binding fragment thereof (AB1) that binds CD3 , where the
AB1 is attached to a masking moiety (MM1) such that coupling of the
MM1 reduces the ability of the AB1 to bind CD3 , and the cancer
targeting antibody or antigen-binding fragment thereof includes a
second antibody or fragment thereof that includes a second antibody
or antigen-binding fragment thereof (AB2) that binds a second,
cancer-related target, where the AB2 is attached to a masking
moiety (MM2) such that coupling of the MM2 reduces the ability of
the AB2 to bind the second, cancer-related target.
[0294] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CD3 scFv and a cancer
targeting IgG antibody or antigen-binding fragment thereof, where
at least one of the anti-CD3 scFv and/or the cancer targeting IgG
antibody or antigen-binding portion thereof is masked. In some
embodiments, the CD3 scFv includes a first antibody or
antigen-binding fragment thereof (AB1) that binds CD3 , where the
AB1 is attached to a masking moiety (MM1) such that coupling of the
MM1 reduces the ability of the AB1 to bind CD3 . In some
embodiments, the cancer targeting IgG antibody or antigen-binding
fragment thereof includes a second antibody or fragment thereof
that includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second, cancer-related target, where the AB2 is
attached to a masking moiety (MM2) such that coupling of the MM2
reduces the ability of the AB2 to bind the second, cancer-related
target. In some embodiments, the CD3 scFv includes a first antibody
or antigen-binding fragment thereof (AB1) that binds CD3 , where
the AB1 is attached to a masking moiety (MM1) such that coupling of
the MM1 reduces the ability of the AB1 to bind CD3 , and the cancer
targeting antibody IgG or antigen-binding fragment thereof includes
a second antibody or fragment thereof that includes a second
antibody or antigen-binding fragment thereof (AB2) that binds a
second, cancer-related target, where the AB2 is attached to a
masking moiety (MM2) such that coupling of the MM2 reduces the
ability of the AB2 to bind the second, cancer-related target.
[0295] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CD3 epsilon (CD3 ) scFv that
is derived from OKT3, where at least one of the targeting antibody
or antigen-binding fragment thereof and/or the OKT3 scFv or
OKT3-derived scFv is masked. In some embodiments, the OKT3 scFv or
OKT3-derived scFv includes a first antibody or antigen-binding
fragment thereof (AB1) that binds CD3 , where the AB1 is attached
to a masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CD3 . In some embodiments, the targeting
antibody or antigen-binding fragment thereof includes a second
antibody or fragment thereof that includes a second antibody or
antigen-binding fragment thereof (AB2) that binds a second target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second target. In some embodiments, the OKT3 scFv or OKT3-derived
scFv includes a first antibody or antigen-binding fragment thereof
(AB1) that binds CD3 , where the AB1 is attached to a masking
moiety (MM1) such that coupling of the MM1 reduces the ability of
the AB1 to bind CD3 , and the targeting antibody or antigen-binding
fragment thereof includes a second antibody or fragment thereof
that includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second target, where the AB2 is attached to a
masking moiety (MM2) such that coupling of the MM2 reduces the
ability of the AB2 to bind the second target.
[0296] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an OKT3 scFv or OKT3-derived scFv and
a cancer targeting antibody or antigen-binding fragment thereof,
where at least one of the OKT3 scFv or OKT3-derived scFv and/or the
cancer targeting antibody or antigen-binding portion thereof is
masked. In some embodiments, the OKT3 scFv or OKT3-derived scFv
includes a first antibody or antigen-binding fragment thereof (AB1)
that binds CD3 , where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind CD3 . In some embodiments, the cancer targeting antibody or
antigen-binding fragment thereof includes a second antibody or
fragment thereof that includes a second antibody or antigen-binding
fragment thereof (AB2) that binds a second, cancer-related target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second, cancer-related target. In some embodiments, the OKT3 scFv
or OKT3-derived scFv includes a first antibody or antigen-binding
fragment thereof (AB1) that binds CD3 , where the AB1 is attached
to a masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CD3 , and the cancer targeting antibody
or antigen-binding fragment thereof includes a second antibody or
fragment thereof that includes a second antibody or antigen-binding
fragment thereof (AB2) that binds a second, cancer-related target,
where the AB2 is attached to a masking moiety (MM2) such that
coupling of the MM2 reduces the ability of the AB2 to bind the
second, cancer-related target.
[0297] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an OKT3 scFv or OKT3-derived scFv and
a cancer targeting IgG antibody or antigen-binding fragment
thereof, where at least one of the OKT3 scFv or OKT3-derived scFv
and/or the cancer targeting IgG antibody or antigen-binding portion
thereof is masked. In some embodiments, the OKT3 scFv or
OKT3-derived scFv includes a first antibody or antigen-binding
fragment thereof (AB1) that binds CD3 , where the AB1 is attached
to a masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CD3 . In some embodiments, the cancer
targeting IgG antibody or antigen-binding fragment thereof includes
a second antibody or fragment thereof that includes a second
antibody or antigen-binding fragment thereof (AB2) that binds a
second, cancer-related target, where the AB2 is attached to a
masking moiety (MM2) such that coupling of the MM2 reduces the
ability of the AB2 to bind the second, cancer-related target. In
some embodiments, the OKT3 scFv or OKT3-derived scFv includes a
first antibody or antigen-binding fragment thereof (AB1) that binds
CD3 , where the AB1 is attached to a masking moiety (MM1) such that
coupling of the MM1 reduces the ability of the AB1 to bind CD3 ,
and the cancer targeting antibody IgG or antigen-binding fragment
thereof includes a second antibody or fragment thereof that
includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second, cancer-related target, where the AB2 is
attached to a masking moiety (MM2) such that coupling of the MM2
reduces the ability of the AB2 to bind the second, cancer-related
target.
[0298] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CTLA-4 scFv, where at least
one of the targeting antibody or antigen-binding fragment thereof
and/or the anti-CTLA-4 scFv is masked. In some embodiments, the
anti-CTLA-4 scFv includes a first antibody or antigen-binding
fragment thereof (AB1) that binds CTLA-4, where the AB1 is attached
to a masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CTLA-4. In some embodiments, the
targeting antibody or antigen-binding fragment thereof includes a
second antibody or fragment thereof that includes a second antibody
or antigen-binding fragment thereof (AB2) that binds a second
target, where the AB2 is attached to a masking moiety (MM2) such
that coupling of the MM2 reduces the ability of the AB2 to bind the
second target. In some embodiments, the anti-CTLA-4 scFv includes a
first antibody or antigen-binding fragment thereof (AB1) that binds
CTLA-4, where the AB1 is attached to a masking moiety (MM11) such
that coupling of the MM1 reduces the ability of the AB1 to bind
CTLA-4, and the targeting antibody or antigen-binding fragment
thereof includes a second antibody or fragment thereof that
includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second target, where the AB2 is attached to a
masking moiety (MM2) such that coupling of the MM2 reduces the
ability of the AB2 to bind the second target.
[0299] In some embodiments, the T-cell engaging multispecific
activatable antibody includes an anti-CTLA-4 scFv and a targeting
IgG antibody or antigen-binding fragment thereof, where at least
one of the anti-CTLA-4 scFv and/or the targeting IgG antibody or
antigen-binding portion thereof is masked. In some embodiments, the
anti-CTLA-4 scFv includes a first antibody or antigen-binding
fragment thereof (AB1) that binds CTLA-4, where the AB1 is attached
to a masking moiety (MM1) such that coupling of the MM1 reduces the
ability of the AB1 to bind CTLA-4. In some embodiments, the
targeting IgG antibody or antigen-binding fragment thereof includes
a second antibody or fragment thereof that includes a second
antibody or antigen-binding fragment thereof (AB2) that binds a
second target, where the AB2 is attached to a masking moiety (MM2)
such that coupling of the MM2 reduces the ability of the AB2 to
bind the second target. In some embodiments, the anti-CTLA-4 scFv
includes a first antibody or antigen-binding fragment thereof (AB1)
that binds CTLA-4, where the AB1 is attached to a masking moiety
(MM1) such that coupling of the MM1 reduces the ability of the AB1
to bind CTLA-4, and the targeting antibody IgG or antigen-binding
fragment thereof includes a second antibody or fragment thereof
that includes a second antibody or antigen-binding fragment thereof
(AB2) that binds a second target, where the AB2 is attached to a
masking moiety (MM2) such that coupling of the MM2 reduces the
ability of the AB2 to bind the second target.
[0300] In some embodiments, the multi-antigen targeting antibodies
and/or multi-antigen targeting activatable antibodies include at
least a first antibody or antigen-binding fragment thereof that
binds a first target and/or first epitope and a second antibody or
antigen-binding fragment thereof that binds a second target and/or
a second epitope. In some embodiments, the multi-antigen targeting
antibodies and/or multi-antigen targeting activatable antibodies
bind two or more different targets. In some embodiments, the
multi-antigen targeting antibodies and/or multi-antigen targeting
activatable antibodies bind two or more different epitopes on the
same target. In some embodiments, the multi-antigen targeting
antibodies and/or multi-antigen targeting activatable antibodies
bind a combination of two or more different targets and two or more
different epitopes on the same target.
[0301] In some embodiments, a multispecific activatable antibody
comprising an IgG has the IgG variable domains masked. In some
embodiments, a multispecific activatable antibody comprising a scFv
has the scFv domains masked. In some embodiments, a multispecific
activatable antibody has both IgG variable domains and scFv
domains, where at least one of the IgG variable domains is coupled
to a masking moiety. In some embodiments, a multispecific
activatable antibody has both IgG variable domains and scFv
domains, where at least one of the scFv domains is coupled to a
masking moiety. In some embodiments, a multispecific activatable
antibody has both IgG variable domains and scFv domains, where at
least one of the IgG variable domains is coupled to a masking
moiety and at least one of the scFv domains is coupled to a masking
moiety. In some embodiments, a multispecific activatable antibody
has both IgG variable domains and scFv domains, where each of the
IgG variable domains and the scFv domains is coupled to its own
masking moiety. In some embodiments, one antibody domain of a
multispecific activatable antibody has specificity for a target
antigen and another antibody domain has specificity for a T-cell
surface antigen. In some embodiments, one antibody domain of a
multispecific activatable antibody has specificity for a target
antigen and another antibody domain has specificity for another
target antigen. In some embodiments, one antibody domain of a
multispecific activatable antibody has specificity for an epitope
of a target antigen and another antibody domain has specificity for
another epitope of the target antigen.
[0302] In a multispecific activatable antibody, a scFv can be fused
to the carboxyl terminus of the heavy chain of an IgG activatable
antibody, to the carboxyl terminus of the light chain of an IgG
activatable antibody, or to the carboxyl termini of both the heavy
and light chains of an IgG activatable antibody. In a multispecific
activatable antibody, a scFv can be fused to the amino terminus of
the heavy chain of an IgG activatable antibody, to the amino
terminus of the light chain of an IgG activatable antibody, or to
the amino termini of both the heavy and light chains of an IgG
activatable antibody. In a multispecific activatable antibody, a
scFv can be fused to any combination of one or more carboxyl
termini and one or more amino termini of an IgG activatable
antibody. In some embodiments, a masking moiety (MM) linked to a
CM1-CM2 substrate is attached to and masks an antigen binding
domain of the IgG. In some embodiments, a masking moiety (MM)
linked to a CM1-CM2 substrate is attached to and masks an antigen
binding domain of at least one scFv. In some embodiments, a masking
moiety (MM) linked to a CM1-CM2 substrate is attached to and masks
an antigen binding domain of an IgG and a masking moiety (MM)
linked to a CM1-CM2 substrate is attached to and masks an antigen
binding domain of at least one scFv.
[0303] The disclosure provides examples of multispecific
activatable antibody structures that include, but are not limited
to, the following:
(VL-CL).sub.2:(VH-CH1-CH2-CH3-L4-VH*-L3-VL*-L2-CM1-CM2
substrate-L1-MM).sub.2;
(VL-CL).sub.2:(VH-CH1-CH2-CH3-L4-VL*-L3-VH*-L2-CM1-CM2
substrate-L1-MM).sub.2; (MM-L1-CM1-CM2
substrate-L2-VL-CL).sub.2:(VH-CH1-CH2-CH3-L4-VH*-L3-VL*).sub.2;
(MM-L1-CM1-CM2
substrate-L2-VL-CL).sub.2:(VH-CH1-CH2-CH3-L4-VL*-L3-VH*).sub.2;
(VL-CL).sub.2:(MM-L1-CM1-CM2
substrate-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL).sub.2:(MM-L1-CM1-CM2
substrate-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2; (MM-L1-CM1-CM2
substrate-L2-VL-CL).sub.2:(VL*-L3-VH*-L-VH-CH1-CH2-CH3).sub.2;
(MM-L1-CM1-CM2
substrate-L2-VL-CL).sub.2:(VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4A-VH*-L3-VL*-L2-CM1-CM2
substrate-L1-MM).sub.2:(VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VL*-L3-VH*-L2-CM1-CM2
substrate-L1-MM).sub.2:(VH-CH1-CH2-CH3).sub.2; (MM-L1-CM1-CM2
substrate-L2-VL*-L3-VH*-L4-VL-CL).sub.2:(VH-CH1-CH2-CH3).sub.2;
(MM-L1-CM1-CM2
substrate-L2-VH*-L3-VL*-L4-VL-CL).sub.2:(VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*-L2-CM1-CM2 substrate-L1-MM).sub.2:
(MM-L1-CM1-CM2 substrate-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*-L2-CM1-CM2 substrate-L I-MM).sub.2: (MM-L
I-CM1-CM2 substrate-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VL*-L3-VH*-L2-CM1-CM2 substrate-L1-MM).sub.2:
(MM-L1-CM1-CM2 substrate-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VL*-L3-VH*-L2-CM1-CM2 substrate-L1-MM).sub.2:
(MM-L1-CM1-CM2 substrate-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*).sub.2: (MM-L1-CM1-CM2
substrate-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*).sub.2: (MM-L1-CM1-CM2
substrate-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VL*-L3-VH*.sub.2: (MM-L1-CM1-CM2
substrate-L2-VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2,
(VL-CL-L4-VL*-L3-VH*).sub.2: (MM-L1-CM1-CM2
substrate-L2-VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*-L2-CM1-CM2 substrate-L-MM).sub.2:
(VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VH*-L3-VL*-L2-CM1-CM2 substrate-L1-MM).sub.2:
(VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2;
(VL-CL-L4-VL*-L3-VH*-L2-CM1-CM2 substrate-L-MM).sub.2:
(VL*-L3-VH*-L4-VH-CH1-CH2-CH3).sub.2; or
(VL-CL-L4-VL*-L3-VH*-L2-CM1-CM2 substrate-L1-MM).sub.2:
(VH*-L3-VL*-L4-VH-CH1-CH2-CH3).sub.2, wherein: VL and VH represent
the light and heavy variable domains of the first specificity,
contained in the IgG; VL* and VH* represent the variable domains of
the second specificity, contained in the scFv; L1 is a linker
peptide connecting the masking moiety (MM) and the CM1-CM2
substrate; L2 is a linker peptide connecting the CM1-CM2 substrate,
and the antibody; L3 is a linker peptide connecting the variable
domains of the scFv; L4 is a linker peptide connecting the antibody
of the first specificity to the antibody of the second specificity;
CL is the light-chain constant domain; and CH1, CH2, CH3 are the
heavy chain constant domains. The first and second specificities
may be toward any antigen or epitope.
[0304] In some embodiments of a T-cell engaging multispecific
activatable antibody, one antigen is typically an antigen present
on the surface of a tumor cell or other cell type associated with
disease, such as, but not limited to, any target listed in Table 1,
such as, but not limited to, EGFR, erbB2, EpCAM, Jagged, PD-L1,
B7H3, or CD71 (transferrin receptor), and another antigen is
typically a stimulatory (also referred to herein as activating) or
inhibitory receptor present on the surface of a T-cell, natural
killer (NK) cell, myeloid mononuclear cell, macrophage, and/or
other immune effector cell, such as, but not limited to, B7-H4,
BTLA, CD3, CD4, CD8, CD16a, CD25, CD27, CD28, CD32, CD56, CD137
(also referred to as TNFRSF9), CTLA-4, GITR, HVEM, ICOS, LAG3,
NKG2D, OX40, PD-1, TIGIT, TIM3, or VISTA. The antibody domain
conferring specificity to the T-cell surface antigen may also be
substituted by a ligand or ligand domain that binds to a T-cell
receptor, a NK-cell receptor, a macrophage receptor, and/or other
immune effector cell receptor, such as, but not limited to, B7-1,
B7-2, B7H3, PD-L1, PD-L2, or TNFSF9. In some embodiments of a
multi-antigen targeting activatable antibody, one antigen is
selected from the group of targets listed in Table 1, and another
antigen is selected from the group of targets listed in Table
1.
[0305] In some embodiments, the targeting antibody is an anti-EGFR
antibody. In some embodiments, the targeting antibody is C225v5,
which is specific for binding to EGFR. In some embodiments, the
targeting antibody is C225, which is specific for binding to EGFR.
In some embodiments, the targeting antibody is C225v4, which is
specific for binding to EGFR. In some embodiments, the targeting
antibody is C225v6, which is specific for binding to EGFR. In some
embodiments, the targeting antibody is an anti-Jagged antibody. In
some embodiments, the targeting antibody is 4D11, which is specific
for binding to human and mouse Jagged 1 and Jagged 2. In some
embodiments, the targeting antibody is 4D11v2, which is specific
for binding to human and mouse Jagged 1 and Jagged 2.
[0306] In some embodiments, the targeting antibody can be in the
form an activatable antibody. In some embodiments, the scFv(s) can
be in the form of a Pro-scFv (see, e.g., WO 2009/025846, WO
2010/081173).
[0307] In some embodiments, the scFv is specific for binding CD3 ,
and is or is derived from an antibody or fragment thereof that
binds CD3 , e.g., CH2527, FN18, H2C, OKT3, 2C11, UCHT1, or V9. In
some embodiments, the scFv is specific for binding CTLA-4 (also
referred to herein as CTLA and CTLA4).
[0308] In some embodiments, the anti-CTLA-4 scFv includes the amino
acid sequence:
TABLE-US-00011 (SEQ ID NO: 347)
GGGSGGGGSGSGGGSGGGGSGGGEIVLTQSPGTLSLSPGERATLSCRASQ
SVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTIS
RLEPEDFAVYYCQQYGSSPLTFGGGTKVEIKRSGGSTITSYNVYYTKLSS
SGTQVQLVQTGGGVVQPGRSLRLSCAASGSTFSSYAMSWVRQAPGKGLEW
VSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA
TNSLYWYFDLWGRGTLVTVSSAS
[0309] In some embodiments, the anti-CTLA-4 scFv includes the amino
acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99% or more identical to the amino acid sequence of SEQ
ID NO: 347.
[0310] In some embodiments, the anti-CD3 scFv includes the amino
acid sequence:
TABLE-US-00012 (SEQ ID NO: 349)
GGGSGGGGSGSGGGSGGGGSGGGQVQLQQSGAELARPGASVKMSCKASGY
TFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSS
TAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSSGGGGSGGG
GSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSP
KRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSN
PFTFGSGTKLEINR
[0311] In some embodiments, the anti-CD3 scFv includes the amino
acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99% or more identical to the amino acid sequence of SEQ
ID NO: 349.
[0312] In some embodiments, the scFv is specific for binding one or
more T-cells, one or more NK-cells and/or one or more macrophages.
In some embodiments, the scFv is specific for binding a target
selected from the group consisting of B7-H4, BTLA, CD3, CD4, CD8,
CD16a, CD25, CD27, CD28, CD32, CD56, CD137, CTLA-4, GITR, HVEM,
ICOS, LAG3, NKG2D, OX40, PD-1, TIGIT, TIM3, or VISTA.
[0313] In some embodiments, the multispecific activatable antibody
also includes an agent conjugated to the AB. In some embodiments,
the agent is a therapeutic agent. In some embodiments, the agent is
an antineoplastic agent. In some embodiments, the agent is a toxin
or fragment thereof. In some embodiments, the agent is conjugated
to the multispecific activatable antibody via a linker. In some
embodiments, the agent is conjugated to the AB via a cleavable
linker. In some embodiments, the agent is conjugated to the AB via
a linker that includes at least one CM1-CM2 substrate sequence. In
some embodiments, the linker is a non-cleavable linker. In some
embodiments, the agent is a microtubule inhibitor. In some
embodiments, the agent is a nucleic acid damaging agent, such as a
DNA alkylator or DNA intercalator, or other DNA damaging agent. In
some embodiments, the linker is a cleavable linker. In some
embodiments, the agent is an agent selected from the group listed
in Table 4. In some embodiments, the agent is a dolastatin. In some
embodiments, the agent is an auristatin or derivative thereof. In
some embodiments, the agent is auristatin E or a derivative
thereof. In some embodiments, the agent is monomethyl auristatin E
(MMAE). In some embodiments, the agent is monomethyl auristatin D
(MMAD). In some embodiments, the agent is a maytansinoid or
maytansinoid derivative. In some embodiments, the agent is DM1 or
DM4. In some embodiments, the agent is a duocarmycin or derivative
thereof. In some embodiments, the agent is a calicheamicin or
derivative thereof. In some embodiments, the agent is a
pyrrolobenzodiazepine. In some embodiments, the agent is a
pyrrolobenzodiazepine dimer.
[0314] In some embodiments, the multispecific activatable antibody
also includes a detectable moiety. In some embodiments, the
detectable moiety is a diagnostic agent.
[0315] In some embodiments, the multispecific activatable antibody
naturally contains one or more disulfide bonds. In some
embodiments, the multispecific activatable antibody can be
engineered to include one or more disulfide bonds.
[0316] The disclosure also provides an isolated nucleic acid
molecule encoding a multispecific activatable antibody described
herein, as well as vectors that include these isolated nucleic acid
sequences. The disclosure provides methods of producing a
multispecific activatable antibody by culturing a cell under
conditions that lead to expression of the activatable antibody,
wherein the cell comprises such a nucleic acid molecule. In some
embodiments, the cell comprises such a vector.
[0317] The disclosure also provides a method of manufacturing
multispecific activatable antibodies of the disclosure by (a)
culturing a cell comprising a nucleic acid construct that encodes
the multispecific activatable antibody under conditions that lead
to expression of the multispecific activatable, and (b) recovering
the multispecific activatable antibody.
[0318] The disclosure also provides multispecific activatable
antibodies and/or multispecific activatable antibody compositions
that include at least a first antibody or antigen-binding fragment
thereof (AB1) that specifically binds a first target or first
epitope and a second antibody or antigen-biding fragment thereof
(AB2) that binds a second target or a second epitope, where at
least AB1 is coupled or otherwise attached to a masking moiety
(MM1), such that coupling of the MM1 reduces the ability of AB1 to
bind its target. In some embodiments, the MM1 is coupled to AB1 via
a CM1-CM2 substrate for an MMP and a SP, where at least one of the
MMP and the SP is co-localized with the target of AB1 at a
treatment site or a diagnostic site in a subject. The multispecific
activatable antibodies provided herein are stable in circulation,
activated at intended sites of therapy and/or diagnosis but not in
normal, i.e., healthy tissue, and, when activated, exhibit binding
to the target of AB1 that is at least comparable to the
corresponding, unmodified multispecific antibody.
[0319] In some embodiments, the multispecific activatable antibody
comprises a linking peptide between the MM1 and the CM1-CM2
substrate.
[0320] In some embodiments, the multispecific activatable antibody
comprises a linking peptide between the CM1-CM2 substrate and the
AB1.
[0321] In some embodiments, the activatable antibody comprises a
first linking peptide (LP1) and a second linking peptide (LP2), and
at least a portion of the multispecific activatable antibody has
the structural arrangement from N-terminus to C-terminus as follows
in the uncleaved state: MM1-LP1-CM1-CM2 substrate-LP2-AB1 or
AB1-LP2-CM1-CM2 substrate-LP1-MM1. In some embodiments, the two
linking peptides need not be identical to each other.
[0322] In some embodiments, at least one of LP1 or LP2 includes an
amino acid sequence selected from the group consisting of
(GS).sub.n, (GGS).sub.n, (GSGGS).sub.n (SEQ ID NO: 381) and
(GGGS).sub.n (SEQ ID NO: 382), where n is an integer of at least
one. In some embodiments, at least one of LP1 or LP2 includes an
amino acid sequence selected from the group consisting of GGSG (SEQ
ID NO: 383), GGSGG (SEQ ID NO: 384), GSGSG (SEQ ID NO: 385), GSGGG
(SEQ ID NO: 386), GGGSG (SEQ ID NO: 387), and GSSSG (SEQ ID NO:
388).
[0323] In some embodiments, the activatable antibody includes a
linking peptide (LP') between CM1 and CM2.
[0324] In some embodiments, the activatable antibody comprises a
first linking peptide (LP1), a second linking peptide (LP2), and a
linking peptide (LP') between CM1 and CM2, and at least a portion
of the multispecific activatable antibody has the structural
arrangement from N-terminus to C-terminus as follows in the
uncleaved state: MM1-LP1-CM1-CM2 substrate-LP2-AB1 or
AB1-LP2-CM1-CM2 substrate-LP1-MM1. In some embodiments, linking
peptides need not be identical to each other.
[0325] In some embodiments, LP' is GG. In some embodiments, LP' is
GGSGGS (SEQ ID NO: 350).
[0326] In some embodiments, the multispecific activatable antibody
includes at least a first antibody or antigen-binding fragment
thereof (AB1) that specifically binds a first target or first
epitope and a second antibody or antigen-binding fragment thereof
(AB2) that specifically binds a second target or second epitope. In
some embodiments, each of the AB in the multispecific activatable
antibody is independently selected from the group consisting of a
monoclonal antibody, domain antibody, single chain, Fab fragment, a
F(ab').sub.2 fragment, a scFv, a scAb, a dAb, a single domain heavy
chain antibody, and a single domain light chain antibody. In some
embodiments, each of the AB in the multispecific activatable
antibody is a rodent (e.g., mouse or rat), chimeric, humanized or
fully human monoclonal antibody.
[0327] In some embodiments, each of the AB in the multispecific
activatable antibody has a dissociation constant of about 100 nM or
less for binding to its corresponding target or epitope.
[0328] In some embodiments, MM1 has a dissociation constant for
binding to its corresponding AB that is greater than the
dissociation constant of the AB to its corresponding target or
epitope.
[0329] In some embodiments, MM1 has a dissociation constant for
binding to its corresponding AB that is no more than the
dissociation constant of the AB to its corresponding target or
epitope.
[0330] In some embodiments, MM1 does not interfere or compete with
its corresponding AB for binding to the corresponding target or
epitope when the multispecific activatable antibody is in a cleaved
state.
[0331] In some embodiments, MM1 is a polypeptide of about 2 to 40
amino acids in length. In some embodiments, each of the MM in the
multispecific activatable antibody is a polypeptide of no more than
40 amino acids in length.
[0332] In some embodiments, MM1 has a polypeptide sequence that is
different from that of target of the corresponding AB.
[0333] In some embodiments, MM1 has a polypeptide sequence that is
no more than 50% identical to any natural binding partner of the
corresponding AB. In some embodiments, MM1 has a polypeptide
sequence that is no more than 25% identical to any natural binding
partner of the corresponding AB. In some embodiments, MM1 has a
polypeptide sequence that is no more than 100% identical to any
natural binding partner of the corresponding AB.
[0334] In some embodiments, the coupling of MM1 reduces the ability
of the corresponding AB to bind its target or epitope such that the
dissociation constant (K.sub.d) of the AB when coupled to the MM1
towards its corresponding target or epitope is at least 20 times
greater than the K.sub.d of the AB when not coupled to the MM1
towards its corresponding target or epitope.
[0335] In some embodiments, the coupling of MM1 reduces the ability
of the corresponding AB to bind its target or epitope such that the
dissociation constant (K.sub.d) of the AB when coupled to the MM1
towards its corresponding target or epitope is at least 40 times
greater than the K.sub.d of the AB when not coupled to the MM1
towards its corresponding target or epitope.
[0336] In some embodiments, the coupling of MM1 reduces the ability
of the corresponding AB to bind its target or epitope such that the
dissociation constant (K.sub.d) of the AB when coupled to the MM1
towards its corresponding target or epitope is at least 100 times
greater than the K.sub.d of the AB when not coupled to the MM1
towards its corresponding target or epitope.
[0337] In some embodiments, the coupling of MM1 reduces the ability
of the corresponding AB to bind its target or epitope such that the
dissociation constant (K.sub.d) of the AB when coupled to the MM1
towards its corresponding target or epitope is at least 1000 times
greater than the K.sub.d of the AB when not coupled to the MM1
towards its corresponding target or epitope.
[0338] In some embodiments, the coupling of MM1 reduces the ability
of the corresponding AB to bind its target or epitope such that the
dissociation constant (K.sub.d) of the AB when coupled to the MM1
towards its corresponding target or epitope is at least 10,000
times greater than the K.sub.d of the AB when not coupled to the
MM1 towards its corresponding target or epitope.
[0339] In some embodiments, MM1 is an amino acid sequence selected
from a MM disclosed herein.
[0340] In some embodiments, the multispecific activatable antibody
includes at least a second masking moiety (MM2) that inhibits the
binding of the AB2 to its target when the multispecific activatable
antibody is in an uncleaved state, and an additional cleavable
moiety (CM') coupled to the AB2, wherein the CM' is either a
CM1-CM2 substrate or a polypeptide that functions as a substrate
for a second protease. In some embodiments, CM' is a polypeptide of
no more than 15 amino acids long. In some embodiments, CM' is a
CM1-CM2 substrate, wherein each of CM1 and CM2 in the CM1-CM2
substrate is independently no more than 15 amino acids long.
[0341] In some embodiments, the MMP protease, the SP protease,
and/or the second protease is co-localized with the second target
or epitope in a tissue, and wherein the MMP protease, the SP
protease, and/or the second protease cleaves the CM' in the
multispecific activatable antibody when the multispecific
activatable antibody is exposed to the MMP protease, the SP
protease, and/or the second protease. In some embodiments, the MMP
protease, the SP protease, and/or the second protease are
co-localized with the first target or epitope and the second target
or epitope in a tissue. In some embodiments, the MMP protease, the
SP protease, and/or the second protease are the same MMP protease
and the same SP protease. In some embodiments, the MMP protease,
the SP protease, and/or the second protease are not the same MMP
protease and not the same SP protease. In some embodiments, the
CM1-CM2 substrate and CM' are different substrates for the same MMP
protease and same SP protease. In some embodiments, the protease
that cleaves CM' is selected from the group consisting of those
shown in Table 6.
[0342] In some embodiments, each of the MM in the multispecific
activatable antibody, e.g., MM1 and at least MM2, has a
dissociation constant for binding to its corresponding AB that is
greater than the dissociation constant of the AB to its
corresponding target or epitope.
[0343] In some embodiments, each of the MM in the multispecific
activatable antibody has a dissociation constant for binding to its
corresponding AB that is no more than the dissociation constant of
the AB to its corresponding target or epitope.
[0344] In some embodiments, each of the MM in the multispecific
activatable antibody does not interfere or compete with its
corresponding AB for binding to the corresponding target or epitope
when the multispecific activatable antibody is in a cleaved
state.
[0345] In some embodiments, each of the MM in the multispecific
activatable antibody is a polypeptide of about 2 to 40 amino acids
in length. In some embodiments, each of the MM in the multispecific
activatable antibody is a polypeptide of no more than 40 amino
acids in length.
[0346] In some embodiments, each of the MM in the multispecific
activatable antibody has a polypeptide sequence that is different
from that of target of the corresponding AB.
[0347] In some embodiments, each of the MM in the multispecific
activatable antibody has a polypeptide sequence that is no more
than 50% identical to any natural binding partner of the
corresponding AB. In some embodiments, each of the MM in the
multispecific activatable antibody has a polypeptide sequence that
is no more than 25% identical to any natural binding partner of the
corresponding AB. In some embodiments, each of the MM in the
multispecific activatable antibody has a polypeptide sequence that
is no more than 10% identical to any natural binding partner of the
corresponding AB.
[0348] In some embodiments, the coupling of each of the MM reduces
the ability of the corresponding AB to bind its target or epitope
such that the dissociation constant (K.sub.d) of the AB when
coupled to the MM towards its corresponding target or epitope is at
least 20 times greater than the K.sub.d of the AB when not coupled
to the MM towards its corresponding target or epitope.
[0349] In some embodiments, the coupling of each of the MM reduces
the ability of the corresponding AB to bind its target or epitope
such that the dissociation constant (K.sub.d) of the AB when
coupled to the MM towards its corresponding target or epitope is at
least 40 times greater than the K.sub.d of the AB when not coupled
to the MM towards its corresponding target or epitope.
[0350] In some embodiments, the coupling of each of the MM reduces
the ability of the corresponding AB to bind its target or epitope
such that the dissociation constant (K.sub.d) of the AB when
coupled to the MM towards its corresponding target or epitope is at
least 100 times greater than the K.sub.d of the AB when not coupled
to the MM towards its corresponding target or epitope.
[0351] In some embodiments, the coupling of each of the MM reduces
the ability of the corresponding AB to bind its target or epitope
such that the dissociation constant (K.sub.d) of the AB when
coupled to the MM towards its corresponding target or epitope is at
least 1000 times greater than the K.sub.d of the AB when not
coupled to the MM towards its corresponding target or epitope.
[0352] In some embodiments, the coupling of each of the MM reduces
the ability of the corresponding AB to bind its target or epitope
such that the dissociation constant (K.sub.d) of the AB when
coupled to the MM towards its corresponding target or epitope is at
least 10,000 times greater than the K.sub.d of the AB when not
coupled to the MM towards its corresponding target or epitope.
[0353] In some embodiments, each of the MM is an amino acid
sequence selected from a MM disclosed herein.
[0354] In some embodiments, the protease that cleaves the CM1-CM2
substrate sequence is co-localized with the target of the AB1 in
the multispecific activatable antibody in a tissue, and the MMP
protease and/or SP protease, i.e., at least one of the MMP protease
and the SP protease, cleave the CM1-CM2 substrate in the
multispecific activatable antibody when the multispecific
activatable antibody is exposed to the proteases.
[0355] In some embodiments, the multispecific activatable antibody
includes more than one CM1-CM2 substrate sequence, and the MMP
protease and/or the SP protease that cleaves at least one CM1-CM2
substrate sequence is co-localized with the target of at least one
of the AB regions in the multispecific activatable antibody in a
tissue, and the MMP protease and/or SP protease cleaves the CM1-CM2
substrate in the multispecific activatable antibody when the
multispecific activatable antibody is exposed to the proteases.
[0356] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least twofold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0357] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least threefold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0358] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least fourfold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0359] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least fivefold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0360] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least tenfold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0361] In some embodiments, each CM1-CM2 substrate, is positioned
in the multispecific activatable antibody such that in the
uncleaved state, binding of the multispecific activatable antibody
to a target of one of the AB regions is reduced to occur with a
dissociation constant that is at least 20-fold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0362] In some embodiments, each CM1-CM2 substrate is positioned in
the multispecific activatable antibody such that in the uncleaved
state, binding of the multispecific activatable antibody to a
target of one of the AB regions is reduced to occur with a
dissociation constant that is at least 40-fold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0363] In some embodiments, each CM1-CM2 substrate is positioned in
the multispecific activatable antibody such that in the uncleaved
state, binding of the multispecific activatable antibody to a
target of one of the AB regions is reduced to occur with a
dissociation constant that is at least 50-fold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0364] In some embodiments, each CM1-CM2 substrate is positioned in
the multispecific activatable antibody such that in the uncleaved
state, binding of the multispecific activatable antibody to a
target of one of the AB regions is reduced to occur with a
dissociation constant that is at least 100-fold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0365] In some embodiments, each CM1-CM2 substrate is positioned in
the multispecific activatable antibody such that in the uncleaved
state, binding of the multispecific activatable antibody to a
target of one of the AB regions is reduced to occur with a
dissociation constant that is at least 200-fold greater than the
dissociation constant of an unmodified AB binding to its target,
and whereas in the cleaved state, the AB binds its target.
[0366] The disclosure also provides compositions and methods that
include a multispecific activatable antibody that includes at least
a first antibody or antibody fragment (AB1) that specifically binds
a target and a second antibody or antibody fragment (AB2), where at
least the first AB in the multispecific activatable antibody is
coupled to a masking moiety (MM1) that decreases the ability of AB1
to bind its target. In some embodiments, each AB is coupled to a MM
that decreases the ability of its corresponding AB to each target.
For example, in bispecific activatable antibody embodiments, AB1 is
coupled to a first masking moiety (MM1) that decreases the ability
of AB1 to bind its target, and AB2 is coupled to a second masking
moiety (MM2) that decreases the ability of AB2 to bind its target.
In some embodiments, the multispecific activatable antibody
comprises more than two AB regions; in such embodiments, AB1 is
coupled to a first masking moiety (MM1) that decreases the ability
of AB1 to bind its target, AB2 is coupled to a second masking
moiety (MM2) that decreases the ability of AB2 to bind its target,
AB3 is coupled to a third masking moiety (MM3) that decreases the
ability of AB3 to bind its target, and so on for each AB in the
multispecific activatable antibody.
[0367] In some embodiments, the multispecific activatable antibody
further includes at least one CM1-CM2 substrate that is a substrate
for a MMP protease and a SP protease, where the CM1-CM2 substrate
links a MM to an AB. For example, in some embodiments, the
multispecific activatable antibody includes at least a first
antibody or antibody fragment (AB1) that specifically binds a
target and a second antibody or antibody fragment (AB2), where at
least the first AB in the multispecific activatable antibody is
coupled via a first CM1-CM2 substrate to a masking moiety (MM1)
that decreases the ability of AB1 to bind its target. In some
bispecific activatable antibody embodiments, AB1 is coupled via the
first CM1-CM2 substrate to MM1, and AB2 is coupled via a second
CM1-CM2 substrate to a second masking moiety (MM2) that decreases
the ability of AB2 to bind its target. In some embodiments, the
multispecific activatable antibody comprises more than two AB
regions; in some of these embodiments, AB1 is coupled via the first
CM1-CM2 substrate to MM1, AB2 is coupled via the second CM1-CM2
substrate to MM2, and AB3 is coupled via a third CM1-CM2 substrate
to a third masking moiety (MM3) that decreases the ability of AB3
to bind its target, and so on for each AB in the multispecific
activatable antibody.
[0368] Activatable Antibodies Having Non-Binding Steric Moieties or
Binding Partners for Non-Binding Steric Moieties
[0369] The disclosure also provides activatable antibodies that
include non-binding steric moieties (NB) or binding partners (BP)
for non-binding steric moieties, where the BP recruits or otherwise
attracts the NB to the activatable antibody. The activatable
antibodies provided herein include, for example, an activatable
antibody that includes a non-binding steric moiety (NB), a CM1-CM2
substrate and antibody or antibody fragment (AB) that binds a
target; an activatable antibody that includes a binding partner for
a non-binding steric moiety (BP), a CM1-CM2 substrate and an AB;
and an activatable antibody that includes a BP to which an NB has
been recruited, a CM1-CM2 substrate and an AB that binds the
target. Activatable antibodies in which the NB is covalently linked
to the CM1-CM2 substrate and AB of the activatable antibody or is
associated by interaction with a BP that is covalently linked to
the CM1-CM2 substrate and AB of the activatable antibody are
referred to herein as "NB-containing activatable antibodies." By
activatable or switchable is meant that the activatable antibody
exhibits a first level of binding to a target when the activatable
antibody is in an inhibited, masked or uncleaved state (i.e., a
first conformation), and a second level of binding to the target
when the activatable antibody is in an uninhibited, unmasked and/or
cleaved state (i.e., a second conformation, i.e., activated
antibody), where the second level of target binding is greater than
the first level of target binding. The activatable antibody
compositions can exhibit increased bioavailability and more
favorable biodistribution compared to conventional antibody
therapeutics.
[0370] In some embodiments, activatable antibodies provide for
reduced toxicity and/or adverse side effects that could otherwise
result from binding of the at non-treatment sites and/or
non-diagnostic sites if the AB were not masked or otherwise
inhibited from binding to such a site.
[0371] In one embodiment, the activatable antibody includes a
non-binding steric moiety (NB); a CM1-CM2 substrate; and an
antibody or antibody fragment (AB) that binds specifically to the
target, wherein the NB is a polypeptide that does not bind
specifically to the AB; the CM1-CM2 substrate is a polypeptide that
includes a substrate (S) for an enzyme; the CM1-CM2 substrate is
positioned such that in an uncleaved state, the NB interferes with
binding of the AB to the target and in a cleaved state, the NB does
not interfere with binding of the AB to the target; and the NB does
not inhibit cleavage of the CM1-CM2 substrate by the enzyme. As
used herein and throughout, the term polypeptide refers to any
polypeptide that includes at least two amino acid residues,
including larger polypeptides, full-length proteins and fragments
thereof, and the term polypeptide is not limited to single-chain
polypeptides and can include multi-unit, e.g., multi-chain,
polypeptides. In cases where the polypeptide is of a shorter
length, for example, less than 50 amino acids total, the terms
peptide and polypeptide are used interchangeably herein, and in
cases where the polypeptide is of a longer length, e.g., 50 amino
acids or greater, the terms polypeptide and protein are used
interchangeably herein.
[0372] In one embodiment, the activatable antibody includes a
non-binding steric moiety (NB); a CM1-CM2 substrate; and an
antibody or antibody fragment (AB) that binds specifically to the
target, wherein (i) the NB includes a polypeptide that does not
bind specifically to the AB; (ii) CM1-CM2 substrate is a
polypeptide of up to 50 amino acids in length that includes a
substrate (S) for an enzyme; (iii) the CM1-CM2 substrate is
positioned such that in an uncleaved state, the NB interferes with
binding of the AB to the target and in a cleaved state, the NB does
not interfere with binding of the AB to the target; and (iv) the NB
does not inhibit cleavage of the CM1-CM2 substrate by the enzyme.
For example, each of the CM substrate sequence and the CM2
substrate sequence in the CM1-CM2 substrate independent has a
length of up to 15 amino acids.
[0373] In one embodiment, the activatable antibody includes a
non-binding steric moiety (NB); a CM1-CM2 substrate; and an
antibody or antibody fragment (AB) that binds specifically to the
target, wherein (i) the NB includes a polypeptide that does not
bind specifically to the AB; (ii) the CM1-CM2 substrate is a
polypeptide that includes a substrate (S) for an enzyme; (iii) the
CM1-CM2 substrate is positioned such that in an uncleaved state,
the NB interferes with binding of the AB to the target and in a
cleaved state, the NB does not interfere with binding of the AB to
the target; (iv) the NB does not inhibit cleavage of the CM1-CM2
substrate by the enzyme; and (v) the activatable antibody has the
structural arrangement from N-terminus to C-terminus as follows in
the uncleaved state: NB-CM1-CM2 substrate-AB or AB-CM1-CM2
substrate-NB.
[0374] In one embodiment, the activatable antibody includes a
non-binding steric moiety (NB); a CM1-CM2 substrate; and an
antibody or antibody fragment (AB) that binds specifically to the
target, wherein (i) the NB includes a polypeptide that does not
bind specifically to the AB; (ii) the CM1-CM2 substrate is a
polypeptide that includes a substrate (S) for an enzyme; (iii) the
CM1-CM2 substrate is positioned such that in an uncleaved state,
the NB interferes with binding of the AB to the target and in a
cleaved state, the NB does not interfere with binding of the AB to
the target, and wherein the NB in the uncleaved activatable
antibody reduces the ability of the AB to bind the target by at
least 50%, for example, by at least 60%, by at least 70%, by at
least 75%, by at least 80%, by at least 85%, by at least 90%, by at
least 95%, by at least 96%, by at least 97%, by at least 98%, by at
least 99%, by at least 100% as compared to the ability of the
cleaved AB to bind the target; and (iv) the NB does not inhibit
cleavage of the CM1-CM2 substrate by the enzyme. The reduction in
the ability of the AB to bind the target is determined, e.g., using
an assay as described herein or an in vitro target displacement
assay such as, for example, the assay described in PCT Publication
Nos. WO 2009/025846 and WO 2010/081173.
[0375] In one embodiment, the activatable antibody includes a
binding partner (BP) for a non-binding steric moiety (NB); a
CM1-CM2 substrate; and an antibody or antibody fragment (AB) that
binds specifically to the target, wherein the BP is a polypeptide
that binds to the NB when exposed thereto; the NB does not bind
specifically to the AB; the CM1-CM2 substrate is a polypeptide that
includes a substrate (S) for an enzyme; the CM1-CM2 substrate is
positioned such that in an uncleaved state in the presence of the
NB, the NB interferes with binding of the AB to the target and in a
cleaved state, the NB does not interfere with binding of the AB to
the target and the BP does not interfere with binding of the AB to
the target; and the NB and the BP do not inhibit cleavage of the
CM1-CM2 substrate by the enzyme. In some examples of this
embodiment, the BP of the activatable antibody is optionally bound
to the NB. In one embodiment, the NB is recruited by the BP of the
activatable antibody in vivo.
[0376] In some examples of any of these activatable antibody
embodiments, the activatable antibody is formulated as a
composition. In some of these embodiments, the composition also
includes the NB, where the NB is co-formulated with the activatable
antibody that includes the BP, the CM1-CM2 substrate, and the AB.
In some examples of this embodiment, the BP is selected from the
group consisting of an albumin binding peptide, a fibrinogen
binding peptide, a fibronectin binding peptide, a hemoglobin
binding peptide, a transferrin binding peptide, an immunoglobulin
domain binding peptide, and other serum protein binding
peptides.
[0377] In some examples of any of these activatable antibody
embodiments, the NB is a soluble, globular protein. In some
examples of any of these activatable antibody embodiments, the NB
is a protein that circulates in the bloodstream. In some examples
of any of these activatable antibody embodiments, the NB is
selected from the group consisting of albumin, fibrinogen,
fibronectin, hemoglobin, transferrin, an immunoglobulin domain, and
other serum proteins.
[0378] In some examples of any of these activatable antibody
embodiments, the CM1-CM2 substrate is a polypeptide that includes a
substrate (S) for a protease. In some examples of any of these
activatable antibody embodiments, the protease is co-localized with
the in a tissue, and the protease cleaves the CM1-CM2 substrate in
the activatable antibody when the activatable antibody is exposed
to the protease. In some examples of any of these activatable
antibody embodiments, the CM1-CM2 substrate is a polypeptide of up
to 50 amino acids in length. In some examples of any of these
activatable antibody embodiments, the CM1-CM2 substrate is a
polypeptide that includes a substrate (S) having a length of up to
15 amino acids, e.g., 3 amino acids long, 4 amino acids long. 5
amino acids long, 6 amino acids long, 7 amino acids long, 8 amino
acids long, 9 amino acids long, 10 amino acids long, 11 amino acids
long, 12 amino acids long, 13 amino acids long, 14 amino acids
long, or 15 amino acids long.
[0379] In some examples of any of these activatable antibody
embodiments, the activatable antibody has the structural
arrangement from N-terminus to C-terminus as follows in the
uncleaved state: NB-CM1-CM2 substrate-AB, AB-CM1-CM2 substrate-NB,
BP-CM1-CM2 substrate-AB or AB-CM1-CM2 substrate-BP. In embodiments
where the activatable antibody includes a BP and the activatable
antibody is in the presence of the corresponding NB, the
activatable antibody has a structural arrangement from N-terminus
to C-terminus as follows in the uncleaved state: NB:BP-CM1-CM2-AB,
NB:BP-CM2-CM1-AB, AB-CM1-CM2-BP:NB or AB-CM2-CM1-BP:NB, where ":"
represents an interaction, e.g., binding, between the NB and
BP.
[0380] In some examples of any of these activatable antibody
embodiments, the activatable antibody includes an antibody or
antigen-binding fragment thereof that specifically binds a given
target and is a monoclonal antibody, domain antibody, single chain,
Fab fragment, a F(ab').sub.2 fragment, a scFv, a scab, a dAb, a
single domain heavy chain antibody, or a single domain light chain
antibody. In some embodiments, such an antibody or immunologically
active fragment thereof that binds the target a mouse, other
rodent, chimeric, humanized or fully human monoclonal antibody.
[0381] In some examples of any of these activatable antibody
embodiments, the activatable antibody includes a combination of a
variable heavy chain region comprising an amino acid sequence
presented herein and a variable light chain region comprising an
amino acid sequence presented herein. In some embodiments, the
activatable antibody includes a combination of a variable heavy
chain region comprising an amino acid sequence that is at least
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%0 or more identical
to an amino acid sequence presented herein, and a variable light
chain region comprising an amino acid sequence that is at least
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical
to an amino acid sequence presented herein.
[0382] In some examples of any of these activatable antibody
embodiments, the activatable antibody also includes an agent
conjugated to the AB. In some embodiments, the agent is a
therapeutic agent. In some embodiments, the agent is an
antineoplastic agent. In some embodiments, the agent is a toxin or
fragment thereof. In some embodiments, the agent is conjugated to
the AB via a linker. In some embodiments, the linker is a cleavable
linker. In some embodiments, the agent is conjugated to the AB via
a noncleavable linker. In some embodiments, the agent is an agent
selected from the group listed in Table 3. In some embodiments, the
agent is a microtubule inhibitor. In some embodiments, the agent is
a nucleic acid damaging agent, such as a DNA alkylator or DNA
intercalator, or other DNA damaging agent. In some embodiments, the
agent is a dolastatin. In some embodiments, the agent is an
auristatin or derivative thereof. In some embodiments, the agent is
auristatin E or a derivative thereof. In some embodiments, the
agent is monomethyl auristatin E (MMAE). In some embodiments, the
agent is monomethyl auristatin D (MMAD). In some embodiments, the
agent is a maytansinoid or maytansinoid derivative. In some
embodiments, the agent is DM1 or DM4. In some embodiments, the
agent is a duocarmycin or derivative thereof. In some embodiments,
the agent is a calicheamicin or derivative thereof. In some
embodiments, the agent is a pyrrolobenzodiazepine. In some
embodiments, the agent is a pyrrolobenzodiazepine dimer.
[0383] In some examples of any of these activatable antibody
embodiments, the activatable antibody also includes a detectable
moiety. In some embodiments, the detectable moiety is a diagnostic
agent.
[0384] In some examples of any of these activatable antibody
embodiments, the activatable antibody also includes a spacer. In
some examples of any of these activatable antibody embodiments, the
activatable antibody also includes a signal peptide. In some
embodiments, the signal peptide is conjugated to the activatable
antibody via a spacer. In some examples of any of these activatable
antibody embodiments, the spacer is joined directly to the MM of
the activatable antibody.
[0385] In some embodiments, the serum half-life of the activatable
antibody is longer than that of the corresponding antibody; e.g.,
the pK of the activatable antibody is longer than that of the
corresponding antibody. In some embodiments, the serum half-life of
the activatable antibody is similar to that of the corresponding
antibody. In some embodiments, the serum half-life of the
activatable antibody is at least 15 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 12 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 11 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 10 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 9 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 8 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 7 days when administered to an
organism. In some embodiments, the serum half-life of the
activatable antibody is at least 6 days when administered to an
organism. In some examples of any of these activatable antibody
embodiments, the serum half-life of the activatable antibody is at
least 5 days when administered to an organism. In some embodiments,
the serum half-life of the activatable antibody is at least 4 days
when administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 3 days when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 2 days when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 24 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 20 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 18 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 16 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 14 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 12 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 10 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 8 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 6 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 4 hours when
administered to an organism. In some embodiments, the serum
half-life of the activatable antibody is at least 3 hours when
administered to an organism.
[0386] The disclosure also provides an isolated nucleic acid
molecule encoding any of these activatable antibodies, as well as
vectors that include these isolated nucleic acid sequences. The
disclosure provides methods of producing an activatable antibody by
culturing a cell under conditions that lead to expression of the
activatable antibody, wherein the cell comprises such a nucleic
acid sequence. In some embodiments, the cell comprises such a
vector.
[0387] The dissociation constant (K.sub.d) of the NB-containing
activatable antibody toward the target is greater than the K.sub.d
of the AB towards the target when it is not associated with the NB
or NB:BP. The dissociation constant (K.sub.d) of the NB-containing
activatable antibody toward the target is greater than the K.sub.d
of the parental AB towards the target. For example, the K.sub.d of
the NB-containing activatable antibody toward the target is at
least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 10,000,
50,000, 100,000, 500,000, 1,000,000, 5,000,000, 10,000,000,
50,000,000 or greater, or between 5-10, 10-100, 10-1,000,
10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000, 100-1,000,
100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000,
1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000,
10,000-100,000, 10,000-1,000,000, 10,000-10,000,000,
100,000-1,000,000, or 100,000-10,000,000 times greater than the
K.sub.d of the AB when it is not associated with the NB or NB:BP or
the K.sub.d of the parental AB towards the target. Conversely, the
binding affinity of the NB-containing activatable antibody towards
the target is lower than the binding affinity of the AB when it is
not associated with the NB or NB:BP or lower than the binding
affinity of the parental AB towards the target. For example, the
binding affinity of the NB-containing activatable antibody toward
the target is at least 5, 10, 25, 50, 100, 250, 500, 1,000, 2,500,
5,000, 10,000, 50,000, 100,000, 500,000, 1,000,000, 5,000,000,
10,000,000, 50,000,000 or greater, or between 5-10, 10-100,
10-1,000, 10-10,000, 10-100,000, 10-1,000,000, 10-10,000,000,
100-1,000, 100-10,000, 100-100,000, 100-1,000,000, 100-10,000,000,
1,000-10,000, 1,000-100,000, 1,000-1,000,000, 1000-10,000,000,
10,000-100,000, 10,000-1,000,000, 10,000-10,000,000,
100,000-1,000,000, or 100,000-10,000,000 times lower than the
binding affinity of the AB when it is not associated with the NB or
NB:BP or lower than the binding affinity of the parental AB towards
the target.
[0388] When the NB-containing activatable antibody is in the
presence of the target, specific binding of the AB to the target is
reduced or inhibited, as compared to the specific binding of the AB
when it is not associated with the NB or NB:BP. When the
NB-containing activatable antibody is in the presence of the
target, specific binding of the AB to the target is reduced or
inhibited, as compared to the specific binding of the parental AB
to the target. When compared to the binding of the AB not
associated with an NB or NB:BP or the binding of the parental AB to
the target, the ability of the NB-containing activatable antibody
to bind the target is reduced, for example, by at least 50%, 60%,
70%, 80%, 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 100%
for at least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72, 84, or 96
hours, or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180 days, or 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer when
measured in vitro and/or in vivo.
[0389] When the NB-containing activatable antibody is in the
presence of the target but not in the presence of a modifying agent
(for example a protease or other enzyme), specific binding of the
AB to the target is reduced or inhibited, as compared to the
specific binding of the AB when it is not associated with the NB or
NB:BP. When the NB-containing activatable antibody is in the
presence of the target but not in the presence of a modifying agent
(for example a protease, other enzyme, reduction agent, or light),
specific binding of the AB to the target is reduced or inhibited,
as compared to the specific binding of the parental AB to the
target. When compared to the binding of the AB not associated with
an NB or NB:BP or the binding of the parental AB to the target, the
ability of the NB-containing activatable antibody to bind the
target is reduced, for example, by at least 50%, 60%, 70%, 80%,
90%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 100% for at
least 2, 4, 6, 8, 12, 28, 24, 30, 36, 48, 60, 72, 84, or 96 hours,
or 5, 10, 15, 30, 45, 60, 90, 120, 150, or 180 days, or 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, or 12 months or longer when measured in
vitro and/or in vivo.
[0390] In some examples of any of these activatable antibody
embodiments, the activatable antibody includes an agent conjugated
to the AB to produce an activatable antibody conjugate. In some
embodiments of the activatable antibody conjugate, the agent is a
therapeutic agent. In some embodiments, the agent is a diagnostic
agent. In some embodiments, the agent is a detectable marker. In
some embodiments of the activatable antibody conjugate, the agent
is an antineoplastic agent. In some embodiments of the activatable
antibody conjugate, the agent is a toxin or fragment thereof. In
some embodiments of the activatable antibody conjugate, the agent
is conjugated to the AB via a linker. In some embodiments of the
activatable antibody conjugate, the linker is a cleavable linker.
In some embodiments, the agent is conjugated to the AB via a
noncleavable linker. In some embodiments, the agent is a
microtubule inhibitor. In some embodiments, the agent is a nucleic
acid damaging agent, such as a DNA alkylator or DNA intercalator,
or other DNA damaging agent. In some embodiments, the agent is an
agent selected from the group listed in Table 3. In some
embodiments, the agent is a dolastatin. In some embodiments, the
agent is an auristatin or derivative thereof. In some embodiments,
the agent is auristatin E or a derivative thereof. In some
embodiments, the agent is monomethyl auristatin E (MMAE). In some
embodiments, the agent is monomethyl auristatin D (MMAD). In some
embodiments, the agent is a maytansinoid or maytansinoid
derivative. In some embodiments, the agent is DM1 or DM4. In some
embodiments, the agent is a duocarmycin or derivative thereof. In
some embodiments, the agent is a calicheamicin or derivative
thereof. In some embodiments, the agent is a pyrrolobenzodiazepine.
In some embodiments, the agent is a pyrrolobenzodiazepine
dimer.
[0391] In some examples of any of these activatable antibody
embodiments, the activatable antibodies are dual-target binding
activatable antibodies. Such dual target binding activatable
antibodies contain two Abs that may bind the same or different
targets. In specific embodiments, dual-targeting activatable
antibodies contain bispecific antibodies or antibody fragments.
[0392] Dual target binding activatable antibodies are designed so
as to have a CM1-CM2 substrate cleavable by a cleaving agent that
is co-localized in a target tissue with one or both of the targets
capable of binding to the ABs of the activatable antibodies. Dual
target binding activatable antibodies with more than one AB to the
same or different targets can be designed so as to have more than
one CM1-CM2 substrate, wherein the first CM1-CM2 substrate is
cleavable by a cleaving agent in a first target tissue and wherein
the second CM1-CM2 substrate is cleavable by a cleaving agent in a
second target tissue, with one or more of the targets binding to
the ABs of the activatable antibodies. In one embodiment, the first
and second target tissues are spatially separated, for example, at
different sites in the organism. In one embodiment, the first and
second target tissues are the same tissue temporally separated, for
example the same tissue at two different points in time, for
example the first time point is when the tissue is an early stage
tumor, and the second time point is when the tissue is a late stage
tumor.
[0393] The disclosure also provides nucleic acid molecules encoding
the activatable antibodies described herein. The disclosure also
provides vectors that include these nucleic acids. The activatable
antibodies described herein are produced by culturing a cell under
conditions that lead to expression of the activatable antibody,
wherein the cell includes these nucleic acid molecules or
vectors.
[0394] The disclosure also provides methods of manufacturing
activatable antibodies. In one embodiment, the method includes the
steps of (a) culturing a cell that includes a nucleic acid
construct that encodes the activatable antibody under conditions
that lead to expression of the activatable antibody, wherein the
activatable antibody includes (i) a non-binding steric moiety (NB);
(ii) a CM1-CM2 substrate; and (iii) an antibody or an antigen
binding fragment thereof (AB) that specifically binds a target,
wherein (1) the NB does not bind specifically to the AB; (2) the
CM1-CM2 substrate is a polypeptide that includes a substrate (S)
for an enzyme; (3) the CM1-CM2 substrate is positioned such that in
an uncleaved state, the NB interferes with binding of the AB to the
target and in a cleaved state, the NB does not interfere with
binding of the AB to the target; and (4) the NB does not inhibit
cleavage of the CM1-CM2 substrate by the enzyme; and (b) recovering
the activatable antibody.
[0395] In some embodiments, the method includes the steps of (a)
culturing a cell that includes a nucleic acid construct that
encodes the activatable antibody under conditions that lead to
expression of the activatable antibody, wherein the activatable
antibody includes (i) a binding partner (BP) for a non-binding
steric moiety (NB); (ii) a CM1-CM2 substrate; and (iii) an antibody
or an antigen binding fragment thereof (AB) that specifically binds
a target, wherein (1) the NB does not bind specifically to the AB;
(2) the CM1-CM2 substrate is a polypeptide that includes a
substrate (S) for an enzyme; (3) the CM1-CM2 substrate is
positioned such that in an uncleaved state in the presence of the
NB, the NB interferes with binding of the AB to the target and in a
cleaved state, the NB does not interfere with binding of the AB to
the target and the BP does not interfere with binding of the AB to
the target; and (4) the NB and the BP do not inhibit cleavage of
the CM1-CM2 substrate by the enzyme; and (b) recovering the
activatable antibody. In some examples of this embodiment, the BP
of the activatable antibody is bound to the NB.
[0396] Use of Activatable Antibodies and Conjugated Activatable
Antibodies
[0397] It will be appreciated that administration of therapeutic
entities in accordance with the disclosure will be administered
with suitable carriers, excipients, and other agents that are
incorporated into formulations to provide improved transfer,
delivery, tolerance, and the like. A multitude of appropriate
formulations can be found in the formulary known to all
pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th
ed, Mack Publishing Company, Easton, Pa. (1975)), particularly
Chapter 87 by Blaug, Seymour, therein. These formulations include,
for example, powders, pastes, ointments, jellies, waxes, oils,
lipids, lipid (cationic or anionic) containing vesicles (such as
Lipofectin.TM.), DNA conjugates, anhydrous absorption pastes,
oil-in-water and water-in-oil emulsions, emulsions carbowax
(polyethylene glycols of various molecular weights), semi-solid
gels, and semi-solid mixtures containing carbowax. Any of the
foregoing mixtures may be appropriate in treatments and therapies
in accordance with the present disclosure, provided that the active
ingredient in the formulation is not inactivated by the formulation
and the formulation is physiologically compatible and tolerable
with the route of administration. See also Baldrick P.
"Pharmaceutical excipient development: the need for preclinical
guidance." Regul. Toxicol Pharmacol. 32(2):210-8 (2000), Wang W.
"Lyophilization and development of solid protein pharmaceuticals."
Int. J. Pharm. 203(1-2): 1-60 (2000), Charman WN "Lipids,
lipophilic drugs, and oral drug delivery-some emerging concepts." J
Pharm Sci.89(8):967-78 (2000), Powell et al. "Compendium of
excipients for parenteral formulations" PDA J Pharm Sci Technol.
52:238-311 (1998) and the citations therein for additional
information related to formulations, excipients and carriers well
known to pharmaceutical chemists.
[0398] Therapeutic formulations of the disclosure, which include a
conjugated antibody, an activatable antibody and/or a conjugated
activatable antibody, are used to prevent, treat or otherwise
ameliorate a disease or disorder associated with aberrant target
expression and/or activity. For example, therapeutic formulations
of the disclosure, which include a conjugated antibody, an
activatable antibody and/or a conjugated activatable antibody, are
used to treat or otherwise ameliorate inflammation, an inflammatory
disorder, an autoimmune disease and/or a cancer or other neoplastic
condition. In some embodiments, the cancer is a solid tumor or a
hematologic malignancy where the target is expressed. In some
embodiments, the cancer is a solid tumor where the target is
expressed. In some embodiments, the cancer is a hematologic
malignancy where the target is expressed. In some embodiments, the
target is expressed on parenchyma (e.g., in cancer, the portion of
an organ or tissue that often carries out function(s) of the organ
or tissue). In some embodiments, the target is expressed on a cell,
tissue, or organ. In some embodiments, the target is expressed on
stroma (i.e., the connective supportive framework of a cell,
tissue, or organ). In some embodiments, the target is expressed on
an osteoblast. In some embodiments, the target is expressed on the
endothelium (vasculature). In some embodiments, the target is
expressed on a cancer stem cell. In some embodiments, the agent to
which the activatable antibody is conjugated is a microtubule
inhibitor. In some embodiments, the agent to which the activatable
antibody is conjugated is a nucleic acid damaging agent.
[0399] Efficaciousness of prevention, amelioration or treatment is
determined in association with any known method for diagnosing or
treating the disease or disorder associated with target expression
and/or activity, such as, for example, aberrant target expression
and/or activity. Prolonging the survival of a subject or otherwise
delaying the progression of the disease or disorder associated with
target expression and/or activity, e.g., aberrant target expression
and/or activity, in a subject indicates that the conjugated
antibody, activatable antibody and/or conjugated activatable
antibody confers a clinical benefit.
[0400] A conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody can be administered in the form of
pharmaceutical compositions. Principles and considerations involved
in preparing such compositions, as well as guidance in the choice
of components are provided, for example, in Remington: The Science
And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al.,
editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption
Enhancement: Concepts, Possibilities, Limitations, And Trends,
Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And
Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4),
1991, M. Dekker, New York.
[0401] In some embodiments where antibody fragments are used, the
smallest fragment that specifically binds to the binding domain of
the target protein is selected. For example, based upon the
variable-region sequences of an antibody, peptide molecules can be
designed that retain the ability to bind the target protein
sequence. Such peptides can be synthesized chemically and/or
produced by recombinant DNA technology. (See, e.g., Marasco et al.,
Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993)). The formulation
can also contain more than one active compounds as necessary for
the particular indication being treated, for example, in some
embodiments, those with complementary activities that do not
adversely affect each other. In some embodiments, or in addition,
the composition can comprise an agent that enhances its function,
such as, for example, a cytotoxic agent, cytokine, chemotherapeutic
agent, or growth-inhibitory agent. Such molecules are suitably
present in combination in amounts that are effective for the
purpose intended.
[0402] The active ingredients can also be entrapped in
microcapsules prepared, for example, by coacervation techniques or
by interfacial polymerization, for example, hydroxymethylcellulose
or gelatin-microcapsules and poly-(methylmethacrylate)
microcapsules, respectively, in colloidal drug delivery systems
(for example, liposomes, albumin microspheres, microemulsions,
nano-particles, and nanocapsules) or in macroemulsions.
[0403] The formulations to be used for in vivo administration must
be sterile. This is readily accomplished by filtration through
sterile filtration membranes.
[0404] Sustained-release preparations can be prepared. Suitable
examples of sustained-release preparations include semipermeable
matrices of solid hydrophobic polymers containing the antibody,
which matrices are in the form of shaped articles, e.g., films, or
microcapsules. Examples of sustained-release matrices include
polyesters, hydrogels (for example,
poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and .gamma. ethyl-L-glutamate, non-degradable ethylene-vinyl
acetate, degradable lactic acid-glycolic acid copolymers such as
the LUPRON DEPOT.TM. (injectable microspheres composed of lactic
acid-glycolic acid copolymer and leuprolide acetate), and
poly-D-(-)-3-hydroxybutyric acid. While polymers such as
ethylene-vinyl acetate and lactic acid-glycolic acid enable release
of molecules for over 100 days, certain hydrogels release proteins
for shorter time periods.
[0405] In some embodiments, the conjugated antibody, activatable
antibody and/or conjugated activatable antibody contains a
detectable label. An intact antibody, or a fragment thereof (e.g.,
Fab, scFv, or F(ab).sub.2) is used. The term "labeled", with regard
to the probe or antibody, is intended to encompass direct labeling
of the probe or antibody by coupling (i.e., physically linking) a
detectable substance to the probe or antibody, as well as indirect
labeling of the probe or antibody by reactivity with another
reagent that is directly labeled. Examples of indirect labeling
include detection of a primary antibody using a
fluorescently-labeled secondary antibody and end-labeling of a DNA
probe with biotin such that it can be detected with
fluorescently-labeled streptavidin. The term "biological sample" is
intended to include tissues, cells and biological fluids isolated
from a subject, as well as tissues, cells and fluids present within
a subject. Included within the usage of the term "biological
sample", therefore, is blood and a fraction or component of blood
including blood serum, blood plasma, or lymph. That is, the
detection method of the disclosure can be used to detect an analyte
mRNA, protein, or genomic DNA in a biological sample in vitro as
well as in vivo. For example, in vitro techniques for detection of
an analyte mRNA include Northern hybridizations and in situ
hybridizations. In vitro techniques for detection of an analyte
protein include enzyme linked immunosorbent assays (ELISAs),
Western blots, immunoprecipitations, immunochemical staining, and
immunofluorescence. In vitro techniques for detection of an analyte
genomic DNA include Southern hybridizations. Procedures for
conducting immunoassays are described, for example in "ELISA:
Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R.
Crowther (Ed.) Human Press, Totowa, N.J., 1995; "Immunoassay", E.
Diamandis and T. Christopoulus, Academic Press, Inc., San Diego,
Calif., 1996; and "Practice and Theory of Enzyme Immunoassays", P.
Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore,
in vivo techniques for detection of an analyte protein include
introducing into a subject a labeled anti-analyte protein antibody.
For example, the antibody can be labeled with a radioactive marker
whose presence and location in a subject can be detected by
standard imaging techniques.
[0406] The conjugated antibodies, activatable antibodies and/or
conjugated activatable antibodies of the disclosure are also useful
in a variety of diagnostic and prophylactic formulations. In one
embodiment, a conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody is administered to patients that
are at risk of developing one or more of the aforementioned
disorders. A patient's or organ's predisposition to one or more of
the aforementioned disorders can be determined using genotypic,
serological or biochemical markers.
[0407] In some embodiments, a conjugated antibody, an activatable
antibody and/or a conjugated activatable antibody is administered
to human individuals diagnosed with a clinical indication
associated with one or more of the aforementioned disorders. Upon
diagnosis, a conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody is administered to mitigate or
reverse the effects of the clinical indication.
[0408] A conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody of the disclosure is also useful in
the detection of a target in patient samples and accordingly are
useful as diagnostics. For example, the antibodies and/or
activatable antibodies, and conjugated versions thereof, of the
disclosure are used in in vitro assays. e.g., ELISA, to detect
target levels in a patient sample.
[0409] In one embodiment, a conjugated antibody, an activatable
antibody and/or a conjugated activatable antibody of the disclosure
is immobilized on a solid support (e.g., the well(s) of a
microtiter plate). The immobilized conjugated antibody, activatable
antibody and/or conjugated activatable antibody serves as a capture
antibody for any target that may be present in a test sample. Prior
to contacting the immobilized antibody with a patient sample, the
solid support is rinsed and treated with a blocking agent such as
milk protein or albumin to prevent nonspecific adsorption of the
analyte.
[0410] Subsequently the wells are treated with a test sample
suspected of containing the antigen, or with a solution containing
a standard amount of the antigen. Such a sample is, e.g., a serum
sample from a subject suspected of having levels of circulating
antigen considered to be diagnostic of a pathology. After rinsing
away the test sample or standard, the solid support is treated with
a second antibody that is detectably labeled. The labeled second
antibody serves as a detecting antibody. The level of detectable
label is measured, and the concentration of target antigen in the
test sample is determined by comparison with a standard curve
developed from the standard samples.
[0411] It will be appreciated that based on the results obtained
using the antibodies of the disclosure, and conjugated versions
thereof, in an in vitro diagnostic assay, it is possible to stage a
disease in a subject based on expression levels of the target
antigen. For a given disease, samples of blood are taken from
subjects diagnosed as being at various stages in the progression of
the disease, and/or at various points in the therapeutic treatment
of the disease. Using a population of samples that provides
statistically significant results for each stage of progression or
therapy, a range of concentrations of the antigen that may be
considered characteristic of each stage is designated.
[0412] A conjugated antibody, an activatable antibody and/or a
conjugated activatable antibody can also be used in diagnostic
and/or imaging methods. In some embodiments, such methods are in
vitro methods. In some embodiments, such methods are in vivo
methods. In some embodiments, such methods are in situ methods. In
some embodiments, such methods are ex vivo methods. For example,
activatable antibodies having an enzymatically cleavable CM1-CM2
substrate can be used to detect the presence or absence of an
enzyme that is capable of cleaving the CM1-CM2 substrate. Such
activatable antibodies can be used in diagnostics, which can
include in vivo detection (e.g., qualitative or quantitative) of
enzyme activity (or, in some embodiments, an environment of
increased reduction potential such as that which can provide for
reduction of a disulfide bond) through measured accumulation of
activated antibodies (i.e., antibodies resulting from cleavage of
an activatable antibody) in a given cell or tissue of a given host
organism. Such accumulation of activated antibodies indicates not
only that the tissue expresses enzymatic activity (or an increased
reduction potential depending on the nature of the CM1-CM2
substrate) but also that the tissue expresses target to which the
activated antibody binds.
[0413] For example, the CM1-CM2 substrate can be selected to be
substrate for a matrix metalloprotease (MMP) and a serine protease
(SP) found at the site of a tumor, at the site of a viral or
bacterial infection at a biologically confined site (e.g., such as
in an abscess, in an organ, and the like), and the like. The AB can
be one that binds a target antigen. Using methods as disclosed
herein, or when appropriate, methods familiar to one skilled in the
art, a detectable label (e.g., a fluorescent label or radioactive
label or radiotracer) can be conjugated to an AB or other region of
an antibody and/or activatable antibody. Suitable detectable labels
are discussed in the context of the above screening methods and
additional specific examples are provided below. Using an AB
specific to a protein or peptide of the disease state, along with
an MMP whose activity is elevated in the disease tissue of
interest, activatable antibodies will exhibit an increased rate of
binding to disease tissue relative to tissues where the CM1-CM2
substrate specific enzyme is not present at a detectable level or
is present at a lower level than in disease tissue or is inactive
(e.g., in zymogen form or in complex with an inhibitor). Since
small proteins and peptides are rapidly cleared from the blood by
the renal filtration system, and because the enzyme specific for
the CM1-CM2 substrate is not present at a detectable level (or is
present at lower levels in non-disease tissues or is present in
inactive conformation), accumulation of activated antibodies in the
disease tissue is enhanced relative to non-disease tissues.
[0414] In another example, activatable antibodies can be used to
detect the presence or absence of a cleaving agent in a sample. For
example, where the activatable antibodies contain a CM1-CM2
substrate susceptible to cleavage by an enzyme, the activatable
antibodies can be used to detect (either qualitatively or
quantitatively) the presence of an enzyme in the sample. In another
example, where the activatable antibodies contain a CM1-CM2
substrate susceptible to cleavage by reducing agent, the
activatable antibodies can be used to detect (either qualitatively
or quantitatively) the presence of reducing conditions in a sample.
To facilitate analysis in these methods, the activatable antibodies
can be detectably labeled, and can be bound to a support (e.g., a
solid support, such as a slide or bead). The detectable label can
be positioned on a portion of the activatable antibody that is not
released following cleavage, for example, the detectable label can
be a quenched fluorescent label or other label that is not
detectable until cleavage has occurred. The assay can be conducted
by, for example, contacting the immobilized, detectably labeled
activatable antibodies with a sample suspected of containing an
enzyme and/or reducing agent for a time sufficient for cleavage to
occur, then washing to remove excess sample and contaminants. The
presence or absence of the cleaving agent (e.g., enzyme or reducing
agent) in the sample is then assessed by a change in detectable
signal of the activatable antibodies prior to contacting with the
sample e.g., the presence of and/or an increase in detectable
signal due to cleavage of the activatable antibody by the cleaving
agent in the sample.
[0415] Such detection methods can be adapted to also provide for
detection of the presence or absence of a target that is capable of
binding the AB of the activatable antibodies when cleaved. Thus,
the assays can be adapted to assess the presence or absence of a
cleaving agent and the presence or absence of a target of interest.
The presence or absence of the cleaving agent can be detected by
the presence of and/or an increase in detectable label of the
activatable antibodies as described above, and the presence or
absence of the target can be detected by detection of a target-AB
complex e.g., by use of a detectably labeled anti-target
antibody.
[0416] Activatable antibodies are also useful in in situ imaging
for the validation of activatable antibody activation, e.g., by
protease cleavage, and binding to a particular target. In situ
imaging is a technique that enables localization of proteolytic
activity and target in biological samples such as cell cultures or
tissue sections. Using this technique, it is possible to confirm
both binding to a given target and proteolytic activity based on
the presence of a detectable label (e.g., a fluorescent label).
[0417] These techniques are useful with any frozen cells or tissue
derived from a disease site (e.g. tumor tissue) or healthy tissues.
These techniques are also useful with fresh cell or tissue
samples.
[0418] In these techniques, an activatable antibody is labeled with
a detectable label. The detectable label may be a fluorescent dye,
(e.g. a fluorophore, Fluorescein Isothiocyanate (FITC), Rhodamine
Isothiocyanate (TRITC), an Alexa Fluor.RTM. label), a near infrared
(NIR) dye (e.g., Qdot.RTM. nanocrystals), a colloidal metal, a
hapten, a radioactive marker, biotin and an amplification reagent
such as streptavidin, or an enzyme (e.g. horseradish peroxidase or
alkaline phosphatase).
[0419] Detection of the label in a sample that has been incubated
with the labeled, activatable antibody indicates that the sample
contains the target and contains a matrix metalloprotease (MMP) and
one serine protease (SP) that are specific for the CM1-CM2
substrate of the activatable antibody. In some embodiments, the
presence of the MMP can be confirmed using broad spectrum protease
inhibitors such as those described herein, and/or by using an agent
that is specific for the protease, for example, an antibody such as
A11, which is specific for the protease matriptase (MT-SP1) and
inhibits the proteolytic activity of matriptase; see e.g.,
International Publication Number WO 2010/129609, published 11 Nov.
2010. The same approach of using broad spectrum protease inhibitors
such as those described herein, and/or by using a more selective
inhibitory agent can be used to identify a MMP and a SP specific
for the CM1-CM2 substrate of the activatable antibody. In some
embodiments, the presence of the target can be confirmed using an
agent that is specific for the target, e.g., another antibody, or
the detectable label can be competed with unlabeled target. In some
embodiments, unlabeled activatable antibody could be used, with
detection by a labeled secondary antibody or more complex detection
system.
[0420] Similar techniques are also useful for in vivo imaging where
detection of the fluorescent signal in a subject, e.g., a mammal,
including a human, indicates that the disease site contains the
target and contains a MMP and a SP that is specific for the CM1-CM2
substrate of the activatable antibody.
[0421] These techniques are also useful in kits and/or as reagents
for the detection, identification or characterization of protease
activity in a variety of cells, tissues, and organisms based on the
protease-specific CM1-CM2 substrate in the activatable
antibody.
[0422] The disclosure provides methods of using the antibodies
and/or activatable antibodies in a variety of diagnostic and/or
prophylactic indications. For example, the disclosure provides
methods of detecting presence or absence of a cleaving agent and a
target of interest in a subject or a sample by (i) contacting a
subject or sample with an activatable antibody, wherein the
activatable antibody comprises a masking moiety (MM), a CM1-CM2
substrate that is cleaved by the cleaving agent, and an antigen
binding domain or fragment thereof (AB) that specifically binds the
target of interest, wherein the activatable antibody in an
uncleaved, non-activated state comprises a structural arrangement
from N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB
or AB-CM1-CM2 substrate-MM; (a) wherein the MM is a peptide that
inhibits binding of the AB to the target, and wherein the MM does
not have an amino acid sequence of a naturally occurring binding
partner of the AB and is not a modified form of a natural binding
partner of the AB; and (b) wherein, in an uncleaved, non-activated
state, the MM interferes with specific binding of the AB to the
target, and in a cleaved, activated state the MM does not interfere
or compete with specific binding of the AB to the target; and (ii)
measuring a level of activated activatable antibody in the subject
or sample, wherein a detectable level of activated activatable
antibody in the subject or sample indicates that the cleaving agent
and the target are present in the subject or sample and wherein no
detectable level of activated activatable antibody in the subject
or sample indicates that the cleaving agent, the target or both the
cleaving agent and the target are absent and/or not sufficiently
present in the subject or sample. In some embodiments, the
activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0423] The disclosure also provides methods of detecting presence
or absence of a cleaving agent in a subject or a sample by (i)
contacting a subject or sample with an activatable antibody in the
presence of a target of interest, e.g., the target, wherein the
activatable antibody comprises a masking moiety (MM), a CM1-CM2
substrate that is cleaved by the cleaving agent, and an antigen
binding domain or fragment thereof (AB) that specifically binds the
target of interest, wherein the activatable antibody in an
uncleaved, non-activated state comprises a structural arrangement
from N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB
or AB-CM1-CM2 substrate-MM; (a) wherein the MM is a peptide that
inhibits binding of the AB to the target, and wherein the MM does
not have an amino acid sequence of a naturally occurring binding
partner of the AB and is not a modified form of a natural binding
partner of the AB; and (b) wherein, in an uncleaved, non-activated
state, the MM interferes with specific binding of the AB to the
target, and in a cleaved, activated state the MM does not interfere
or compete with specific binding of the AB to the target; and (ii)
measuring a level of activated activatable antibody in the subject
or sample, wherein a detectable level of activated activatable
antibody in the subject or sample indicates that the cleaving agent
is present in the subject or sample and wherein no detectable level
of activated activatable antibody in the subject or sample
indicates that the cleaving agent is absent and/or not sufficiently
present in the subject or sample. In some embodiments, the
activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0424] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent and the target in
a subject or a sample, where the kits include at least an
activatable antibody comprises a masking moiety (MM), a CM1-CM2
substrate that is cleaved by the cleaving agent, and an antigen
binding domain or fragment thereof (AB) that specifically binds the
target of interest, wherein the activatable antibody in an
uncleaved, non-activated state comprises a structural arrangement
from N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB
or AB-CM1-CM2 substrate-MM; (a) wherein the MM is a peptide that
inhibits binding of the AB to the target, and wherein the MM does
not have an amino acid sequence of a naturally occurring binding
partner of the AB and is not a modified form of a natural binding
partner of the AB; and (b) wherein, in an uncleaved, non-activated
state, the MM interferes with specific binding of the AB to the
target, and in a cleaved, activated state the MM does not interfere
or compete with specific binding of the AB to the target; and (ii)
measuring a level of activated activatable antibody in the subject
or sample, wherein a detectable level of activated activatable
antibody in the subject or sample indicates that the cleaving agent
is present in the subject or sample and wherein no detectable level
of activated activatable antibody in the subject or sample
indicates that the cleaving agent is absent and/or not sufficiently
present in the subject or sample. In some embodiments, the
activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0425] The disclosure also provides methods of detecting presence
or absence of a cleaving agent in a subject or a sample by (i)
contacting a subject or sample with an activatable antibody,
wherein the activatable antibody comprises a masking moiety (MM), a
CM1-CM2 substrate that is cleaved by the cleaving agent, an antigen
binding domain (AB) that specifically binds the target, and a
detectable label, wherein the activatable antibody in an uncleaved,
non-activated state comprises a structural arrangement from
N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB or
AB-CM1-CM2 substrate-MM; wherein the MM is a peptide that inhibits
binding of the AB to the target, and wherein the MM does not have
an amino acid sequence of a naturally occurring binding partner of
the AB and is not a modified form of a natural binding partner of
the AB; wherein, in an uncleaved, non-activated state, the MM
interferes with specific binding of the AB to the target, and in a
cleaved, activated state the MM does not interfere or compete with
specific binding of the AB to the target; and wherein the
detectable label is positioned on a portion of the activatable
antibody that is released following cleavage of the CM1-CM2
substrate; and (ii) measuring a level of detectable label in the
subject or sample, wherein a detectable level of the detectable
label in the subject or sample indicates that the cleaving agent is
absent and/or not sufficiently present in the subject or sample and
wherein no detectable level of the detectable label in the subject
or sample indicates that the cleaving agent is present in the
subject or sample. In some embodiments, the activatable antibody is
an activatable antibody to which a therapeutic agent is conjugated.
In some embodiments, the activatable antibody is not conjugated to
an agent. In some embodiments, the activatable antibody comprises a
detectable label. In some embodiments, the detectable label is
positioned on the AB. In some embodiments, measuring the level of
activatable antibody in the subject or sample is accomplished using
a secondary reagent that specifically binds to the activated
antibody, wherein the reagent comprises a detectable label. In some
embodiments, the secondary reagent is an antibody comprising a
detectable label.
[0426] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent and the target in
a subject or a sample, where the kits include at least an
activatable antibody and/or conjugated activatable antibody (e.g.,
an activatable antibody to which a therapeutic agent is conjugated)
described herein for use in contacting a subject or biological
sample and means for detecting the level of activated activatable
antibody and/or conjugated activatable antibody in the subject or
biological sample, wherein a detectable level of activated
activatable antibody in the subject or biological sample indicates
that the cleaving agent and the target are present in the subject
or biological sample and wherein no detectable level of activated
activatable antibody in the subject or biological sample indicates
that the cleaving agent, the target or both the cleaving agent and
the target are absent and/or not sufficiently present in the
subject or biological sample, such that the target binding and/or
protease cleavage of the activatable antibody cannot be detected in
the subject or biological sample.
[0427] The disclosure also provides methods of detecting presence
or absence of a cleaving agent in a subject or a sample by (i)
contacting a subject or biological sample with an activatable
antibody in the presence of the target, and (ii) measuring a level
of activated activatable antibody in the subject or biological
sample, wherein a detectable level of activated activatable
antibody in the subject or biological sample indicates that the
cleaving agent is present in the subject or biological sample and
wherein no detectable level of activated activatable antibody in
the subject or biological sample indicates that the cleaving agent
is absent and/or not sufficiently present in the subject or
biological sample at a detectable level, such that protease
cleavage of the activatable antibody cannot be detected in the
subject or biological sample. Such an activatable antibody includes
a masking moiety (MM), a CM1-CM2 substrate that is cleaved by the
cleaving agent, and an antigen binding domain or fragment thereof
(AB) that specifically binds the target, wherein the activatable
antibody in an uncleaved (i.e., non-activated) state comprises a
structural arrangement from N-terminus to C-terminus as follows:
MM-CM1-CM2 substrate-AB or AB-CM1-CM2 substrate-MM; (a) wherein the
MM is a peptide that inhibits binding of the AB to the target, and
wherein the MM does not have an amino acid sequence of a naturally
occurring binding partner of the AB; and (b) wherein the MM of the
activatable antibody in an uncleaved state interferes with specific
binding of the AB to the target, and wherein the MM of an
activatable antibody in a cleaved (i.e., activated) state does not
interfere or compete with specific binding of the AB to the target.
In some embodiments, the activatable antibody is an activatable
antibody to which a therapeutic agent is conjugated. In some
embodiments, the activatable antibody is not conjugated to an
agent. In some embodiments, the detectable label is attached to the
masking moiety. In some embodiments, the detectable label is
attached to the cleavable moiety N-terminal to the protease
cleavage site. In some embodiments, a single antigen binding site
of the AB is masked. In some embodiments wherein an antibody of the
disclosure has at least two antigen binding sites, at least one
antigen binding site is masked and at least one antigen binding
site is not masked. In some embodiments, all antigen binding sites
are masked. In some embodiments, the measuring step includes use of
a secondary reagent comprising a detectable label.
[0428] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent and the target in
a subject or a sample, where the kits include at least an
activatable antibody and/or conjugated activatable antibody
described herein for use in contacting a subject or biological
sample with an activatable antibody in the presence of the target,
and measuring a level of activated activatable antibody in the
subject or biological sample, wherein a detectable level of
activated activatable antibody in the subject or biological sample
indicates that the cleaving agent is present in the subject or
biological sample and wherein no detectable level of activated
activatable antibody in the subject or biological sample indicates
that the cleaving agent is absent and/or not sufficiently present
in the subject or biological sample at a detectable level, such
that protease cleavage of the activatable antibody cannot be
detected in the subject or biological sample. Such an activatable
antibody includes a masking moiety (MM), a CM1-CM2 substrate that
is cleaved by the cleaving agent, and an antigen binding domain or
fragment thereof (AB) that specifically binds the target, wherein
the activatable antibody in an uncleaved (i.e., non-activated)
state comprises a structural arrangement from N-terminus to
C-terminus as follows: MM-CM1-CM2 substrate-AB or AB-CM1-CM2
substrate-MM; (a) wherein the MM is a peptide that inhibits binding
of the AB to the target, and wherein the MM does not have an amino
acid sequence of a naturally occurring binding partner of the AB;
and (b) wherein the MM of the activatable antibody in an uncleaved
state interferes with specific binding of the AB to the target, and
wherein the MM of an activatable antibody in a cleaved (i.e.,
activated) state does not interfere or compete with specific
binding of the AB to the target. In some embodiments, the
activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the detectable label is attached to the masking
moiety. In some embodiments, the detectable label is attached to
the cleavable moiety N-terminal to the protease cleavage site. In
some embodiments, a single antigen binding site of the AB is
masked. In some embodiments wherein an antibody of the disclosure
has at least two antigen binding sites, at least one antigen
binding site is masked and at least one antigen binding site is not
masked. In some embodiments, all antigen binding sites are masked.
In some embodiments, the measuring step includes use of a secondary
reagent comprising a detectable label.
[0429] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent in a subject or a
sample, where the kits include at least an activatable antibody
and/or conjugated activatable antibody described herein for use in
contacting a subject or biological sample and means for detecting
the level of activated activatable antibody and/or conjugated
activatable antibody in the subject or biological sample, wherein
the activatable antibody includes a detectable label that is
positioned on a portion of the activatable antibody that is
released following cleavage of the CM11-CM2 substrate, wherein a
detectable level of activated activatable antibody in the subject
or biological sample indicates that the cleaving agent is absent
and/or not sufficiently present in the subject or biological sample
such that the target binding and/or protease cleavage of the
activatable antibody cannot be detected in the subject or
biological sample, and wherein no detectable level of activated
activatable antibody in the subject or biological sample indicates
that the cleaving agent is present in the subject or biological
sample at a detectable level.
[0430] The disclosure provides methods of detecting presence or
absence of a cleaving agent and the target in a subject or a sample
by (i) contacting a subject or biological sample with an
activatable antibody, wherein the activatable antibody includes a
detectable label that is positioned on a portion of the activatable
antibody that is released following cleavage of the CM1-CM2
substrate and (ii) measuring a level of activated activatable
antibody in the subject or biological sample, wherein a detectable
level of activated activatable antibody in the subject or
biological sample indicates that the cleaving agent, the target or
both the cleaving agent and the target are absent and/or not
sufficiently present in the subject or biological sample, such that
the target binding and/or protease cleavage of the activatable
antibody cannot be detected in the subject or biological sample,
and wherein a reduced detectable level of activated activatable
antibody in the subject or biological sample indicates that the
cleaving agent and the target are present in the subject or
biological sample. A reduced level of detectable label is, for
example, a reduction of about 5%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 95% and/or about 100%. Such an
activatable antibody includes a masking moiety (MM), a CM1-CM2
substrate that is cleaved by the cleaving agent, and an antigen
binding domain or fragment thereof (AB) that specifically binds the
target, wherein the activatable antibody in an uncleaved (i.e.,
non-activated) state comprises a structural arrangement from
N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB or
AB-CM1-CM2 substrate-MM; (a) wherein the MM is a peptide that
inhibits binding of the AB to the target, and wherein the MM does
not have an amino acid sequence of a naturally occurring binding
partner of the AB; and (b) wherein the MM of the activatable
antibody in an uncleaved state interferes with specific binding of
the AB to the target, and wherein the MM of an activatable antibody
in a cleaved (i.e., activated) state does not interfere or compete
with specific binding of the AB to the target. In some embodiments,
the activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0431] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent and the target in
a subject or a sample, where the kits include at least an
activatable antibody and/or conjugated activatable antibody
described herein for use in contacting a subject or biological
sample and means for detecting the level of activated activatable
antibody and/or conjugated activatable antibody in the subject or
biological sample, wherein a detectable level of activated
activatable antibody in the subject or biological sample indicates
that the cleaving agent, the target or both the cleaving agent and
the target are absent and/or not sufficiently present in the
subject or biological sample, such that the target binding and/or
protease cleavage of the activatable antibody cannot be detected in
the subject or biological sample, and wherein a reduced detectable
level of activated activatable antibody in the subject or
biological sample indicates that the cleaving agent and the target
are present in the subject or biological sample. A reduced level of
detectable label is, for example, a reduction of about 5%, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
400%, about 45%, about 50%, about 55%, about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, about 95% and/or
about 100%.
[0432] The disclosure also provides methods of detecting presence
or absence of a cleaving agent in a subject or a sample by (i)
contacting a subject or biological sample with an activatable
antibody, wherein the activatable antibody includes a detectable
label that is positioned on a portion of the activatable antibody
that is released following cleavage of the CM1-CM2 substrate; and
(ii) measuring a level of detectable label in the subject or
biological sample, wherein a detectable level of the detectable
label in the subject or biological sample indicates that the
cleaving agent is absent and/or not sufficiently present in the
subject or biological sample at a detectable level, such that
protease cleavage of the activatable antibody cannot be detected in
the subject or biological sample, and wherein a reduced detectable
level of the detectable label in the subject or biological sample
indicates that the cleaving agent is present in the subject or
biological sample. A reduced level of detectable label is, for
example, a reduction of about 5%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%, about 90%, about 95% and/or about 100%. Such an
activatable antibody includes a masking moiety (MM), a CM1-CM2
substrate that is cleaved by the cleaving agent, and an antigen
binding domain or fragment thereof (AB) that specifically binds the
target, wherein the activatable antibody in an uncleaved (i.e.,
non-activated) state comprises a structural arrangement from
N-terminus to C-terminus as follows: MM-CM1-CM2 substrate-AB or
AB-CM1-CM2 substrate-MM; (a) wherein the MM is a peptide that
inhibits binding of the AB to the target, and wherein the MM does
not have an amino acid sequence of a naturally occurring binding
partner of the AB; and (b) wherein the MM of the activatable
antibody in an uncleaved state interferes with specific binding of
the AB to the target, and wherein the MM of an activatable antibody
in a cleaved (i.e., activated) state does not interfere or compete
with specific binding of the AB to the target. In some embodiments,
the activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0433] The disclosure also provides kits for use in methods of
detecting presence or absence of a cleaving agent of interest in a
subject or a sample, where the kits include at least an activatable
antibody and/or conjugated activatable antibody described herein
for use in contacting a subject or biological sample and means for
detecting the level of activated activatable antibody and/or
conjugated activatable antibody in the subject or biological
sample, wherein the activatable antibody includes a detectable
label that is positioned on a portion of the activatable antibody
that is released following cleavage of the CM1-CM2 substrate,
wherein a detectable level of the detectable label in the subject
or biological sample indicates that the cleaving agent, the target,
or both the cleaving agent and the target are absent and/or not
sufficiently present in the subject or biological sample, such that
the target binding and/or protease cleavage of the activatable
antibody cannot be detected in the subject or biological sample,
and wherein a reduced detectable level of the detectable label in
the subject or biological sample indicates that the cleaving agent
and the target are present in the subject or biological sample. A
reduced level of detectable label is, for example, a reduction of
about 5%, about 10%, about 15%, about 200, about 25%, about 300,
about 35%, about 400, about 45%, about 500, about 55%, about 60%,
about 65%, about 70%, about 75%, about 80%, about 85%, about 90%,
about 95% and/or about 100%.
[0434] In some embodiments of these methods and kits, the
activatable antibody includes a detectable label. In some
embodiments of these methods and kits, the detectable label
includes an imaging agent, a contrasting agent, an enzyme, a
fluorescent label, a chromophore, a dye, one or more metal ions, or
a ligand-based label. In some embodiments of these methods and
kits, the imaging agent comprises a radioisotope. In some
embodiments of these methods and kits, the radioisotope is indium
or technetium. In some embodiments of these methods and kits, the
contrasting agent comprises iodine, gadolinium or iron oxide. In
some embodiments of these methods and kits, the enzyme comprises
horseradish peroxidase, alkaline phosphatase, or 3-galactosidase.
In some embodiments of these methods and kits, the fluorescent
label comprises yellow fluorescent protein (YFP), cyan fluorescent
protein (CFP), green fluorescent protein (GFP), modified red
fluorescent protein (mRFP), red fluorescent protein tdimer2 (RFP
tdimer2), HCRED, or a europium derivative. In some embodiments of
these methods and kits, the luminescent label comprises an
N-methylacrydium derivative. In some embodiments of these methods,
the label comprises an Alexa Fluor.RTM. label, such as Alex
Fluor.RTM. 680 or Alexa Fluor.RTM. 750. In some embodiments of
these methods and kits, the ligand-based label comprises biotin,
avidin, streptavidin or one or more haptens.
[0435] In some embodiments of these methods and kits, the subject
is a mammal. In some embodiments of these methods and kits, the
subject is a human. In some embodiments, the subject is a non-human
mammal, such as a non-human primate, companion animal (e.g., cat,
dog, horse), farm animal, work animal, or zoo animal. In some
embodiments, the subject is a rodent.
[0436] In some embodiments of these methods, the method is an in
vivo method. In some embodiments of these methods, the method is an
in situ method. In some embodiments of these methods, the method is
an ex vivo method. In some embodiments of these methods, the method
is an in vitro method.
[0437] In some embodiments, in situ imaging and/or in vivo imaging
are useful in methods to identify which patients to treat. For
example, in in situ imaging, the activatable antibodies are used to
screen patient samples to identify those patients having the
appropriate protease(s) and target(s) at the appropriate location,
e.g., at a tumor site.
[0438] In some embodiments, in situ imaging is used to identify or
otherwise refine a patient population suitable for treatment with
an activatable antibody of the disclosure. For example, patients
that test positive for both the target (e.g., the target) and a
protease that cleaves the substrate in the CM1-CM2 substrate of the
activatable antibody being tested (e.g., accumulate activated
antibodies at the disease site) are identified as suitable
candidates for treatment with such an activatable antibody
comprising such a CM1-CM2 substrate. Likewise, patients that test
negative for either or both of the target (e.g., the target) and
the protease that cleaves the substrate in the CM1-CM2 substrate in
the activatable antibody being tested using these methods might be
identified as suitable candidates for another form of therapy. In
some embodiments, such patients that test negative with respect to
a first activatable antibody can be tested with other activatable
antibodies comprising different CM1-CM2 substrates until a suitable
activatable antibody for treatment is identified (e.g., an
activatable antibody comprising a CM1-CM2 substrate that is cleaved
by the patient at the site of disease). In some embodiments, the
patient is then administered a therapeutically effective amount of
the conjugated activatable antibody for which the patient tested
positive.
[0439] In some embodiments, in vivo imaging is used to identify or
otherwise refine a patient population suitable for treatment with
an activatable antibody of the disclosure. For example, patients
that test positive for both the target (e.g., the target) and a
protease that cleaves the substrate in the CM1-CM2 substrate of the
activatable antibody being tested (e.g., accumulate activated
antibodies at the disease site) are identified as suitable
candidates for treatment with such an activatable antibody
comprising such a CM1-CM2 substrate. Likewise, patients that test
negative might be identified as suitable candidates for another
form of therapy. In some embodiments, such patients that test
negative with respect to a first activatable antibody can be tested
with other activatable antibodies comprising different CM1-CM2
substrates until a suitable activatable antibody for treatment is
identified (e.g., an activatable antibody comprising a CM1-CM2
substrate that is cleaved by the patient at the site of disease).
In some embodiments, the patient is then administered a
therapeutically effective amount of the conjugated activatable
antibody for which the patient tested positive.
[0440] In some embodiments of the methods and kits, the method or
kit is used to identify or otherwise refine a patient population
suitable for treatment with an activatable antibody of the
disclosure. For example, patients that test positive for both the
target (e.g., the target) and a protease that cleaves the substrate
in the CM1-CM2 substrate of the activatable antibody being tested
in these methods are identified as suitable candidates for
treatment with such an activatable antibody comprising such a
CM1-CM2 substrate. Likewise, patients that test negative for both
of the targets (e.g., the target) and the protease that cleaves the
substrate in the CM1-CM2 substrate in the activatable antibody
being tested using these methods might be identified as suitable
candidates for another form of therapy. In some embodiments, such
patients can be tested with other activatable antibodies until a
suitable activatable antibody for treatment is identified (e.g., an
activatable antibody comprising a CM1-CM2 substrate that is cleaved
by the patient at the site of disease). In some embodiments,
patients that test negative for either of the target (e.g., the
target) are identified as suitable candidates for treatment with
such an activatable antibody comprising such a CM1-CM2 substrate.
In some embodiments, patients that test negative for either of the
target (e.g., the target) are identified as not being suitable
candidates for treatment with such an activatable antibody
comprising such a CM1-CM2 substrate. In some embodiments, such
patients can be tested with other activatable antibodies until a
suitable activatable antibody for treatment is identified (e.g., an
activatable antibody comprising a CM1-CM2 substrate that is cleaved
by the patient at the site of disease). In some embodiments, the
activatable antibody is an activatable antibody to which a
therapeutic agent is conjugated. In some embodiments, the
activatable antibody is not conjugated to an agent. In some
embodiments, the activatable antibody comprises a detectable label.
In some embodiments, the detectable label is positioned on the AB.
In some embodiments, measuring the level of activatable antibody in
the subject or sample is accomplished using a secondary reagent
that specifically binds to the activated antibody, wherein the
reagent comprises a detectable label. In some embodiments, the
secondary reagent is an antibody comprising a detectable label.
[0441] In some embodiments, a method or kit is used to identify or
otherwise refine a patient population suitable for treatment with
an anti-the target activatable antibody and/or conjugated
activatable antibody (e.g., activatable antibody to which a
therapeutic agent is conjugated) of the disclosure, followed by
treatment by administering that activatable antibody and/or
conjugated activatable antibody to a subject in need thereof. For
example, patients that test positive for both the targets (e.g.,
the target) and a protease that cleaves the CM1-CM2 substrate of
the activatable antibody and/or conjugated activatable antibody
being tested in these methods are identified as suitable candidates
for treatment with such antibody and/or such a conjugated
activatable antibody comprising such a CM1-CM2 substrate, and the
patient is then administered a therapeutically effective amount of
the activatable antibody and/or conjugated activatable antibody
that was tested. Likewise, patients that test negative for either
or both of the target (e.g., the target) and the protease that
cleaves the substrate in the CM1-CM2 substrate in the activatable
antibody being tested using these methods might be identified as
suitable candidates for another form of therapy. In some
embodiments, such patients can be tested with other antibody and/or
conjugated activatable antibody until a suitable antibody and/or
conjugated activatable antibody for treatment is identified (e.g.,
an activatable antibody and/or conjugated activatable antibody
comprising a CM1-CM2 substrate that is cleaved by the patient at
the site of disease). In some embodiments, the patient is then
administered a therapeutically effective amount of the activatable
antibody and/or conjugated for which the patient tested
positive.
[0442] In some embodiments of these methods and kits, the MM is a
peptide having a length from about 4 to 40 amino acids. In some
embodiments of these methods and kits, the activatable antibody
comprises a linker peptide, wherein the linker peptide is
positioned between the MM and the CM1-CM2 substrate. In some
embodiments of these methods and kits, the activatable antibody
comprises a linker peptide, where the linker peptide is positioned
between the AB and the CM1-CM2 substrate. In some embodiments of
these methods and kits, the activatable antibody comprises a first
linker peptide (L1) and a second linker peptide (L2), wherein the
first linker peptide is positioned between the MM and the CM1-CM2
substrate and the second linker peptide is positioned between the
AB and the CM1-CM2 substrate. In some embodiments of these methods
and kits, each of L1 and L2 is a peptide of about 1 to 20 amino
acids in length, and wherein each of L1 and L2 need not be the same
linker. In some embodiments of these methods and kits, one or both
of L1 and L2 comprises a glycine-serine polymer. In some
embodiments of these methods and kits, at least one of L1 and L2
comprises an amino acid sequence selected from the group consisting
of (GS)n, (GSGGS)n (SEQ ID NO: 381) and (GGGS)n (SEQ ID NO: 382),
where n is an integer of at least one. In some embodiments of these
methods and kits, at least one of L1 and L2 comprises an amino acid
sequence having the formula (GGS)n, where n is an integer of at
least one. In some embodiments of these methods and kits, at least
one of L1 and L2 comprises an amino acid sequence selected from the
group consisting of Gly-Gly-Ser-Gly (SEQ ID NO: 383),
Gly-Gly-Ser-Gly-Gly (SEQ ID NO: 384), Gly-Ser-Gly-Ser-Gly (SEQ ID
NO: 385), Gly-Ser-Gly-Gly-Gly (SEQ ID NO: 386), Gly-Gly-Gly-Ser-Gly
(SEQ ID NO: 387), and Gly-Ser-Ser-Ser-Gly (SEQ ID NO: 388).
[0443] In some embodiments of these methods and kits, the AB
comprises an antibody or antibody fragment sequence selected from
the cross-reactive antibody sequences presented herein. In some
embodiments of these methods and kits, the AB comprises a Fab
fragment, a scFv or a single chain antibody (scAb).
[0444] In some embodiments of these methods and kits, the cleaving
agent is a protease that is co-localized in the subject or sample
with the target and the CM1-CM2 substrate is a polypeptide that
functions as a substrate for the protease, wherein the protease
cleaves the CM1-CM2 substrate in the activatable antibody when the
activatable antibody is exposed to the protease. In some
embodiments of these methods and kits, each of the CM1 substrate
sequence and the CM2 substrate sequence in the CM1-CM2 substrate is
independently a polypeptide of up to 15 amino acids in length. In
some embodiments of these methods and kits, the CM1-CM2 substrate
is coupled to the N-terminus of the AB. In some embodiments of
these methods and kits, the CM1-CM2 substrate is coupled to the
C-terminus of the AB. In some embodiments of these methods and
kits, the CM1-CM2 substrate is coupled to the N-terminus of a VL
chain of the AB.
[0445] The activatable antibodies and/or conjugated activatable
antibodies of the disclosure are used in diagnostic and
prophylactic formulations. In one embodiment, an activatable
antibody is administered to patients that are at risk of developing
one or more of the aforementioned inflammation, inflammatory
disorders, cancer or other disorders.
[0446] A patient's or organ's predisposition to one or more of the
aforementioned disorders can be determined using genotypic,
serological or biochemical markers.
[0447] In some embodiments, an activatable antibody and/or
conjugated activatable antibodies is administered to human
individuals diagnosed with a clinical indication associated with
one or more of the aforementioned disorders. Upon diagnosis, an
activatable antibody and/or conjugated activatable antibodies is
administered to mitigate or reverse the effects of the clinical
indication.
[0448] Activatable antibodies and/or conjugated activatable
antibodies of the disclosure are also useful in the detection of
the target in patient samples and accordingly are useful as
diagnostics. For example, the activatable antibodies and/or
conjugated activatable antibodies of the disclosure are used in in
vitro assays, e.g., ELISA, to detect target levels in a patient
sample.
[0449] In one embodiment, an activatable antibody of the disclosure
is immobilized on a solid support (e.g., the well(s) of a
microtiter plate). The immobilized activatable antibody serves as a
capture antibody for any target that may be present in a test
sample. Prior to contacting the immobilized antibody with a patient
sample, the solid support is rinsed and treated with a blocking
agent such as milk protein or albumin to prevent nonspecific
adsorption of the analyte.
[0450] Subsequently the wells are treated with a test sample
suspected of containing the antigen, or with a solution containing
a standard amount of the antigen. Such a sample is, e.g., a serum
sample from a subject suspected of having levels of circulating
antigen considered to be diagnostic of a pathology. After rinsing
away the test sample or standard, the solid support is treated with
a second antibody that is detectably labeled. The labeled second
antibody serves as a detecting antibody. The level of detectable
label is measured, and the concentration of target antigen in the
test sample is determined by comparison with a standard curve
developed from the standard samples.
[0451] It will be appreciated that based on the results obtained
using the antibodies of the disclosure in an in vitro diagnostic
assay, it is possible to stage a disease in a subject based on
expression levels of the Target antigen. For a given disease,
samples of blood are taken from subjects diagnosed as being at
various stages in the progression of the disease, and/or at various
points in the therapeutic treatment of the disease. Using a
population of samples that provides statistically significant
results for each stage of progression or therapy, a range of
concentrations of the antigen that may be considered characteristic
of each stage is designated.
[0452] Activatable antibodies and/or conjugated activatable
antibodies can also be used in diagnostic and/or imaging methods.
In some embodiments, such methods are in vitro methods. In some
embodiments, such methods are in vivo methods. In some embodiments,
such methods are in situ methods. In some embodiments, such methods
are ex vivo methods. For example, activatable antibodies having an
enzymatically cleavable CM1-CM2 substrate can be used to detect the
presence or absence of an enzyme that is capable of cleaving the
CM1-CM2 substrate. Such activatable antibodies can be used in
diagnostics, which can include in vivo detection (e.g., qualitative
or quantitative) of enzyme activity (or, in some embodiments, an
environment of increased reduction potential such as that which can
provide for reduction of a disulfide bond) through measured
accumulation of activated antibodies (i.e., antibodies resulting
from cleavage of an activatable antibody) in a given cell or tissue
of a given host organism. Such accumulation of activated antibodies
indicates not only that the tissue expresses enzymatic activity (or
an increased reduction potential depending on the nature of the
CM1-CM2 substrate) but also that the tissue expresses target to
which the activated antibody binds.
[0453] For example, the CM1-CM2 substrate can be selected to be a
protease substrate for a protease found at the site of a tumor, at
the site of a viral or bacterial infection at a biologically
confined site (e.g., such as in an abscess, in an organ, and the
like), and the like. The AB can be one that binds a target antigen.
Using methods familiar to one skilled in the art, a detectable
label (e.g., a fluorescent label or radioactive label or
radiotracer) can be conjugated to an AB or other region of an
activatable antibody. Suitable detectable labels are discussed in
the context of the above screening methods and additional specific
examples are provided below. Using an AB specific to a protein or
peptide of the disease state, along with a protease whose activity
is elevated in the disease tissue of interest, activatable
antibodies will exhibit an increased rate of binding to disease
tissue relative to tissues where the CM1-CM2 substrate specific
enzyme is not present at a detectable level or is present at a
lower level than in disease tissue or is inactive (e.g., in zymogen
form or in complex with an inhibitor). Since small proteins and
peptides are rapidly cleared from the blood by the renal filtration
system, and because the enzyme specific for the CM1-CM2 substrate
is not present at a detectable level (or is present at lower levels
in non-disease tissues or is present in inactive conformation),
accumulation of activated antibodies in the disease tissue is
enhanced relative to non-disease tissues.
[0454] In another example, activatable antibodies can be used to
detect the presence or absence of a cleaving agent in a sample. For
example, where the activatable antibodies contain a CM1-CM2
substrate susceptible to cleavage by an enzyme, the activatable
antibodies can be used to detect (either qualitatively or
quantitatively) the presence of an enzyme in the sample. In another
example, where the activatable antibodies contain a CM1-CM2
substrate susceptible to cleavage by reducing agent, the
activatable antibodies can be used to detect (either qualitatively
or quantitatively) the presence of reducing conditions in a sample.
To facilitate analysis in these methods, the activatable antibodies
can be detectably labeled, and can be bound to a support (e.g., a
solid support, such as a slide or bead). The detectable label can
be positioned on a portion of the activatable antibody that is not
released following cleavage, for example, the detectable label can
be a quenched fluorescent label or other label that is not
detectable until cleavage has occurred. The assay can be conducted
by, for example, contacting the immobilized, detectably labeled
activatable antibodies with a sample suspected of containing an
enzyme and/or reducing agent for a time sufficient for cleavage to
occur, then washing to remove excess sample and contaminants. The
presence or absence of the cleaving agent (e.g., enzyme or reducing
agent) in the sample is then assessed by a change in detectable
signal of the activatable antibodies prior to contacting with the
sample e.g., the presence of and/or an increase in detectable
signal due to cleavage of the activatable antibody by the cleaving
agent in the sample.
[0455] Such detection methods can be adapted to also provide for
detection of the presence or absence of a target that is capable of
binding the AB of the activatable antibodies when cleaved. Thus,
the assays can be adapted to assess the presence or absence of a
cleaving agent and the presence or absence of a target of interest.
The presence or absence of the cleaving agent can be detected by
the presence of and/or an increase in detectable label of the
activatable antibodies as described above, and the presence or
absence of the target can be detected by detection of a target-AB
complex e.g., by use of a detectably labeled anti-target
antibody.
[0456] Activatable antibodies are also useful in in situ imaging
for the validation of activatable antibody activation, e.g., by
protease cleavage, and binding to a particular target. In situ
imaging is a technique that enables localization of proteolytic
activity and target in biological samples such as cell cultures or
tissue sections. Using this technique, it is possible to confirm
both binding to a given target and proteolytic activity based on
the presence of a detectable label (e.g., a fluorescent label).
[0457] These techniques are useful with any frozen cells or tissue
derived from a disease site (e.g. tumor tissue) or healthy tissues.
These techniques are also useful with fresh cell or tissue
samples.
[0458] In these techniques, an activatable antibody is labeled with
a detectable label. The detectable label may be a fluorescent dye,
(e.g. Fluorescein Isothiocyanate (FITC), Rhodamine Isothiocyanate
(TRITC), a near infrared (NIR) dye (e.g., Qdot.RTM. nanocrystals),
a colloidal metal, a hapten, a radioactive marker, biotin and an
amplification reagent such as streptavidin, or an enzyme (e.g.
horseradish peroxidase or alkaline phosphatase).
[0459] Detection of the label in a sample that has been incubated
with the labeled, activatable antibody indicates that the sample
contains the target and contains a protease that is specific for
the CM1-CM2 substrate of the activatable antibody. In some
embodiments, the presence of the protease can be confirmed using
broad spectrum protease inhibitors such as those described herein,
and/or by using an agent that is specific for the protease, for
example, an antibody such as A11, which is specific for the
protease matriptase (MT-SP1) and inhibits the proteolytic activity
of matriptase; see e.g., International Publication Number WO
2010/129609, published 11 Nov. 2010. The same approach of using
broad spectrum protease inhibitors such as those described herein,
and/or by using a more selective inhibitory agent can be used to
identify a protease or class of proteases specific for the CM1-CM2
substrate of the activatable antibody. In some embodiments, the
presence of the target can be confirmed using an agent that is
specific for the target, e.g., another antibody, or the detectable
label can be competed with unlabeled target. In some embodiments,
unlabeled activatable antibody could be used, with detection by a
labeled secondary antibody or more complex detection system.
[0460] Similar techniques are also useful for in vivo imaging where
detection of the fluorescent signal in a subject, e.g., a mammal,
including a human, indicates that the disease site contains the
target and contains a protease that is specific for the CM1-CM2
substrate of the activatable antibody.
[0461] These techniques are also useful in kits and/or as reagents
for the detection, identification or characterization of protease
activity in a variety of cells, tissues, and organisms based on the
protease-specific CM1-CM2 substrate in the activatable
antibody.
[0462] In some embodiments, in situ imaging and/or in vivo imaging
are useful in methods to identify which patients to treat. For
example, in in situ imaging, the activatable antibodies are used to
screen patient samples to identify those patients having the
appropriate protease(s) and target(s) at the appropriate location,
e.g., at a tumor site.
[0463] In some embodiments, in situ imaging is used to identify or
otherwise refine a patient population suitable for treatment with
an activatable antibody of the disclosure. For example, patients
that test positive for both the target and a protease that cleaves
the substrate in the cleavable moiety (CM1-CM2 substrate) of the
activatable antibody being tested (e.g., accumulate activated
antibodies at the disease site) are identified as suitable
candidates for treatment with such an activatable antibody
comprising such a CM1-CM2 substrate. Likewise, patients that test
negative for either or both of the target and the protease that
cleaves the substrate in the CM1-CM2 substrate in the activatable
antibody being tested using these methods are identified as
suitable candidates for another form of therapy (i.e., not suitable
for treatment with the activatable antibody being tested). In some
embodiments, such patients that test negative with respect to a
first activatable antibody can be tested with other activatable
antibodies comprising different CMs until a suitable activatable
antibody for treatment is identified (e.g., an activatable antibody
comprising a CM1-CM2 substrate that is cleaved by the patient at
the site of disease).
[0464] In some embodiments, in vivo imaging is used to identify or
otherwise refine a patient population suitable for treatment with
an activatable antibody of the disclosure. For example, patients
that test positive for both the target and a protease that cleaves
the substrate in the cleavable moiety (CM1-CM2 substrate) of the
activatable antibody being tested (e.g., accumulate activated
antibodies at the disease site) are identified as suitable
candidates for treatment with such an activatable antibody
comprising such a CM1-CM2 substrate. Likewise, patients that test
negative are identified as suitable candidates for another form of
therapy (i.e., not suitable for treatment with the activatable
antibody being tested). In some embodiments, such patients that
test negative with respect to a first activatable antibody can be
tested with other activatable antibodies comprising different CMs
until a suitable activatable antibody for treatment is identified
(e.g., an activatable antibody comprising a CM1-CM2 substrate that
is cleaved by the patient at the site of disease).
[0465] Pharmaceutical Compositions
[0466] The conjugated antibodies, activatable antibodies and/or
conjugated activatable antibodies of the disclosure (also referred
to herein as "active compounds"), and derivatives, fragments,
analogs and homologs thereof, can be incorporated into
pharmaceutical compositions suitable for administration. Such
compositions typically comprise the conjugated antibody,
activatable antibody and/or conjugated activatable antibody and a
pharmaceutically acceptable carrier. As used herein, the term
"pharmaceutically acceptable carrier" is intended to include any
and all solvents, dispersion media, coatings, antibacterial and
antifungal agents, isotonic and absorption delaying agents, and the
like, compatible with pharmaceutical administration. Suitable
carriers are described in the most recent edition of Remington's
Pharmaceutical Sciences, a standard reference text in the field,
which is incorporated herein by reference. Suitable examples of
such carriers or diluents include, but are not limited to, water,
saline, ringer's solutions, dextrose solution, and 5% human serum
albumin. Liposomes and non-aqueous vehicles such as fixed oils may
also be used. The use of such media and agents for pharmaceutically
active substances is well known in the art. Except insofar as any
conventional media or agent is incompatible with the active
compound, use thereof in the compositions is contemplated.
Supplementary active compounds can also be incorporated into the
compositions.
[0467] A pharmaceutical composition of the disclosure is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation),
transdermal (i.e., topical), transmucosal, and rectal
administration. Solutions or suspensions used for parenteral,
intradermal, or subcutaneous application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid (EDTA); buffers such as acetates,
citrates or phosphates, and agents for the adjustment of tonicity
such as sodium chloride or dextrose. The pH can be adjusted with
acids or bases, such as hydrochloric acid or sodium hydroxide. The
parenteral preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0468] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. For intravenous
administration, suitable carriers include physiological saline,
bacteriostatic water. Cremophor EL.TM. (BASF, Parsippany, N.J.) or
phosphate buffered saline (PBS). In all cases, the composition must
be sterile and should be fluid to the extent that easy
syringeability exists. It must be stable under the conditions of
manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), and suitable
mixtures thereof. The proper fluidity can be maintained, for
example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. Prevention of the action of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In some embodiments, it
will be desirable to include isotonic agents, for example, sugars,
polyalcohols such as manitol, sorbitol, sodium chloride in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent that
delays absorption, for example, aluminum monostearate and
gelatin.
[0469] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, methods of preparation are vacuum
drying and freeze-drying that yields a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0470] Oral compositions generally include an inert diluent or an
edible carrier. They can be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound can be incorporated with
excipients and used in the form of tablets, troches, or capsules.
Oral compositions can also be prepared using a fluid carrier for
use as a mouthwash, wherein the compound in the fluid carrier is
applied orally and swished and expectorated or swallowed.
Pharmaceutically compatible binding agents, and/or adjuvant
materials can be included as part of the composition. The tablets,
pills, capsules, troches and the like can contain any of the
following ingredients, or compounds of a similar nature: a binder
such as microcrystalline cellulose, gum tragacanth or gelatin; an
excipient such as starch or lactose, a disintegrating agent such as
alginic acid, Primogel, or corn starch; a lubricant such as
magnesium stearate or Sterotes; a glidant such as colloidal silicon
dioxide; a sweetening agent such as sucrose or saccharin; or a
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring.
[0471] For administration by inhalation, the compounds are
delivered in the form of an aerosol spray from pressured container
or dispenser that contains a suitable propellant, e.g., a gas such
as carbon dioxide, or a nebulizer.
[0472] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the active
compounds are formulated into ointments, salves, gels, or creams as
generally known in the art.
[0473] The compounds can also be prepared in the form of
suppositories (e.g., with conventional suppository bases such as
cocoa butter and other glycerides) or retention enemas for rectal
delivery.
[0474] In one embodiment, the active compounds are prepared with
carriers that will protect the compound against rapid elimination
from the body, such as a controlled release formulation, including
implants and microencapsulated delivery systems. Biodegradable,
biocompatible polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Methods for preparation of such formulations will
be apparent to those skilled in the art. The materials can also be
obtained commercially from Alza Corporation and Nova
Pharmaceuticals, Inc. Liposomal suspensions (including liposomes
targeted to infected cells with monoclonal antibodies to viral
antigens) can also be used as pharmaceutically acceptable carriers.
These can be prepared according to methods known to those skilled
in the art, for example, as described in U.S. Pat. No.
4,522,811.
[0475] It is especially advantageous to formulate oral or
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subject to be treated; each unit containing a
predetermined quantity of active compound calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms
of the disclosure are dictated by and directly dependent on the
unique characteristics of the active compound and the particular
therapeutic effect to be achieved, and the limitations inherent in
the art of compounding such an active compound for the treatment of
individuals.
[0476] The pharmaceutical compositions can be included in a
container, pack, or dispenser together with instructions for
administration.
[0477] The invention will be further described in the following
examples, which do not limit the scope of the invention described
in the claims.
Examples
Example 1
Matrix Metalloprotease (MMP) and Serine Protease (SP) Cleavable
Anti-Jagged Activatable Antibodies
[0478] This Example demonstrates the generation and evaluation of
activatable antibodies that bind a Jagged target, e.g., Jagged 1
and/or Jagged 2, where the activatable antibodies are activated in
the presence of at least one matrix metalloprotease (MMP) and at
least one serine protease.
[0479] The studies described herein used the following substrate
sequences, where LP' is a linking peptide between CM1 and CM2. For
the CM1-CM2 substrate 1001/LP'/0001, LP' is GGSGGS (SEQ ID NO:
350), and for all other CM1-CM2 in the Table below, LP' is GG:
TABLE-US-00013 CM1-CM2 Substrate AA sequence SEQ ID NO: 2001
ISSGLLSGRSDNH 1 1001/LP'/0001 ISSGLLSSGGSGGSLSGRSDNH 2
1004/LP'/0003 AVGLLAPPGGTSTSGRSANPRG 3 0003/LP'/1004
TSTSGRSANPRGGGAVGLLAPP 4 1003/LP'/0003 VHMPLGFLGPGGTSTSGRSANPRG 5
0003/LP'/1003 TSTSGRSANPRGGGVHMPLGFLGP 6 1004/LP'/0001
AVGLLAPPGGLSGRSDNH 7 0001/LP'/1004 LSGRSDNHGGAVGLLAPP 8
1003/LP'/0001 VHMPLGFLGPGGLSGRSDNH 9 0001/LP'/1003
LSGRSDNHGGVHMPLGFLGP 10
[0480] Construction of the Anti-Jagged activatable antibody light
chains was performed as follows.
[0481] The CM1-CM2 substrates were incorporated into the Jagged
activatable antibody vector (described in PCT Publication No.
WO2013/192550) as follows. Using standard molecular biology
techniques, the forward (F) primers encoding the CM1-CM2 substrates
(see Table A) and the reverse (R) primer CX1198 were used to
amplify the substrate and VL domain of the Jagged activatable
antibody and were subsequently cloned into the activatable antibody
vector using the XhoI and BsiWI restriction sites. The resulting
vectors encoded the following anti-Jagged activatable antibody
light chains.
TABLE-US-00014 TABLE A Primers used to construct the CM1-CM2
expression vectors CX1198 Light chain R
Gtgcagccaccgtacgtttgatttccaccttggtccc (SEQ ID NO: 37) CX2066 2001 F
CaggggggctcgagcGGCGGCTCTATCTCTTCCGGACTGCT
GTCCGGCAGATCCGACAATCACGGCGGAGGCTCTGacatcc agatgacccagtctc (SEQ ID
NO: 38) CX2067 1001/LP'/0001 F
CaggggggctcgagcGGCGGCTCTATCTCTTCTGGCCTGCT
GTCTAGCGGCGGCTCCGGCGGATCTCTGTCTGGCAGATCTG
ACAACCACGGCGGAGGCTCCGacatccagatgacccagtct c (SEQ ID NO: 39) CX2190
1004/LP'/0003 F CaggggggctcgagcGGAGGATCTGCTGTGGGACTGCTGGC
TCCTCCTGGCGGCACATCTACCTCTGGCAGATCCGCCAACC
CTCGGGGCGGAGGATCTGacatccagatgacccagtctc (SEQ ID NO: 40) CX2191
0003/LP'/1004 F CaggggggctcgagcGGCGGCTCCACATCTACCTCTGGCAG
ATCCGCCAACCCCAGAGGTGGCGGAGCTGTGGGACTGCTGG
CTCCACCAGGCGGATCTGacatccagatgacccagtctc (SEQ ID NO: 41) CX2192
1003/LP'/0003 F CaggggggctcgagcGGCGGCTCTGTGCATATGCCCCTGGG
CTTTCTGGGCCCTGGCGGCACATCTACCTCTGGCAGATCCG
CCAACCCTCGGGGCGGAGGATCTGacatccagatgacccag tctc (SEQ ID NO: 42)
CX2193 0003/LP'/1003 F CaggggggctcgagcGGCGGCTCCACATCTACCTCTGGCAG
ATCCGCCAACCCCAGAGGCGGCGGAGTGCATATGCCTCTGG
GCTTTCTGGGACCTGGCGGCTCTGacatccagatgacccag tctc (SEQ ID NO: 43)
CX2242 1004/LP'/0001 F CaggggggctcgagcGGAGGATCTGCTGTGGGACTGCTGGC
TCCTCCTGGTGGCCTGTCTGGCAGATCTGATAACCACGGCG
GCTCCGacatccagatgacccagtctc (SEQ ID NO: 44) CX2243 0001/LP'/1004 F
CaggggggctcgagcGGAGGCTCTGGCCTGTCTGGCAGATC
CGATAACCATGGCGGCGCTGTGGGACTGCTGGCTCCTCCTG
GTGGATCTGacatccagatgacccagtctc (SEQ ID NO: 45) CX2244 1003/LP'/0001
F CaggggggctcgagcGGCGGCTCTGTGCATATGCCCCTGGG
CTTTCTGGGACCTGGCGGCCTGTCTGGCAGATCCGATAATC
ACGGCGGCTCCGacatccagatgacccagtctc (SEQ ID NO: 46) CX2245
0001/LP'/1003 F CaggggggctcgagcGGAGGCTCTGGCCTGTCTGGCAGATC
TGATAACCACGGCGGCGTGCACATGCCCCTGGGCTTTCTGG
GACCTGGCGGATCTGacatccagatgacccagtctc (SEQ ID NO: 47)
TABLE-US-00015 Anti-Jagged 2001 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 48)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctctatctcttccggactgctgtccggcagatccgacaatcacggcggagg
ctctgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcacc
atcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccaggga
aagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaaggttcag
tggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgca
acttactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaaggtggaaa
tcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatc
tggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtgg
aaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaagg
acagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagt
ctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggga
gagtgt Amino Acid sequence (SEQ ID NO: 49)
QGQSGQCNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDNHGGGSDIQMTQSPSSLSASVGDRVT
ITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA
TYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW
KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPYTKSFNRG EC
Anti-Jagged 2001 activatable antibody Lc Nucleotide sequence (SEQ
ID NO: 419)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctcta
tctcttccggactgctgtccggcagatccgacaatcacggcggaggctctgacatccagatgac
ccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagt
cagagcattagcagctatttaaattggtatcagcagaaaccagggaaagcccctaagctcctga
tctatgcggcatccagtttgcaaagtggggtcccatcaaggttcagtggcagtggatctgggac
agatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttactactgtcaacag
acggttgtggcgcctccgttattcggccaagggaccaaggtggaaatcaaacgtacggtggctg
caccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgt
gtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctc
caatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctca
gcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcac
ccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt Amino Acid
sequence (SEQ ID NO: 420)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDNHGGGSDIQMTQSPSSLSASVGDRVTITCRAS
QSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ
TWAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAPCVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-Jagged activatable antibody 1001/LP'/0001 Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 50)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctctatctcttctggcctgctgtctagcggcggctccggcggatctctgtc
tggcagatctgacaaccacggcggaggctccgacatccagatgacccagtctccatcctccctg
tctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatt
taaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagttt
gcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatc
agcagtctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgt
tattcggccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatctt
cccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttc
tatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccagg
agagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgag
caaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcg
cccgtcacaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO:
51)
QGQSGQCNIWLVGGDCRGWQGGSSGGSISSGLLSSGGSGGSLSGRSDNHGGGSDIQMTQSPSSL
SASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTI
SSLQPEDFATYYCQQTWAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS
PVTKSFNRGEC Anti-Jagged activatable antibody 1001/LP'/0001 Lc
Nucleotide sequence (SEQ ID NO: 421)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctcta
tctcttctggcctgctgtctagcggcggctccggcggatctctgtctggcagatctgacaacca
cggcggaggctccgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagac
agagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcaga
aaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatc
aaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaa
gattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaagggacca
aggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagca
gttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaa
gtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcagg
acagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaa
acacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttc
aacaggggagagtgt Amino Acid sequence (SEQ ID NO: 422)
CNIWLVGGDCRGWQGGSSGGSISSGLLSSGGSGGSLSGRSDNHGGGSDIQMTQSPSSLSASVGD
RVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPE
DFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC Anti-Jagged 1004/LP'/0003 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 52)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggaggatctgctgtgggactgctggctcctcctggcggcacatctacctctggcag
atccgccaaccctcggggcggaggatctgacatccagatgacccagtctccatcctccctgtct
gcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaa
attggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgca
aagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagc
agtctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttat
tcggccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttccc
gccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctat
cccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga
gtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaa
agcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgccc
gtcacaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 53)
QGQSGQCNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGTSTSGRSANPRGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTIS
SLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAPCVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP
VTKSFNRGEC Anti-Jagged 1004/LP'/0003 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 423)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggaggatctg
ctgtgggactgctggctcctcctggcggcacatctacctctggcagatccgccaaccctcgggg
cggaggatctgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacaga
gtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaac
cagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaag
gttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagat
tttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaagg
tggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagtt
gaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagta
cagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggaca
gcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca
caaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaac
aggggagagtgt Amino Acid sequence (SEQ ID NO: 424)
CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGTSTSGRSANPRGGGSDIQMTQSPSSLSASVGDR
VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPED
FATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN
RGEC Anti-Jagged 0003/LP'/1004 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 54)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctccacatctacctctggcagatccgccaaccccagaggtggcggagctgt
gggactgctggctccaccaggcggatctgacatccagatgacccagtctccatcctccctgtct
gcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaa
attggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgca
aagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagc
agtctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttat
tcggccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttccc
gccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctat
cccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggaga
gtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaa
agcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgccc
gtcacaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 55)
QGQSGQCNIWLVGGDCRGWQGGSSGGSTSTSGRSANPRGGGAVGLLAPPGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTIS
SLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP
VTKSFNRGEC Anti-Jagged 0003/LP'/1004 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 425)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctcca
catctacctctggcagatccgccaaccccagaggtggcggagctgtgggactgctggctccacc
aggcggatctgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacaga
gtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaac
cagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaag
gttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagat
tttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaagg
tggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagtt
gaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagta
cagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggaca
gcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaaca
caaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaac
aggggagagtgt Amino Acid sequence (SEQ ID NO: 426)
CNIWLVGGDCRGWQGGSSGGSTSTSGRSANPRGGGAVGLLAPPGGSDIQMTQSPSSLSASVGDR
VTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPED
FATYYCQQTWAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN
RGEC Anti-Jagged 1003/LP'/0003 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 56)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctctgtgcatatgcccctgggctttctgggccctggcggcacatctacctc
tggcagatccgccaaccctcggggcggaggatctgacatccagatgacccagtctccatcctcc
ctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagct
atttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccag
tttgcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcacc
atcagcagtctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctc
cgttattcggccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcat
cttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataac
ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccc
aggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgct
gagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagc
tcgcccgtcacaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID
NO: 57)
QGQSGQCNIWLVGGDCRGWQGGSSGGSVHMPLGFLGPGGTSTSGRSANPRGGGSDIQMTQSPSS
LSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLT
ISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN
FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS
SPYTKSFNRGEC Anti-Jagged 1003/LP'/0003 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 427)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctctg
tgcatatgcccctgggctttctgggccctggcggcacatctacctctggcagatccgccaaccc
tcggggcggaggatctgacatccagatgacccagtctccatcctccctgtctgcatctgtagga
gacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagc
agaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtccc
atcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct
gaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaaggga
ccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatga
gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggcc
aaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagc
aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacga
gaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc
ttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 428)
CNIWLVGGDCRGWQGGSSGGSVHMPLGFLGPGGTSTSGRSANPRGGGSDIQMTQSPSSLSASVG
DRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP
EDFATTYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS
FNRGEC Anti-Jagged 0003/LP'/1003 activatable antibody LC with
spacer sequence Nucleotide sequence (SEQ ID NO: 58)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctccacatctacctctggcagatccgccaaccccagaggcggcggagtgca
tatgcctctgggctttctgggacctggcggctctgacatccagatgacccagtctccatcctcc
ctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagct
atttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccag
tttgcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcacc
atcagcagtctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctc
cgttattcggccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcat
cttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataac
ttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactccc
aggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgct
gagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagc
tcgcccgtcacaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID
NO: 59)
QGQSGQCNIWLVGGDCRGWQGGSSGGSTSTSGRSANPRGGGVHMPLGFLGPGGSDIQMTQSPSS
LSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLT
ISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNN
FYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS
SPVTKSFNRGEC Anti-Jagged 0003/LP'/1003 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 429)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctcca
catctacctctggcagatccgccaaccccagaggcggcggagtgcatatgcctctgggctttct
gggacctggcggctctgacatccagatgacccagtctccatcctccctgtctgcatctgtagga
gacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagc
agaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtccc
atcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct
gaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaaggga
ccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatga
gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggcc
aaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagc
aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacga
gaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc
ttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 430)
CNIWLVGGDCRGWQGGSSGGSTSTSGRSANPRGGGVHMPLGFLGPGGSDIQMTQSPSSLSASVG
DRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFILTISSLQP
EDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS
FNRGEC Anti-Jagged 1004/LP'/0001 activatable antibody Lc with
spacer sequence (SEQ ID NO: 60)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctccagcggaggatctgctgtgggactgctggctcctcctggtggcctgtctggcagatctga
taaccacggcggctccgacatccagatgacccagtctccatcctccctgtctgcatctgtagga
gacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagc
agaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtccc
atcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct
gaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaaggga
ccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatga
gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggcc
aaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagc
aggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacga
gaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagc
ttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 61)
QGQSGQCNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDNHGGSDIQMTQSPSSLSASVG
DRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQP
EDFATTYCQQTVVAPPLEGQGIKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKS
FNRGEC Anti-Jagged 1004/LP'/0001 activatable antibody Lc Nucleotide
sequence (SEQ ID NO: 431)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggaggatctg
ctgtgggactgctggctcctcctggtggcctgtctggcagatctgataaccacggcggctccga
catccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcact
tgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccagggaaagccc
ctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaaggttcagtggcag
tggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttac
tactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaaggtggaaatcaaac
gtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaac
tgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtg
gataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca
cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgc
ctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt
Amino Acid sequence (SEQ ID NO: 432)
CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDNHGGSDIQMTQSPSSLSASVGDRVTIT
CRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATY
YCQOTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-Jagged 0001/LP'/1004 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 62)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggaggctctggcctgtctggcagatccgataaccatggcggcgctgtgggactgct
ggctcctcctggtggatctgacatccagatgacccagtctccatcctccctgtctgcatctgta
ggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatc
agcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggt
cccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaa
cctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaag
ggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctga
tgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagag
gccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacag
agcaggacagcaaggacagcacctacagcctcagcaccaccctgacgctgagcaaagcagacta
cgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaag
agcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 63)
QGQSGQCNIWLVGGDCRGWQGGSSGGSGLSGRSDNHGGAVGLLAPPGGSDIQMTQSPSSLSASV
GDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQ
PEDFATTYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPRE
AKVQWKVDNALQSGNEQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK
SFNRGEC Anti-Jagged 0001/LP'/1004 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 433)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggaggctctg
gcctgtctggcagatccgataaccatggcggcgctgtgggactgctggctcctcctggtggatc
tgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatc
acttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccagggaaag
cccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaaggttcagtgg
cagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaact
tactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaaggtggaaatca
aacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctgg
aactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaag
gtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggaca
gcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtcta
cgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagag
tgt Amino Acid sequence (SEQ ID NO: 434)
CNIWLVGGDCRGWQGGSSGGSGLSGRSDNHGGAVGLLAPPGGSDIQMTQSPSSLSASVGDRVTI
TCRASQSISSYINWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFAT
YYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGE C
Anti-Jagged 1003/LP'/0001 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 64)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggcggctctgtgcatatgcccctgggctttctgggacctggcggcctgtctggcag
atccgataatcacggcggctccgacatccagatgacccagtctccatcctccctgtctgcatct
gtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggt
atcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtgg
ggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctg
caacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcggcc
aagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatc
tgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccaga
gaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtca
cagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcaga
ctacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcaca
aagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 65)
QGQSGQCNIWLVGGDCRGWQGGSSGGSVHMPLGFLGPGGLSGRSDNHGGSDIQMTQSPSSLSAS
VGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSL
QPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT
KSFNRGEC Anti-Jagged 1003/LP'/0001 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 435)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggcggctctg
tgcatatgcccctgggctttctgggacctggcggcctgtctggcagatccgataatcacggcgg
ctccgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcacc
atcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccaggga
aagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaaggttcag
tggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgca
acttactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaaggtggaaa
tcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatc
tggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtgg
aaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaagg
acagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagt
ctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagggga
gagtgt Amino Acid sequence (SEQ ID NO: 436)
CNIWLVGGDCRGWQGGSSGGSVHMPLGFLGPGGLSGRSDNHGGSDIQMTQSPSSLSASVGDRVT
ITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFA
TYYCQQTVVAPPLEGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW
KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC
Anti-Jagged 0001/LP'/1003 activatable antibody Lc with spacer
sequence Nucleotide sequence (SEQ ID NO: 66)
Caaggccagtctggccagtgcaatatttggctcgtaggtggtgattgcaggggctggcaggggg
gctcgagcggaggctctggcctgtctggcagatctgataaccacggcggcgtgcacatgcccct
gggctttctgggacctggcggatctgacatccagatgacccagtctccatcctccctgtctgca
tctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaatt
ggtatcagcagaaaccagggaaagcccctaagctcctgatctatgcggcatccagtttgcaaag
tggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagt
ctgcaacctgaagattttgcaacttactactgtcaacagacggttgtggcgcctccgttattcg
gccaagggaccaaggtggaaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgcc
atctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatccc
agagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtg
tcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagc
agactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtc
acaaagagcttcaacaggggagagtgt Amino Acid sequence (SEQ ID NO: 437)
QGQSGQCNIWLVGGDCRGWQGGSSGGSGLSGRSDNHGGVHMPLGFLGPGGSDIQMTQSPSSLSA
SVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISS
LQPEDEATTYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWICLLNNFYP
REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKEKVYACEVTHQGLSSPV
TKSFNRGEC Anti-Jagged 0001/LP'/1003 activatable antibody Lc
Nucleotide sequence (SEQ ID NO: 438)
Tgcaatatttggctcgtaggtggtgattgcaggggctggcaggggggctcgagcggaggctctg
gcctgtctggcagatctgataaccacggcggcgtgcacatgcccctgggctttctgggacctgg
cggatctgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtc
accatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccag
ggaaagcccctaagctcctgatctatgcggcatccagtttgcaaagtggggtcccatcaaggtt
cagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagatttt
gcaacttactactgtcaacagacggttgtggcgcctccgttattcggccaagggaccaaggtgg
aaatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaa
atctggaactgactctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacag
tggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagca
aggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaa
agtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacagg
ggagagtgt Amino Acid sequence (SEQ ID NO: 439)
CNIWLVGGDCRGWQGGSSGGSGLSGRSDNHGGVHMPLGFLGPGGSDIQMTQSPSSLSASVGDRV
TITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDF
ATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ
WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR
GEC Anti-Jagged activatable antibody Hc (SEQ ID NO: 67)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSV
KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSSASTKGPSVF
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNEGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS
RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE
YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
K
[0482] Anti-Jagged CM1-CM2 Activatable antibody in vitro binding
and activation was evaluated as follows.
[0483] Anti-Jagged activatable antibodies were expressed from
transiently transfected HEK-293 cells and purified from the culture
supernatant by Protein A chromatography. To verify that the
anti-Jagged CM1-CM2 activatable antibodies could be activated by
both MMPs and serine proteases, the purified activatable antibodies
were digested with uPA and/or MMP14 and subsequently evaluated for
their ability to bind to human Jagged 1-Fc by ELISA. ELISA plates
(Greiner Bio-One #655061) were coated with human Jag1-Fc (R&D
#1277-JG-050) in Hank's Balanced Salt Solution pH 7.4 (HBSS)
(Teknova #H8057) at 1 microgram/mi overnight at 4.degree. C.; as
used herein, microgram(s) is also represented by ug and .mu.g.
Plates were blocked with 2% Nonfat dry milk (NFDM) in HBSS for 1
hour at room temperature (RT). The block was removed and
anti-Jagged antibody 4D11, an anti-Jagged CM1-CM2 activatable
antibody, or a digested activatable antibody was added to the
indicated concentration in 2% NFDM/HBSS and incubated at RT for 1
hours. The ELISA plate was washed 3 times with excess HBSS, 0.05%
TWEEN (HBSS-T) before adding the mouse anti-human IgG, F'.sub.Ab(2)
specific, HRP conjugated (Jackson ImmunoResearch #209-035-097)
diluted to 1:30,000 in 2% NFDM/HBSS. The ELISA plate was
subsequently washed 3.times. with HBSS-T and developed using 1-Step
TMB Substrate (Pierce/Thermo Fisher #NC0140927). The plates were
read at OD.sub.450 and plotted using Prism software.
[0484] FIG. 1 demonstrates the anti-Jagged CM1-CM2 activatable
antibodies (a) were effectively masked prior to cleavage by uPA or
MMP14 and (b) showed binding equivalent to the antibody when
cleaved by uPA or MMP14 or a combination of uPA and MMP14.
[0485] Anti-Jagged activatable antibody containing CM1-CM2
Substrate pharmacokinetics were evaluated in non-tumor bearing nude
mice as follows.
[0486] As a surrogate for the stability of the mask and substrate,
the pharmacokinetics of the anti-Jagged activatable antibodies
containing the CM1-CM2 substrates 2001 and 1001/LP'/0001 were
compared to that of the anti-Jagged antibody in non-tumor bearing
mice.
[0487] The mouse/human cross-reactive anti-Jagged antibody shows
rapid clearance in mice due to the binding of Jagged 1/2 in normal
tissues. If the anti-Jagged CM1-CM2 Activatable antibody remains
masked (stable) in circulation, then the activatable antibody
should avoid target-mediated clearance and show prolonged serum
half-life.
[0488] The plasma pharmacokinetics of the anti-Jagged antibody and
activatable antibodies were evaluated as follows. As shown in Table
B, each group consisted of 2 cohorts of 5 mice. Mice were given a
single intravenous dose of 5 mg/kg of the indicated compound.
Lithium heparinized plasma was collected from cohort 1 at 24 hours,
96 hours, and 10 days post dose while plasma was collected from
cohort 2 at 48 hours, 7 days, and 14 days by the retro-orbital
route with isoflurane anesthesia. Total plasma human IgG levels
were detected using a human IgG sandwich ELISA. Briefly, ELISA
plates (Costar 3590 Fisher Scientific Cat. #07-200-35) were coated
with AffiniPure Goat Anti-Human IgG F(ab')2 Fragment Specific,
(Jackson ImmunoResearch Cat. #109-006-097) in phosphate buffered
saline (PBS) at 1 ug/ml overnight at 4.degree. C. Plates were
blocked with Superblock (ScyTek Laboratories Cat. #AAA500) for 1
hour at room temperature (RT). The block was removed and an
appropriate dilution of standard (test article) and test samples
(plasma samples) were added to the plate and incubated at RT for 1
hour. The ELISA plate was washed 3 times with excess PBS, 0.05%
TWEEN (PBS-T) before adding the AffiniPure Goat Anti-Human IgG
F.sub.(ab')2 Fragment Specific Horseradish Peroxidase (HRP)
(Jackson ImmunoResearch Cat. #109-035-097) diluted to 1:25,000. The
ELISA plate was subsequently washed 3.times. with PBS-T and
developed using 1-Step TMB Substrate (Pierce/Thermo Fisher
#NC0140927) following the manufacturers protocol. Serum human IgG
levels were calculated by comparing the test sample values to the
standard curve. Pharmacokinetic parameters were calculated using a
noncompartmental analysis with sparse sampling (Phoenix WinNonlin
v6.3).
[0489] As shown in FIG. 2, the anti-Jagged antibody was rapidly
cleared and was below the detection limit of the assay by day 10.
In contrast, the anti-Jagged CM1-CM2 activatable antibodies
1001/LP'/0001 and 2001 showed significantly extended half-life
indicating that the activatable antibodies remained stable and well
masked in circulation.
TABLE-US-00016 TABLE B Groups and dosing for the pharmacokinetic
analysis of the anti-Jagged CM1-CM2 Activatable antibodies 2001 and
1001/LP'/0001. Dose Dose volume Group N Treatment (mg/kg) (mL/kg)
Schedule Route 1 2 .times. 5 Anti-Jagged 5 10 Single IP 2 2 .times.
5 Anti-Jagged 5 10 Single IP Activatable antibody 2001 3 2 .times.
5 Anti-Jagged 5 10 Single IP Activatable antibody 1001/LP'/0001
[0490] In vivo evaluation of the safety and efficacy of an
anti-Jagged CM1-CM2 substrate containing activatable antibody drug
conjugate was performed as follows.
[0491] The efficacy of the anti-Jagged CM1-CM2 substrate containing
2001 activatable antibody drug conjugate, which comprised the
anti-Jagged 2001 activatable antibody conjugated to maytansinoid
DM4 (see, e.g., U.S. Pat. No. 7,276,497) via a SPDB linker, was
evaluated in the human breast cancer cell line HCC1806 xenograft
tumor model. HCC1806 cells were harvested during log phase growth
and resuspended in 50% Matrigel (BD Biosciences) in PBS at a
concentration of 5.times.10' cells/ml. Mice were injected
subcutaneously in the right flank with 5.times.10.sup.6 cells and
allowed to grow to a mean volume of 100-150 mm.sup.3. Mice were
randomized and dosed as indicated in Table C. Tumor volume and body
weight were measured twice weekly for the duration of the study,
and measures of efficacy and safety, respectively were
obtained.
[0492] FIG. 3 shows the group mean tumor volume.+-.the standard
error of the mean (SEM) for the PBS, Isotype-SPDB-DM4,
anti-Jagged-SPDB-DM4 drug conjugate (ADC), and anti-Jagged 2001
activatable antibody drug conjugate treated animals. Neither
control group (PBS nor Isotype-SPDB-DM4) showed tumor growth
inhibition while both the anti-Jagged ADC and anti-Jagged 2001
activatable antibody drug conjugate groups showed tumor regression.
The animals treated with the anti-Jagged ADC showed significant
side effects as measured by weight loss, as shown in FIG. 4.
However, animals treated with anti-Jagged 2001 activatable antibody
drug conjugate showed no weight loss (also shown in FIG. 4)
demonstrating that the anti-Jagged CM1-CM2 activatable antibody
drug conjugate's activity was localized to the tumor.
TABLE-US-00017 TABLE C Groups and dose schedule for the HCC1806
study Dose Group Count Treatment (mg/kg) Schedule Route 1 8 PBS 10
q7dx2 IV 3 8 Isotype-SPDB-DM4 10 q7dx2 IV 4 8 Anti-Jagged-SPDB-DM4
10 q7dx2 IV 5 8 Anti-Jagged 2001 10 q7dx2 IV activatable antibody-
SPDB-DM4
Example 2
Matrix Metalloprotease (MMP) and Serine Protease (SP) Cleavable
Anti-EGFR Activatable Antibodies
[0493] This Example demonstrates the generation and evaluation of
activatable antibodies that bind Epidermal Growth Factor Receptor
(EGFR), where the activatable antibodies are activated in the
presence of at least one matrix metalloprotease (MMP) and at least
one serine protease.
[0494] The activatable anti-EGFR antibodies used in this Example
were generated using a method similar to the methods used in
Example 1 to generate activatable anti-Jagged antibodies.
[0495] The studies described herein used the following substrate
sequences, where LP' is a linking peptide between CM1 and CM2. For
all CM1-CM2 substrates in the Table below, LP' is GGSGGS (SEQ ID
NO: 350):
TABLE-US-00018 CM1-CM2 Substrate Amino Acid Sequence Nucleotide
Sequence 0001 LSGRSDNH TTAAGCGGGCGGTCGGACAACCAC (SEQ ID NO: 18)
(SEQ ID NO: 23) 0002 LSGRSGNE CTTAGCGGGCGGAGCGGCAACCAC (SEQ ID NO:
19) (SEQ ID NO: 24) 1001 ISSGLLSS ATCTCCTCCGGGCTACTGAGTTCT (SEQ ID
NO: 20) (SEQ ID NO: 25) 1002 QNQALRMA CAGAACCAGGCGCTCAGAATGGCA (SEQ
ID NO: 21) (SEQ ID NO: 26) 2001 ISSGLLSGRSDNE
ATATCATCCGGCCTCCTTAGCGGC (SEQ ID NO: 1) CGTTCCGACAATCAC (SEQ ID NO:
27) 2002 ISSGLLSGRSGNH ATAAGTTCTGGGCTCCTGTCGGGC (SEQ ID NO: 22)
CGGAGTGGAAATCAC (SEQ ID NO: 28) 0001/LP'/1001 LSGRSDNHGGSGSISSGLLSS
CTGAGCGGGCGGTCCGATAATCAT (SEQ ID NO: 11) GGTGGTTCAGGAGGGAGTATTTCT
TCCGGCTTACTGAGTAGC (SEQ ID NO: 29) 1001/LP'/0001
ISSGLLSSGGSGGSLSGRSDNE ATCTCCTCTGGTTGCTTTCTTCA (SEQ ID NO: 2)
GGAGGTTCAGGGGGGAGCCTGAGC GGACGCTCCACAACCAT (SEQ ID NO: 30)
0002/LP'/1001 LSGRSGNHGGSGGSISSGLLSS CTCTCAGGAAGATCCGAAATCAT (SEQ
ID NO: 12) GGGGGGTCTGGGGGGAGTATCTCA TCAGGTCTGCTGACAGC (SEQ ID NO:
31) 1001/LP'/0002 ISSGLLSSGGSGGSLSGRSGNH ATCTCAAGTGGGCTGTTAAGTTCC
(SEQ ID NO: 13) GGCGGCAGTGGAGGGTCCCTAAGC GGCCGCAGCGGGAATCAC (SEQ ID
NO: 32) 0001/LP'/1002 LSGRSDNHGGSGGSQNQALRMA
CTCTCTGGCCGCTCCGATAATCAT (SEQ ID NO: 14) GGTGGATCCGGTGGCTCTCAGAAC
CAGGCACTACGGATGGCA (SEQ ID NO: 33) 1002/LP'/0001
QNQALRMAGGSGGSLSGRSDNH CAGAACCAGGCGCTCAGGATGGCA (SEQ ID NO: 15)
GGGGGGAGTGGCGGAAGCCTTTCT GGTCGATCCGATAATCAC (SEQ ID NO: 34)
0002/LP'/1002 LSGRSGNHGGSGGSQNQALRMA CTTAGCGGACGCTCTGGCAACCAC (SEQ
ID NO: 16) GGAGGATCTGAGGAAGTCAGAAC CAGGCCTTGCGCATGGCC (SEQ ID NO:
35) 1002/LP'/0002 QNQALRMAGGSGGSLSGRSGNH CAAAACCAGGCTCTGCGCATGGCT
(SEQ ID NO: 17) GGGGGGTCTGGTGGGAGCCTGAGC GGGCGGTCAGGAAACCAC (SEQ ID
NO: 36)
TABLE-US-00019 Anti-ECFR Heavy Chain (Hc): Nucleotide sequence:
(SEQ ID NO: 68)
CAGGTAGAGCTGAAACAGTCTGGACCCGGGCTTGTAGAGCCTAGTCAGTCACTGTCTATCACCT
GTACCGTCTCAGGTTTTAGCCTGACAAATTACGGTGTGCATTGGGTACGCCAGTCTCCCGGTAA
GGGGCTGGAGTGGCTCGGCGTGATCTGGTCCGGGGGGAACACAGATTATAATACTCCTTTCACA
TCTAGACTGTCCATCAACAAAGACAACTCCAAATCGCAGGTTTTTTTCAAGATGAATTCCCTGC
AATCACAGGACACTGCCATCTATTATTGCGCGAGGGCCCTGACTTATTATGACTATGAGTTCGC
TTATTGGGGCCAGGGGACGCTTGTGACCGTAAGCGCTGCTAGTACCAAGGGCCCCAGTGTGTTC
CCCCTTGCCCCCAGCAGTAAGTCCACCTCAGGTGGCACAGCTGCCCTTGGGTGCCTTGTGAAGG
ATTACTTCCCAGAACCAGTGACCGTGAGCTGGAATTCCGGAGCCCTTACCAGCGGTGTGCATAC
CTTTCCGGCCGTCCTGCAAAGCAGCGGACTTTACAGTCTGTCTAGCGTGGTCACCGTGCCCAGC
AGCAGCCTGGGTACACAGACGTATATTTGCAACGTTAATCACAAACCCTCAAACACAAAGGTGG
ACAAGAAAGTGGAGCCTAAATCATGTGATAAGACACATACATGCCCTCCCTGCCCTGCACCGGA
GCTCTTAGGTGGACCTTCAGTCTTTTTATTTCCACCTAAACCCAAAGATACACTTATGATCTCA
CGGACACCCGAGGTGACCTGCGTTGTCGTGGATGTCTCACACGAAGACCCTGAAGTGAAATTCA
ATTGGTATGTTGACGGTGTTGAGGTGCATAACGCAAAGACCAAGCCACGCGAGGAGCAGTATAA
TAGCACCTATAGGGTAGTCAGCGTACTGACTGTTCTGCATCAGGATTGGCTGAACGGTAAAGAG
TACAAATGCAAGGTCTCAAACAAGGCTCTCCCTGCCCCGATCGAGAAGACAATTTCTAAGGCCA
AAGGGCAGCCCCGGGAACCACAAGTCTATACCCTGCCACCCAGTCGGGATGAACTAACAAAAAA
TCAGGTGTCTCTAACCTGCCTGGTGAAGGGATTTTACCCTTCCGATATAGCTGTGGAGTGGGAG
TCTAATGGCCAACCAGAGAATAATTACAAGACTACCCCCCCCGTTCTTGACAGTGATGGCTCGT
TCTTCTTATACTCAAAATTAACAGTCGACAAATCCCGATGGCAACAGGGCAATGTGTTTAGCTG
TAGCGTGATGCATGAAGCCCTGCACAACCATTACACACAGAAGTCTCTGTCCTTGTCACCTGGC
AAG Amino acid Sequence: (SEQ ID NO: 69)
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFT
SRLSINKDNSKSQVFFKSLQSQDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Anti-EGFR Light Chain: Nucleotide Sequence: (SEQ ID NO: 70)
ACCCAAATCCTCCTGACCCAGTCCCCTGTTATCCTTTCTGTGTCGCCCGGGGAGCGCGTTAGCT
TTAGCTGCCGCGCCAGTCAGTCAATCGGAACAAACATCCATTGGTACCAGCAGCGTACGAACGG
CAGTCCAAGGCTGCTGATCAAATACGCAAGTGAATCTATATCGGGGATTCCGTCTCGGTTCAGC
GGATCCGGAAGCGGGACTGACTTTACGCTCTCCATAAATAGCGTCGAAAGTGAGGACATTGCAG
ACTATTACTGTCAGCAGAATAACAACTGGCCGACCACATTTGGGGCCGGAACCAAGTTGGAACT
GAAGCGCACTGTGGCAGCTCCTAGTGTTTTTATTTTCCCCCCTTCTGACGAGCAACTGAAAAGT
GGTACAGCTTCAGTAGTTTGTTTGCTCAATAATTTCTAGCCACGGGAAGCAAAGGTGCAGTGGA
AAGTCGACAACGCATTACAGAGCGGCAACTCTCAAGAAAGCGTGACGGAGCAGGATAGCAAGGA
CTCAACATATTCCTTGTCTTCCACTCTCACTCTGTCAAAGGCTGATTATGAGAAGCATAAGGTG
TATGCGTGCGAAGTGACACACCAGGGATTATCAAGCCCAGTGACCAAGTCCTTTAACCGTGGCG
AATGC Amino acid Sequence: (SEQ ID NO: 111)
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSG
SGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSG
TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY
ACEVTHQGLSSPVTKSFNRGEC Anti-EGFR 0001 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 72)
CAGGGCCAGAGCGGCCAATGCATCTCCCCCCGCGGTTGTCCCGACGGGCCGTACGTGATGTACG
GCAGCTCCGGCGGCAGTGGGGGTAGCGGTGGGTCCGGGCTGAGTGGCCGGTCCGACAATCACGG
GAGCTCGGGAACACAGATTCTGCTGACGCAATCTCCCGTGATCCTCTCGGTCTCACCCGGCGAA
CGGGTCTCGTTCAGCTGCAGAGCGTCCCAATCAATCGGGACCAATATTCACTGGTACCAGCAAA
GGACTAATGGGTCTCCCCGGCTGCTGATAAAATACGCCTCCGAGTCTATCTCGGGCATCCCATC
CCGATTTAGTGGTAGCGGAAGCGGCACTGATTTCACCTTGTCTATTAACAGCGTAGAATCTGAG
GACATTGCAGACTATTACTGTCAGCAGAATAACAATTGGCCTACAACTTTCGGCGCCGGGACCA
AACTAGAGTTAAAGCGTACTGTGGCTGCCCCCAGCGTTTTTATTTTTCCGCCCAGCGACGAACA
GCTGAAGTCAGGCACAGCCTCTGTGGTGTGTCTCCTGAATAACTTCTACCCCAGAGAGGCCAAA
GTTCAGTGGAAAGTGGACAATGCCTTGCAGTCCGGAAACAGTCAAGAGTCCGTGACCGAGCAGG
ACAGTAAGGATAGCACGTATAGCCTCTCTAGTACTTTAACACTGTCCAAGGCCGACTACGAGAA
GCACAAGGTGTACGCATGCGAAGTGACCCATCAGGGGCTTTCCTCCCCCGTCACCAAGTCTTTC
AATCGCGGGGAGTGT Amino acid Sequence: (SEQ ID NO: 73)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGSSGTQILLTQSPVILSVSPGE
RVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESE
DIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC Anti-EGFR 0001 Activatable Antibody Light Chain: Nucleotide
sequence: (SEQ ID NO: 440)
TGCATCTCCCCCCGCGGTTGTCCCGACGGGCCGTACGTGATGTACGGCAGCTCCGGCGGCAGTG
GGGGTAGCGGTGGGTCCGGGCTGAGTGGCCGGTCCGACAATCACGGGAGCTCGGGAACACAGAT
TCTGCTGACGCAATCTCCCGTGATCCTCTCGGTCTCACCCGGCGAACGGGTCTCGTTCAGCTGC
AGAGCGTCCCAATCAATCGGGACCAATATTCACTGGTACCAGCAAAGGACTAATGGGTCTCCCC
GGCTGCTGATAAAATACGCCTCCGAGTCTATCTCGGGCATCCCATCCCGATTTAGTGGTAGCGG
AAGCGGCACTGATTTCACCTTGTCTATTAACAGCGTAGAATCTGAGGACATTGCAGACTATTAC
TGTCAGCAGAATAACAATTGGCCTACAACTTTCGGCGCCGGGACCAAACTAGAGTTAAAGCGTA
CTGTGGCTGCCCCCAGCGTTTTTATTTTTCCGCCCAGCGACGAACAGCTGAAGTCAGGCACAGC
CTCTGTGGTGTGTCTCCTGAATAACTTCTACCCCAGAGAGGCCAAAGTTCAGTGGAAAGTGGAC
AATGCCTTGCAGTCCGGAAACAGTCAAGAGTCCGTGACCGAGCAGGACAGTAAGGATAGCACGT
ATAGCCTCTCTAGTACTTTAACACTGTCCAAGGCCGACTAGGAGAAGCACAAGGTGTACGCATG
CGAAGTGACCCATCAGGGGCTTTCCTCCCCCGTCACCAAGTCTTTCAATCGCGGGGAGTGT Amino
acid Sequence: (SEQ ID NO: 441)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGSSGTQILLTQSPVILSVSPGERVSFSC
RASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYY
CQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-EGFR 0002 Activatable Antibody Light Chain with spacer
sequence: Nucleotide sequence: (SEQ ID NO: 74)
CAAGGTCAGTCCGGACAGTGTATTTCCCCTAGAGGTTGCCCTGACGGGCCGTATGTCATGTACG
GTAGTTCTGGCGGTAGTGGCGGATCTGGCGGCAGTGGGCTGAGCGGACGTAGCGGGAATCACGG
CTCATCCGGGACGCAGATACTGCTGACCCAGTCCCCCGTGATCCTGTCCGTGTCACCGGGCGAA
AGGGTCAGTTTCTCTTGCCGAGCATCACAGTCCATAGGTACGAATATCCATTGGTACCAGCAGC
GGACCAATGGGAGCCCAAGACTGCTCATTAAGTACGCATCTGAGAGTATCTCAGGCATTCCAAG
CAGGTTTTCCGGCAGTGGGAGCGGCACTGACTTCACCCTCAGCATTAACAGCGTGGAAAGCGAA
GACATTGCAGATTAGTACTGCCAACAGAACAATAACTGGCCTACTACATTCGGGGCAGGAACTA
AGTTGGAGCTCAAACGTACCGTCGCTGCTCCTAGCGTATTTATTTTCCCTCCTAGCGATGAACA
GTTGAAATCTGGTACCGCTAGTGTTGTGTGCTTACTGAACAACTTTTATCCCCGGGAGGCCAAG
GTACAATGGAAGGTGGACAATGCCCTCCAATCAGGGAACAGCCAGGAGTCTGTTACCGAGCAGG
ACTCCAAGGACAGCACCTACAGCCTGAGCTCTACCCTTACATTGAGCAAGGCTGATTATGAGAA
GCATAAGGTCTACGCTTGTGAGGTGACCCATCAGGGGCTCAGCAGCCCGGTGACAAAAAGCTTT
AACCGGGGGGAATGC Amino acid Sequence: (SEQ ID NO: 75)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGSSGTQILLTQSPVILSVSPGE
RVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESE
DIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC Anti-EGFR 0002 Activatable Antibody Light Chain: Nucleotide
sequence: (SEQ ID NO: 442)
TGTATTTCCCCTAGAGGTTGCCCTGACGGGCCGTATGTCATGTACGGTAGTTCTGGCGGTAGTG
GCGGATCTGGCGGCAGTGGGCTGAGCGGACGTAGCGGGAATCACGGCTCATCCGGGACGCAGAT
ACTGCTGACCCAGTCCCCCGTGATCCTGTCCGTGTCACCGGGCGAAAGGGTCAGTTTCTCTTGC
CGAGCATCACAGTCCATAGGTACGAATATCCATTGGTACCAGCAGCGGACCAATGGGAGCCCAA
GACTGCTCATTAAGTACGCATCTGAGAGTATCTCAGGCATTCCAAGCAGGTTTTCCGGCAGTGG
GAGCGGCACTGACTTCACCCTCAGCATTAACAGCGTGGAAAGCGAAGACATTGCAGATTACTAC
TGCCAACAGAACAATAACTGGCCTACTACATTCGGGGCAGGAACTAAGTTGGAGCTCAAACGTA
CCGTCGCTGCTCCTAGCGTATTTATTTTCCCTCCTAGCGATGAACAGTTGAAATCTGGTACCGC
TAGTGTTGTGTGCTTACTGAACAACTTTTATCCCCGGGAGGCCAAGGTACAATGGAAGGTGGAC
AATGCCCTCCAATCAGGGAACAGCCAGGAGTCTGTTACCGAGCAGGACTCCAAGGACAGCACCT
ACAGCCTGAGCTCTACCCTTACATTGAGCAAGGCTGATTATGAGAAGCATAAGGTCTACGCTTG
TGAGGTGACCCATCAGGGGCTCAGCAGCCCGGTGACAAAAAGCTTTAACCGGGGGGAATGC Amino
acid Sequence: (SEQ ID NO: 443)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGSSGTQILLTQSPVILSVSPGERVSFSC
RASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYY
CQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-EGFR 1001 Activatable Antibody Light Chain with spacer
sequence: Nucleotide sequence: (SEQ ID NO: 76)
CAGGGGCAGTCTGGGCAGTGTATTAGCCCCAGGGGGTGCCCCGACGGGCCTTACGTGATGTATG
GCAGCTCCGGTGGCAGCGGAGGCTCTGGCGGGAGTGGGATCAGTTCCGGCCTGCTGAGCTCCGG
GTCAAGCGGGACCCAGATCTTGCTCACCCAATCACCAGTGATCCTAAGCGTGAGCCCTGGCGAA
CGGGTCAGCTTCTCTTGCCGGGCATCTCAGAGTATTGGCACTAACATACACTGGTACCAGCAGC
GAACCAATGGGTCCCCCCGCCTTCTAATCAAATATGCTAGCGAATCCATTTCAGGAATTCCTAG
CCGATTTAGCGGCAGCGGATCAGGCACTGACTTCACTCTGTCAATCAACTCAGTTGAAAGCGAG
GACATTGCAGACTACTATTGCCAGCAGAATAATAATTGGCCCACTACATTTGGAGCTGGAACAA
AATTGGAGCTTAAGAGGACAGTGGCTGCGCCTAGTGTATTTATCTTTCCCCCCTCTGACGAACA
GTTGAAATCGGGAACCGCATCCGTCGTCTGTTTACTGAACAACTTCTATCCCAGAGAGGCCAAA
GTGCAGTGGAAAGTGGATAATGCTTTGCAGTCTGGCAACAGCCAGGAAAGCGTGACGGAGCAGG
ACTCAAAGGATAGTACATACTCCCTGTCCTCCACCCTGACTCTGAGTAAGGCCGACTACGAGAA
GCACAAGGTCTACGCCTGCGAAGTGACGCACCAAGGGCTATCGAGCCCGGTCACCAAGTCTTTC
AATCGTGGAGAATGC Amino acid Sequence: (SEQ ID NO: 77)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGSSGTQILLTQSPVILSVSPGE
RVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESE
DIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC Anti-EGFR 1001 Activatable Antibody Light Chain: Nucleotide
sequence: (SEQ ID NO: 444)
TGTATTAGCCCGAGGGGGTGCCCCGACGGGCCTTACGTGATGTATGGCAGCTCCGGTGGCAGCG
GAGGCTCTGGCGGGAGTGGGATCAGTTCCGGCCTGCTGAGCTCCGGGTCAAGCGGGACCCAGAT
CTTGCTCACCCAATCACCAGTGATCCTAAGCGTGAGCCCTGGCGAACGGGTCAGCTTCTCTTGC
CGGGCATCTCAGAGTATTGGCACTAACATACACTGGTACCAGCAGCGAACCAATGGGTCCCCCC
GCCTTCTAATCAAATATGCTAGCGAATCCATTTCAGGAATTCCTAGCCGATTTAGCGGCAGCGG
ATCAGGCACTGACTTCACTCTGTCAATCAACTCAGTTGAAAGCGAGGACATTGCAGACTACTAT
TGCCAGCAGAATAATAATTGGCCCACTACATTTGGAGCTGGAACAAAATTGGAGCTTAAGAGGA
CAGTGGCTGCGCCTAGTGTATTTATCTTTCCCCCCTCTGACGAACAGTTGAAATCGGGAACCGC
ATCCGTCGTCTGTTTACTGAACAACTTCTATCCCAGAGAGGCCAAAGTGCAGTGGAAAGTGGAT
AATGCTTTGCAGTCTGGCAACAGCCAGGAAAGCGTGACGGAGCAGGACTCAAAGGATAGTACAT
ACTCCCTGTCCTCCACCCTGACTCTGAGTAAGGCCGACTAGGAGAAGCACAAGGTCTAGGCCTG
CGAAGTGACGCACCAAGGGCTATCGAGCCCGGTCACCAAGTCTTTCAATCGTGGAGAATGC Amino
acid Sequence: (SEQ ID NO: 445)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGSSGTQILLTQSPVILSVSPGERVSFSC
RASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYY
CQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-EGFR 1002 Activatable Antibody Light Chain with spacer
sequence: Nucleotide sequence: (SEQ ID NO: 78)
CAGGGGCAATCAGGACAATGCATCAGCCCTAGGGGCTGCCCAGACGGCCCATATGTGATGTACG
GTAGCTCTGGGGGCTCAGGAGGCAGCGGGGGAAGCGGACAAAACCAGGCCTTACGAATGGCTGG
CAGCTCTGGCACCCAGATATTGCTGACGCAGAGTCCAGTTATCCTTAGTGTCAGCCCTGGTGAA
CGGGTTTCATTTAGTTGCCGTGCCTCCCAGTCTATTGGAACGAACATTCATTGGTACCAGCAAA
GGACCAACGGTTCACCCAGGTTGCTTATCAAGTATGCTTCAGAGTCAATCTCCGGGATTCCCTC
AAGGTTTTCAGGCTCTGGCTCAGGTACCGATTTTACGCTGAGCATCAACTCCGTGGAGAGTGAG
GACATTGCTGATTATTACTGTCAGCAGAATAACAATTGGCCGACAACTTTCGGCGCCGGCACAA
AGCTGGAACTTAAGCGTACTGTGGCTGCGCCATCTGTCTTCATTTTTCCGCCCTCGGACGAGCA
GTTGAAGTCAGGGACCGCCTCTGTCGTGTGCCTTCTCAATAACTTCTATCCCAGAGAGGCTAAA
GTCCAGTGGAAAGTTGATAATGCACTTCAGAGCGGGAATAGCCAGGAGAGCGTGACGGAACAGG
ACTCTAAGGACTCCACCTATTCTCTCTCATCCACCCTTACTCTCTCTAAAGCCGACTAGGAAAA
GCATAAGGTTTATGCTTGCGAAGTCACTCATCAAGGGCTATCTAGTCCGGTCACTAAAAGCTTC
AACAGAGGTGAATGT Amino acid Sequence: (SEQ ID NO: 79)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGSSGTQILLTQSPVILSVSPGE
RVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESE
DIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK
VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF
NRGEC Anti-EGFR 1002 Activatable Antibody Light Chain: Nucleotide
sequence: (SEQ ID NO: 446)
TGCATCAGCCCTAGGGGCTGCCCAGACGGCCCATATGTGATGTACGGTAGCTCTGGGGGCTCAG
GAGGCAGCGGGGGAAGCGGACAAAACCAGGCCTTACGAATGGCTGGCAGCTCTGGCACCCAGAT
ATTGCTGACGCAGAGTCCAGTTATCCTTAGTGTCAGCCCTGGTGAACGGGTTTCATTTAGTTGC
CGTGCCTCCCAGTCTATTGGAACGAACATTCATTGGTACCAGCAAAGGACCAACGGTTCACCCA
GGTTGCTTATCAAGTATGCTTCAGAGTCAATCTCCGGGATTCCCTCAAGGTTTTCAGGCTCTGG
CTCAGGTACCGATTTTACGCTGAGCATCAACTCCGTGGAGAGTGAGGACATTGCTGATTATTAC
TGTCAGCAGAATAACAATTGGCCGACAACTTTCGGCGCCGGCACAAAGCTGGAACTTAAGCGTA
CTGTGGCTGCGCCATCTGTCTTCATTTTTCCGCCCTCGGACGAGCAGTTGAAGTCAGGGACCGC
CTCTGTCGTGTGCCTTCTCAATAACTTCTATCCCAGAGAGGCTAAAGTCCAGTGGAAAGTTGAT
AATGCACTTCAGAGCGGGAATAGCCAGGAGAGCGTGACGGAACAGGACTCTAAGGACTCCACCT
ATTCTCTCTCATCCACCCTTAGTCTCTCTAAAGCCGACTACGAAAAGCATAAGGTTTATGCTTG
CGAAGTCACTCATCAAGGGCTATCTAGTCCGGTCACTAAAAGCTTCAACAGAGGTGAATGT Amino
acid Sequence: (SEQ ID NO: 447)
CISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGSSGTQILLTQSPVILSVSPGERVSFSC
RASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYY
CQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Anti-EGFR 2001 Activatable Antibody Light Chain with spacer
sequence: Nucleotide sequence: (SEQ ID NO: 80)
CAAGGCCAGTCTGGACAATGTATCAGCCCCCGTGGCTGTCCAGACGGTCCTTACGTTATGTATG
GATCTAGCGGGGGCTCTGGAGGGTCTGGCGGCTCTGGAATCTCTAGTGGACTTCTCTCCGGAAG
AAGCGATAATCATGGATCCAGCGGGACACAAATCCTGTTGACACAGTCCCCAGTGATCCTGTCA
GTCTCGCCCGGAGAAAGGGTGTCTTTCTCTTGTAGGGCTAGTCAGTCTATCGGAACTAACATCC
ATTGGTACCAGCAGCGGACAAATGGGAGCCCGAGGCTTCTGATCAAGTATGCTTCAGAGAGTAT
AAGCGGCATCCCCTCAAGATTTAGTGGCAGCGGGTCCGGGACAGATTTCACCTTGTCAATCAAT
TCTGTCGAATCCGAAGACATTGCAGACTACTATTGCCAGCAAAACAACAACTGGCCCACCACTT
TCGGTGCTGGAACCAAACTCGAGCTGAAACGCACTGTGGCAGCTCCTTCAGTGTTCATCTTCCC
ACCTAGCGACGAGCAGTTGAAATCGGGGACAGCCTCAGTGGTGTGTCTACTGAACAACTTTTAC
CCCCGGGAAGCCAAAGTGCAGTGGAAGGTCGACAATGCGCTGCAATCAGGGAACAGTCAGGAGT
CAGTTAGAGAGCAGGACTCTAAGGACAGTACATATTCTTTGAGTTCCACCTTGACATTAAGCAA
GGCAGACTACGAGAAACACAAGGTGTACGCATGTGAAGTTACACACCAGGGCCTTTCCTCCCCA
GTTAGGAAAAGCTTCAACAGAGGCGAATGC Amino acid Sequence: (SEQ ID NO: 81)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDNHGSSGTQILLTQSPVILS
VSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSIN
SVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP
VTKSFNRGEC Anti-EGFR 2001 Activatable Antibody Light Chain:
Nucleotide sequence: (SEQ ID NO: 448)
TGTATCAGCCCCCGTGGCTGTCCAGACGGTCCTTACGTTATGTATGGATCTAGCGGGGGCTCTG
GAGGGTCTGGCGGCTCTGGAATCTCTAGTGGACTTCTCTCCGGAAGAAGCGATAATCATGGATC
CAGCGGGACACAAATCCTGTTGACACAGTCCCCAGTGATCCTGTCAGTCTCGCCCGGAGAAAGG
GTGTCTTTCTCTTGTAGGGCTAGTCAGTCTATCGGAACTAACATCCATTGGTACCAGCAGCGGA
CAAATGGGAGCCCGAGGCTTCTGATCAAGTATGCTTCAGAGAGTATAAGCGGCATCCCCTCAAG
ATTTAGTGGCAGCGGGTCCGGGACAGATTTCACCTTGTCAATCAATTCTGTCGAATCCGAAGAC
ATTGCAGACTACTATTGCCAGCAAAACAACAACTGGCCCACCACTTTCGGTGCTGGAACCAAAC
TCGAGCTGAAACGCACTGTGGCAGCTCCTTCAGTGTTCATCTTCCCACCTAGCGACGAGCAGTT
GAAATCGGGGACAGCCTCAGTGGTGTGTCTACTGAACAACTTTTACCCCCGGGAAGCCAAAGTG
CAGTGGAAGGTCGACAATGCGCTGCAATCAGGGAACAGTCAGGAGTCAGTTACAGAGCAGGACT
CTAAGGACAGTACATATTCTTTGAGTTCCACCTTGACATTAAGCAAGGCAGACTACGAGAAACA
CAAGGTGTACGCATGTGAAGTTACACACCAGGGCCTTTCCTCCCCAGTTACGAAAAGCTTCAAC
AGAGGCGAATGC Amino acid Sequence: (SEQ ID NO: 449)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDNHGSSGTQILLTQSPVILSVSPGER
VSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESED
IADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN
RGEC Anti-EGFR 2002 Activatable Antibody Light Chain with spacer
sequence: Nucleotide sequence: (SEQ ID NO: 82)
CAAGGTCAGAGTGGCCAATGCATATCGCCCAGAGGATGTCCTGACGGACCCTACGTGATGTACG
GGAGTTCTGGGGGGAGTGGAGGCTCTGGCGGGTCAGGGATTAGTTCCGGCCTCTTGTCTGGACG
CTCCGGAAATCACGGATCATCTGGGACCCAGATCCTCCTGACCCAGTCTCCCGTCATTCTGTCT
GTTTCTCCAGGCGAGCGGGTTTCATTTAGCTGTAGGGCCAGTCAGAGCATTGGCACCAACATCC
ATTGGTACCAGCAGAGAACTAATGGCAGTCCCAGACTGCTCATTAAATATGCAAGCGAATCAAT
TTCCGGGATTCCTTCTCGCTTCTCGGGATCTGGATCTGGCACCGACTTCACGCTGTCCATCAAC
AGCGTGGAGAGTGAGGACATCGCCGATTACTAGTGCCAGCAGAACAACAACTGGCCAACAACTT
TTGGCGCCGGGACCAAGCTTGAGTTAAAGAGAACCGTAGCTGCACCCTCTGTTTTCATTTTCCC
ACCCTCAGACGAGCAGCTTAAGTCAGGAACTGCCAGTGTGGTGTGCCTGCTGAACAACTTCTAC
CCGAGAGAGGCTAAAGTCCAGTGGAAGGTAGACAATGCCCTTCAGTCTGGCAACTCTCAGGAGA
GTGTCACAGAGCAGGATTCTAAGGACTCCACGTAGAGTCTGAGTTCCACCCTCACCCTCAGTAA
GGCAGACTACGAGAAGCACAAAGTCTACGCATGTGAGGTTACTCACCAGGGGCTCAGCTCTCCC
GTGACGAAGTCATTTAACAGAGGTGAGTGC Amino acid Sequence: (SEQ ID NO: 83)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSGNHGSSGTQILLTQSPVILS
VSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSIN
SVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP
VTKSFNRGEC Anti-EGFR 2002 Activatable Antibody Light Chain:
Nucleotide sequence: (SEQ ID NO: 450)
TGCATATCGCCCAGAGGATGTCCTGACGGACCCTACGTGATGTACGGGAGTTCTGGGGGGAGTG
GAGGCTCTGGCGGGTCAGGGATTAGTTCCGGCCTCTTGTCTGGACGCTCCGGAAATCACGGATC
ATCTGGGACCCAGATCCTCCTGACCCAGTCTCCCGTCATTCTGTCTGTTTCTCCAGGCGAGCGG
GTTTCATTTAGCTGTAGGGCCAGTCAGAGCATTGGCACCAACATCCATTGGTAGCAGCAGAGAA
CTAATGGCAGTCCCAGACTGCTCATTAAATATGCAAGCGAATCAATTTCCGGGATTCCTTCTCG
CTTCTCGGGATCTGGATCTGGCACCGACTTCACGCTGTCCATCAACAGCGTGGAGAGTGAGGAC
ATCGCCGATTACTACTGCCAGCAGAACAACAACTGGCCAACAACTTTTGGCGCCGGGACCAAGC
TTGAGTTAAAGAGAACCGTAGCTGCACCCTCTGTTTTCATTTTCCCACCCTCAGACGAGCAGCT
TAAGTCAGGAACTGCCAGTGTGGTGTGCCTGCTGAACAACTTCTACCCGAGAGAGGCTAAAGTC
CAGTGGAAGGTAGACAATGCCCTTCAGTCTGGCAACTCTCAGGAGAGTGTCACAGAGCAGGATT
CTAAGGACTCCACGTACAGTCTGAGTTCCACCCTCACCCTCAGTAAGGCAGACTACGAGAAGCA
CAAAGTCTACGCATGTGAGGTTACTCACCAGGGGCTCAGCTCTCCCGTGACGAAGTCATTTAAC
AGAGGTGAGTGC Amino acid Sequence: (SEQ ID NO: 451)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSGNHGSSGTQILLTQSPVILSVSPGER
VSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESED
IADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPYTKSFN
RGEC Anti-EGFR 0001/LP'/1001 Activatable Antibody Light Chain with
spacer sequence: Nucleotide sequence: (SEQ ID NO: 84)
CAGGGACAGTCGGGACAGTGCATTTCTCCGAGAGGCTGCCCTGACGGCCCATACGTAATGTACG
GATCATCCGGTGGCAGTGGAGGGTCCGGGGGATCCGGTCTAAGCGGCAGAAGTGATAATCATGG
AGGCTCTGGCGGGAGCATCAGCTCCGGATTGCTTTCCAGCGGAAGTTCTGGCACTCAAATTCTG
CTGACACAAAGCCCTGTGATCTTGTCAGTCTCACCTGGCGAGCGGGTGAGCTTTTCATGCCGGG
CTTCCCAGAGCATCGGTACAAATATTCACTGGTATCAGCAGAGAACCAATGGCAGTCCGCGGTT
GCTGATTAAGTATGCGAGCGAGAGCATATCAGGCATACCAAGCAGATTTAGCGGGAGTGGCTCT
GGGACCGATTTTACACTCAGTATAAATTCAGTGGAGAGCGAGGATATAGCCGACTACTACTGCC
AGCAAAACAATAACTGGCCCACCACCTTCGGCGCAGGGACCAAGCTTGAACTGAAGCGTACAGT
TGCCGCCCCAAGCGTATTTATTTTCCCTCCAAGCGACGAACAGCTGAAAAGCGGTACCGCAAGC
GTTGTGTGCCTGCTGAATAACTTTTACCCAAGGGAAGCTAAGGTGCAGTGGAAGGTTGACAATG
CGCTGCAGTCAGGCAACTCCCAGGAATCGGTAACAGAGCAGGACTCCAAGGATTCAACTTATAG
TCTTAGTAGTACCCTTACTCTTTCCAAAGCTGATTATGAAAAACACAAAGTGTATGCATGCGAG
GTGACCCACCAAGGACTGTCATCTCCTGTCACCAAGTCCTTCAACCGGGGAGAGTGT Amino
acid Sequence: (SEQ ID NO: 85)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGGSGGSISSGLLSSGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 0001/LP'/1001 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 452)
TGCATTTCTCCGAGAGGCTGCCCTGACGGCCCATACGTAATGTACGGATCATCCGGTGGCAGTG
GAGGGTCCGGGGGATCCGGTCTAAGCGGCAGAAGTGATAATCATGGAGGCTCTGGCGGGAGCAT
CAGCTCCGGATTGCTTTCCAGCGGAAGTTCTGGCACTCAAATTCTGCTGACACAAAGCCCTGTG
ATCTTGTCAGTCTCACCTGGCGAGCGGGTGAGCTTTTCATGCCGGGCTTCCCAGAGCATCGGTA
CAAATATTCACTGGTATCAGCAGAGAACCAATGGCAGTCCGCGGTTGCTGATTAAGTATGCGAG
CGAGAGCATATCAGGCATACCAAGCAGATTTAGCGGGAGTGGCTCTGGGACCGATTTTACACTC
AGTATAAATTCAGTGGAGAGCGAGGATATAGCCGACTAGTACTGCCAGCAAAACAATAACTGGC
CCACCACCTTCGGCGCAGGGACCAAGCTTGAACTGAAGCGTACAGTTGCCGCCCCAAGCGTATT
TATTTTCCCTCCAAGCGAGGAACAGCTGAAAAGCGGTACCGCAAGCGTTGTGTGCCTGCTGAAT
AACTTTTAGCCAAGGGAAGCTAAGGTGCAGTGGAAGGTTGACAATGCGCTGCAGTCAGGCAACT
CCCAGGAATCGGTAACAGAGCAGGACTCCAAGGATTCAACTTATAGTCTTAGTAGTACCCTTAC
TCTTTCCAAAGCTGATTATGAAAAACACAAAGTGTATGCATGCGAGGTGACCCACGAAGGACTG
TCATCTCCTGTCACCAAGTCCTTCAACCGGGGAGAGTGT Amino acid Sequence: (SEQ
ID NO: 453)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGGSGGSISSGLLSSGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 1001/LP'/0001 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 86)
CAAGGTCAGAGCGGCCAGTGCATTAGTCCTCGCGGTTGCCCTGATGGACCATACGTAATGTATG
GAAGCTCTGGTGGATCCGGGGGCTCTGGCGGATCAGGAATCTCCAGCGGGCTGCTCTCATCAGG
TGGCAGCGGGGGCTCATTAAGCGGCCGAAGTGACAATCACGGCTCGTCCGGTACACAGATTCTG
CTCACTCAGTCACCCGTTATACTGTCTGTGTCGCCTGGAGAGCGTGTCAGCTTTTCATGTAGAG
CCTCGCAGTCAATAGGCACGAATATACACTGGTACCAGCAGAGAACTAATGGAAGCCCAAGGTT
GCTCATCAAATACGCATCTGAGTCGATTAGCGGCATTCCGTCCAGGTTTAGTGGCAGTGGAAGC
GGCACCGATTTCACTTTGTCTATTAACTCTGTGGAAAGCGAGGACATCGCCGATTATTATTGTC
AGCAGAATAACAATTGGCCCACCACCTTCGGTGCCGGTACTAAGCTGGAGCTGAAACGTACAGT
TGCCGCTCCCTCTGTGTTTATTTTCCCTCCCTCGGATGAGCAACTCAAATCAGGGACAGCGAGT
GTCGTATGTCTCCTGAACAATTTTTACCCACGTGAAGCTAAAGTTCAGTGGAAGGTGGACAACG
CTCTGCAGTCCGGCAACAGTCAGGAAAGCGTAACTGAACAGGACTCAAAGGATAGCACTTACTC
CTTGAGCAGCACTCTCACTCTTTCCAAGGCTGATTATGAGAAGCACAAGGTGTACGCGTGTGAA
GTCACCCATCAGGGACTGTCAAGTCCGGTGACTAAATCATTTAACAGGGGCGAATGC Amino
acid Sequence: (SEQ ID NO: 87)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGGSGGSLSGRSDNHGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 1001/LP'/0001 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 454)
TGCATTAGTCCTCGCGGTTGCCCTGATGGACCATACGTAATGTATGGAAGCTCTGGTGGATCCG
GGGGCTCTGGCGGATCAGGAATCTCCAGCGGGCTGCTCTCATCAGGTGGCAGCGGGGGCTCATT
AAGCGGCCGAAGTGACAATCACGGCTCGTCCGGTACACAGATTCTGCTCACTCAGTCACCCGTT
ATACTGTCTGTGTCGCCTGGAGAGCGTGTCAGCTTTTCATGTAGAGCCTCGCAGTCAATAGGCA
CGAATATACACTGGTACCAGCAGAGAACTAATGGAAGCCCAAGGTTGCTCATCAAATACGCATC
TGAGTCGATTAGCGGCATTCCGTCCAGGTTTAGTGGCAGTGGAAGCGGCACCGATTTCACTTTG
TCTATTAACTCTGTGGAAAGCGAGGACATCGCCGATTATTATTGTCAGCAGAATAACAATTGGC
CCACCACCTTCGGTGCCGGTAGTAAGCTGGAGCTGAAACGTACAGTTGCCGCTCCCTCTGTGTT
TATTTTCCCTCCCTCGGATGAGCAACTCAAATCAGGGAGAGCGAGTGTCGTATGTCTCCTGAAC
AATTTTTACCCACGTGAAGCTAAAGTTCAGTGGAAGGTGGACAACGCTCTGCAGTCCGGCAACA
GTGAGGAAAGCGTAACTGAACAGGACTCAAAGGATAGCACTTAGTCCTTGAGCAGCACTCTCAC
TCTTTCCAAGGCTGATTATGAGAAGCACAAGGTGTACGCGTGTGAAGTCACCCATCAGGGACTG
TCAAGTCCGGTGACTAAATCATTTAACAGGGGCGAATGC Amino acid Sequence: (SEQ
ID NO: 455)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGGSGGSLSGRSDNHGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 0002/LP'/1001 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 88)
CAGGGCCAGAGTGGGCAGTGTATTTCCCCTCGCGGATGTCCCGACGGTCCATACGTAATGTATG
GGTCAAGCGGGGGATCAGGAGGAAGTGGAGGCTCCGGAGTCAGCGGTCGCTCCGGCAATCACGG
GGGGTCTGGCGGATCAATAAGTTCGGGCCTCCTGAGCTCCGGTTCATCTGGCACTCAGATCCTG
CTCACGCAGTCGCCGGTAATACTGAGTGTCTCACCAGGCGAGCGTGTCAGCTTCAGCTGTCGCG
CCTCACAGTCAATCGGCACAAATATCCATTGGTACCAGCAAAGGACCAATGGCAGCCCTAGGCT
GCTGATAAAATACGCATCCGAGTCAATTTCAGGGATTCCATCGAGATTCTCGGGCAGCGGAAGT
GGGACCGACTTTAGTCTCTCCATCAACAGCGTCGAGTCGGAGGACATCGCGGACTACTACTGCC
AGCAGAATAACAATTGGCCAACAACATTCGGCGCAGGAACAAAGCTAGAGCTCAAGAGGACAGT
GGCTGCACCCAGTGTATTCATCTTCCCACCTAGCGACGAGCAACTGAAGAGCGGGACGGCTTCC
GTCGTTTGTCTATTAAATAATTTCTATCCCCGTGAGGCTAAAGTTCAGTGGAAGGTTGATAATG
CGTTGCAGTCCGGCAACTCCCAGGAATCCGTCACAGAGCAGGATTCTAAGGATTCAACCTATAG
CTTAAGCTCTACACTTACGCTTTCTAAAGCCGATTATGAAAAACACAAGGTGTACGCTTGTGAG
GTTACCCACCAGGGCCTGAGCAGCCCCGTGACCAAGTCGTTCAACCGGGGCGAGTGT Amino
acid Sequence: (SEQ ID NO: 89)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGGSGGSISSGLLSSGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 0002/LP'/1001 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 456)
TGTATTTCCCCTCGCGGATGTCCCGACGGTCCATACGTAATGTATGGGTCAAGCGGGGGATCAG
GAGGAAGTGGAGGCTCCGGACTCAGCGGTCGCTCCGGCAATCACGGGGGGTCTGGCGGATCAAT
AAGTTCGGGCCTCCTGAGCTCCGGTTCATCTGGCACTCAGATCCTGCTCACGCAGTCGCCGGTA
ATACTGAGTGTCTCACCAGGCGAGCGTGTCAGCTTCAGCTGTCGCGCCTCACAGTCAATCGGCA
CAAATATCCATTGGTACCAGCAAAGGACCAATGGCAGCCCTAGGCTGCTGATAAAATACGCATC
CGAGTCAATTTCAGGGATTCCATCGAGATTCTCGGGCAGCGGAAGTGGGACCGACTTTACTCTC
TCCATCAACAGCGTCGAGTCGGAGGACATCGCGGACTACTACTGCCAGCAGAATAACAATTGGC
CAACAACATTCGGCGCAGGAACAAAGCTAGAGCTCAAGAGGACAGTGGCTGCACCCAGTGTATT
CATCTTCCCACCTAGCGACGAGCAACTGAAGAGCGGGACGGCTTCCGTCGTTTGTCTATTAAAT
AATTTCTATCCCCGTGAGGCTAAAGTTCAGTGGAAGGTTGATAATGCGTTGCAGTCCGGCAACT
CCCAGGAATCCGTCACAGAGCAGGATTCTAAGGATTCAACCTATAGCTTAAGCTCTACACTTAC
GCTTTCTAAAGCCGATTATGAAAAACACAAGGTGTACGCTTGTGAGGTTACCCACCAGGGCCTG
AGCAGCCCCGTGACCAAGTCGTTCAACCGGGGCGAGTGT Amino acid Sequence: (SEQ
ID NO: 457)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGGSGGSISSGLLSSGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 1001/LP'/0002 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 90)
CAAGGACAGAGCGGACAGTGTATCTCACCTCGCGGCTGCCCCGAGGGCCCTTAGGTCATGTACG
GCTCCTCGGGTGGGTCCGGGGGAAGTGGCGGGTCTGGCATTAGTTCAGGGCTCTTATCTTCCGG
CGGAAGCGGGGGATCTCTTTCCGGGCGGAGTGGCAATCACGGCAGTAGCGGAACTCAGATCCTA
CTCACTCAGTCACCAGTGATCCTGTCTGTCAGTCCAGGGGAGAGAGTGTCTTTCAGTTGTAGAG
CTTCCCAGTCTATTGGGACAAACATTCACTGGTATCAACAGCGAACTAATGGATCGCCAAGACT
CCTGATTAAATATGCTTCTGAGAGCATCTCTGGAATTCCATCAAGATTCTCAGGGAGTGGTAGC
GGCACCGATTTTACGTTATCGATCAATTCCGTTGAGAGCGAAGATATCGCGGACTATTACTGTC
AGCAGAACAATAACTGGCCTACAACGTTCGGGGCAGGGACGAAATTGGAGCTGAAGCGGACCGT
CGCCGCGCCAAGCGTGTTCATCTTCCCCCCTAGCGACGAGCAATTGAAAAGCGGCACCGCAAGT
GTGGTTTGCCTGCTGAACAACTTTTATCCTCGCGAGGCGAAAGTGCAGTGGAAAGTCGACAATG
CACTCCAGTCAGGGAACAGCCAAGAGTCCGTTACTGAACAAGACTCTAAAGATAGTACTTATAG
CTTATCCAGCACACTGACGCTCAGTAAGGCCGATTATGAAAAACATAAGGTGTATGCGTGTGAG
GTTAGCCATCAAGGATTGTCATCACCCGTCACCAAATCCTTTAACAGAGGAGAATGT Amino
acid Sequence: (SEQ ID NO: 91)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGGSGGSLSGRSGNHGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 1001/LP'/0002 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 458)
TGTATCTCACCTCGCGGCTGCCCCGACGGCCCTTACGTCATGTACGGCTCCTCGGGTGGGTCCG
GGGGAAGTGGCGGGTCTGGCATTAGTTCAGGGCTCTTATCTTCCGGCGGAAGCGGGGGATCTCT
TTCCGGGCGGAGTGGCAATCACGGCAGTAGCGGAACTCAGATCCTACTCACTCAGTCACCAGTG
ATCCTGTCTGTCAGTCCAGGGGAGAGAGTGTCTTTCAGTTGTAGAGCTTCCCAGTCTATTGGGA
CAAACATTCACTGGTATCAACAGCGAACTAATGGATCGCCAAGACTCCTGATTAAATATGCTTC
TGAGAGCATCTCTGGAATTCCATCAAGATTCTCAGGGAGTGGTAGCGGCACCGATTTTACGTTA
TCGATCAATTCCGTTGAGAGCGAAGATATCGCGGACTATTACTGTCAGCAGAACAATAACTGGC
CTACAACGTTCGGGGCAGGGACGAAATTGGAGCTGAAGCGGACCGTCGCCGCGCCAAGCGTGTT
CATCTTCCCCCCTAGCGACGAGCAATTGAAAAGCGGCACCGCAAGTGTGGTTTGCCTGCTGAAC
AACTTTTATCCTCGCGAGGCGAAAGTGCAGTGGAAAGTCGACAATGCACTCCAGTCAGGGAACA
GCCAAGAGTCCGTTACTGAACAAGACTCTAAAGATAGTACTTATAGCTTATCCAGCACACTGAC
GCTCAGTAAGGCCGATTATGAAAAACATAAGGTGTATGCGTGTGAGGTTAGCCATCAAGGATTG
TCATCACCCGTCACCAAATCCTTTAACAGAGGAGAATGT Amino acid Sequence: (SEQ
ID NO: 459)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSSGGSGGSLSGRSGNHGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 0001/LP'/1002 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 92)
CAGGGTCAAAGTGGACAGTGTATCTCGCCCCGCGGCTGCCCAGACGGCCCATATGTGATGTATG
GTTCTTCCGGTGGATCCGGCGGATCAGGTGGGTCTGGCCTCTCAGGTCGTTCCGACAACCACGG
CGGCTCAGGTGGGTCTCAGAATCAGGCACTGCGGATGGCCGGATCTTCTGGCACCCAGATATTG
CTCACACAGTCACCAGTTATTCTGTCCGTATCTCCAGGAGAACGGGTATCTTTCTCTTGTAGGG
CAAGCCAGTCCATCGGAACAAACATCCATTGGTACCAGCAGCGGACCAATGGCAGTCCACGGCT
TCTGATCAAGTATGCTAGTGAAAGCATTAGCGGGATTCCAAGCCGATTTTCTGGGTCGGGTAGT
GGAACCGACTTCACCCTGAGCATTAACTCTGTCGAATCCGAAGATATTGCTGACTATTACTGTC
AGCAGAACAACAATTGGCCGACTACGTTTGGCGCCGGAACCAAATTAGAACTTAAGAGAACCGT
GGCCGCTCCCTCTGTCTTCATTTTCCCGCCTTCCGACGAACAGCTGAAGAGCGGAACTGCCTCC
GTGGTGTGCCTGTTGAATAACTTTTATCCAAGGGAAGCAAAGGTGCAGTGGAAAGTGGACAATG
CTCTGCAGTCTGGCAATAGCCAGGAGTCCGTGACTGAACAGGACAGTAAAGACTCAACCTACTC
ACTGAGGAGTAGTCTCACATTATCCAAAGCCGATTATGAAAAGCATAAGGTTTATGCATGCGAG
GTTAGCCACCAGGGACTGAGCTCCCCCGTGACCAAAAGCTTCAATAGGGGTGAGTGC Amino
acid Sequence: (SEQ ID NO: 93)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGGSGGSQNQALRMAGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 0001/LP'/1002 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 460)
TGTATCTCGCCCCGCGGCTGCCCAGACGGCCCATATGTGATGTATGGTTCTTCCGGTGGATCCG
GCGGATCAGGTGGGTCTGGCCTCTCAGGTCGTTCCGACAACCACGGCGGCTCAGGTGGGTCTCA
GAATGAGGCACTGCGGATGGCCGGATCTTCTGGCACCCAGATATTGCTCACACAGTCACCAGTT
ATTCTGTCCGTATCTCCAGGAGAACGGGTATCTTTCTCTTGTAGGGCAAGCCAGTCCATCGGAA
CAAACATCCATTGGTACCAGCAGCGGACCAATGGCAGTCCACGGCTTCTGATGAAGTATGCTAG
TGAAAGCATTAGCGGGATTCCAAGCCGATTTTCTGGGTCGGGTAGTGGAACCGACTTCACCCTG
AGCATTAACTCTGTCGAATCCGAAGATATTGCTGACTATTAGTGTCAGCAGAACAACAATTGGC
CGACTAGGTTTGGCGCCGGAACCAAATTAGAACTTAAGAGAACCGTGGCCGCTCCCTCTGTCTT
CATTTTCCCGCCTTCCGACGAACAGCTGAAGAGCGGAACTGCCTCCGTGGTGTGCCTGTTGAAT
AACTTTTATCCAAGGGAAGCAAAGGTGCAGTGGAAAGTGGACAATGCTCTGCAGTCTGGCAATA
GCCAGGAGTCCGTGACTGAAGAGGACAGTAAAGACTCAACCTACTCACTGAGGAGTACTCTCAC
ATTATCCAAAGCCGATTATGAAAAGCATAAGGTTTATGCATGCGAGGTTACCCACCAGGGACTG
AGCTCCCCCGTGACCAAAAGCTTCAATAGGGGTGAGTGC Amino acid Sequence: (SEQ
ID NO: 461)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSDNHGGSGGSQNQALRMAGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 1002/LP'/0001 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 94)
CAGGGGCAGTCCGGACAATGCATCAGCCCCCGAGGCTGCCCTGATGGCCCCTACGTGATGTACG
GGTCCAGCGGTGGCAGCGGGGGCTCAGGGGGGAGCGGGCAGAATCAGGCCCTGAGAATGGCGGG
TGGATCCGGGGGGTCCCTTTCTGGCAGGTCCGATAACCACGGTTCTAGTGGAACACAGATTTTG
CTGACACAAAGTCCCGTCATCCTCTCTGTGTCTCCCGGTGAGCGGGTCAGTTTTTCCTGCCGAG
CGTCCCAGAGCATCGGGACAAATATCCATTGGTACCAGCAGAGAACGAACGGCTCTCCTAGACT
GCTCATCAAGTACGCCTCGGAAAGTATTTCCGGCATTCCCTCCCGTTTCAGCGGCTCCGGAAGT
GGTACAGATTTTACCCTGAGTATTAATTCCGTCGAATCTGAGGACATAGCCGACTACTATTGCC
AACAGAATAACAATTGGCCAACAACTTTTGGCGCCGGGACTAAGCTGGAGCTGAAACGGACCGT
CGCAGCACCAAGTGTTTTCATCTTCCCACCAAGTGACGAGCAGCTGAAATCCGGAACAGCGAGC
GTGGTGTGCCTACTCAATAACTTCTATCCACGCGAAGCCAAGGTGCAGTGGAAAGTGGACAACG
CTCTGCAGTCCGGCAATAGCCAGGAAAGCGTGACAGAGCAAGATTCTAAGGACAGTACGTATTC
ATGTCCAGTACGCTCACCTTAAGCAAGGCTGACTACGAAAAACACAAGGTCTACGCCTGTGAG
GTCACACATCAGGGCCTCTCCAGTCCGGTTACAAAAAGTTTCAATCGCGGGGAATGT Amino
acid Sequence: (SEQ ID NO: 95)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGGSGGSLSGRSDNHGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-ECFR 1002/LP'/0001 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 462)
TGCATCAGCCCCCGAGGCTGCCCTGATGGCCCCTACGTGATGTACGGGTCCAGCGGTGGCAGCG
GGGGCTCAGGGGGGAGCGGGCAGAATCAGGCCCTGAGAATGGCGGGTGGATCCGGGGGGTCCCT
TTCTGGCAGGTCCGATAACCACGGTTCTAGTGGAACACAGATTTTGCTGACACAAAGTCCCGTC
ATCCTCTCTGTGTCTCCCGGTGAGCGGGTCAGTTTTTCCTGCCGAGCGTCCCAGAGCATCGGGA
CAAATATCCATTGGTACCAGCAGAGAACGAACGGCTCTCCTAGACTGCTCATCAAGTAGGCCTC
GGAAAGTATTTCCGGCATTCCCTCCCGTTTCAGCGGCTCCGGAAGTGGTAGAGATTTTACCCTG
AGTATTAATTCCGTCGAATCTGAGGACATAGCCGACTAGTATTGCCAACAGAATAACAATTGGC
CAACAACTTTTGGCGCCGGGACTAAGCTGGAGCTGAAACGGACCGTCGCAGCACCAAGTGTTTT
CATCTTCCCACCAAGTGACGAGCAGCTGAAATCCGGAACAGCGAGCGTGGTGTGCCTACTCAAT
AACTTCTATCCACGCGAAGCCAAGGTGCAGTGGAAAGTGGACAACGCTCTGCAGTCCGGCAATA
GCCAGGAAAGCGTGACAGAGCAAGATTCTAAGGACAGTACGTATTCACTGTCCAGTACGCTCAC
CTTAAGCAAGGCTGACTAGGAAAAACACAAGGTCTACGCCTGTGAGGTCACACATCAGGGCCTC
TCCAGTCCGGTTACAAAAAGTTTCAATCGCGGGGAATGT Amino acid Sequence: (SEQ
ID NO: 463)
CISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGGSGGSLSGRSDNHGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCOQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFK 0002/LP'/1002 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 96)
CAAGGCCAATCCGGTCAGTGCATCAGTCCCAGAGGCTGCCCTGACGGGCCCTACGTGATGTATG
GTAGCTCAGGGGGCTCCGGCGGCTCCGGCGGAAGCGGACTTAGCGGCCGTAGCGGCAACCATGG
GGGTTCTGGAGGATCCCAGAATCAGGCTCTGCGCATGGCTGGAAGCAGCGGTACCCAGATCCTG
CTCACCCAATCACCCGTCATCTTGTCTGTGAGTCCTGGCGAAAGGGTGTCGTTCTCTTGTCGCG
CGTCCCAGTCCATTGGGACCAACATTCATTGGTACCAGCAGAGGACTAACGGGAGCCCCCGCCT
GCTGATCAAATACGCCAGTGAATCTATCTCTGGAATCCCATCACGATTTTCAGGGTCCGGTAGT
GGGACCGACTTCACTTTGAGTATTAACAGTGTGGAATCCGAGGACATAGCCGACTATTACTGTC
AGCAGAACAATAACTGGCCAACAACCTTTGGCGCCGGGACAAAGTTAGAGCTTAAGCGGACTGT
TGCAGCCCCCTCCGTTTTTATCTTCCCGCCCAGTGATGAACAGCTGAAAAGCGGTACCGCCTCC
GTAGTGTGCCTTCTCAATAATTTTTACCCCAGAGAAGCTAAAGTACAGTGGAAAGTCGACAACG
CCCTCCAGAGCGGCAACAGTCAGGAGTCCGTCACCGAGCAGGATTCTAAAGACTCAACATATAG
CCTTTCGTCCACCCTAACACTTTCAAAAGCAGACTATGAAAAACATAAGGTGTATGCCTGCGAG
GTCACACACCAGGGGCTCAGCTCTCCAGTTACTAAGTCATTCAACCGCGGAGAGTGT Amino
acid Sequence: (SEQ ID NO: 97)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGGSGGSQNQALRMAGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 0002/LP'/1002 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 464)
TGCATCAGTCCCAGAGGCTGCCCTGACGGGCCCTACGTGATGTATGGTAGCTCAGGGGGCTCCG
GCGGCTCCGGCGGAAGCGGACTTAGCGGCCGTAGCGGCAACCATGGGGGTTCTGGAGGATCCCA
GAATCAGGCTCTGCGCATGGCTGGAAGCAGCGGTACCCAGATCCTGCTCACCCAATCACCCGTC
ATCTTGTCTGTGAGTCCTGGCGAAAGGGTGTCGTTCTCTTGTCGCGCGTCCCAGTCCATTGGGA
CCAACATTCATTGGTAGCAGCAGAGGACTAACGGGAGCCCCCGCCTGCTGATCAAATACGCCAG
TGAATCTATCTCTGGAATCCCATCACGATTTTCAGGGTCCGGTAGTGGGACCGACTTCACTTTG
AGTATTAACAGTGTGGAATCCGAGGACATAGCCGACTATTACTGTCAGCAGAACAATAACTGGC
CAACAACCTTTGGCGCCGGGACAAAGTTAGAGCTTAAGCGGACTGTTGCAGCCCCCTCCGTTTT
TATCTTCCCGCCCAGTGATGAACAGCTGAAAAGCGGTAGCGCCTCCGTAGTGTGCCTTCTCAAT
AATTTTTACCCCAGAGAAGCTAAAGTACAGTGGAAAGTCGACAACGCCCTCCAGAGCGGCAACA
GTCAGGAGTCCGTCACCGAGCAGGATTCTAAAGACTCAACATATAGCCTTTCGTCCACCCTAAC
ACTTTCAAAAGCAGACTATGAAAAACATAAGGTGTATGCCTGCGAGGTCACACACCAGGGGCTC
AGCTCTCCAGTTACTAAGTCATTCAACCGCGGAGAGTGT Amino acid Sequence: (SEQ
ID NO: 465)
CISPRGCPDGPYVMYGSSGGSGGSGGSGLSGRSGNHGGSGGSQNQALRMAGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCOQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC Anti-EGFR 1002/LP'/0002 Activatable Antibody Light
Chain with spacer sequence: Nucleotide sequence: (SEQ ID NO: 98)
CAGGGCCAATCAGGTCAGTGCATTAGCCCCCGAGGGTGTCCCGATGGGCCCTACGTAATGTACG
GATCATCGGGCGGATCTGGGGGCTCCGGTGGCTCTGGTCAGAATCAAGCTCTGCGCATGGCCGG
AGGTAGCGGTGGAAGCCTGAGCGGCCGAAGTGGAAACCACGGCTCCTCTGGCACTCAGATTCTT
CTCACGCAGTCGCCCGTGATCTTGTCCGTGAGCCCAGGCGAGCGGGTGAGCTTCTCTTGCCGGG
CCAGCCAAAGTATAGGTACAAATATTCACTGGTACCAACAGCGAACCAACGGGTCGCCTAGGTT
GCTCATAAAGTACGCATCCGAGAGTATAAGCGGCATACCATCTAGGTTCTCAGGTAGCGGCAGC
GGGACCGATTTTACCCTCAGCATTAATTCGGTTGAATCTGAAGATATCGCCGATTATTATTGTC
AGCAGAATAACAATTGGCCTACTACTTTCGGCGCCGGAACAAAGCTGGAACTTAAGCGCACAGT
GGCCGCTCCTTCTGTCTTTATCTTCCCTCCATCTGACGAGCAATTAAAGAGTGGGACAGCCTCG
GTGGTGTGTTTGCTCAATAACTTCTATCCAAGGGAGGCAAAGGTGCAGTGGAAGGTCGATAACG
CTCTCCAGAGTGGGAATTCCCAGGAGTCCGTGACCGAGCAGGATTCTAAAGATAGCACATACTC
ACTGTCTTCCACCCTGACCCTGTCCAAGGCAGACTACGAGAAGCACAAAGTTTACGCCTGTGAA
GTGACACACCAGGGCCTCAGCTCTCCTGTCACAAAGAGTTTTAATCGGGGCGAGTGT Amino
acid Sequence: (SEQ ID NO: 99)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGGSGGSLSGRSGNHGSSGTQIL
LTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGS
GTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE
VTHQGLSSPVTKSFNRGEC Anti-EGFR 1002/LP'/0002 Activatable Antibody
Light Chain: Nucleotide sequence: (SEQ ID NO: 466)
TGCATTAGCCCCCGAGGGTGTCCCGATGGGCCCTAGGTAATGTACGGATCATCGGGCGGATCTG
GGGGCTCCGGTGGCTCTGGTCAGAATCAAGCTCTGCGCATGGCCGGAGGTAGCGGTGGAAGCCT
GAGCGGCCGAAGTGGAAACCACGGCTCCTCTGGCACTCAGATTCTTCTCACGCAGTCGCCCGTG
ATCTTGTCCGTGAGCCCAGGCGAGCGGGTGAGCTTCTCTTGCCGGGCCAGCCAAAGTATAGGTA
CAAATATTCACTGGTACCAACAGCGAACCAACGGGTCGCCTAGGTTGCTCATAAAGTACGCATC
CGAGAGTATAAGCGGCATACCATCTAGGTTCTCAGGTAGCGGCAGCGGGACCGATTTTACCCTC
AGCATTAATTCGGTTGAATCTGAAGATATCGCCGATTATTATTGTCAGCAGAATAACAATTGGC
CTACTAGTTTCGGCGCCGGAACAAAGCTGGAACTTAAGCGCACAGTGGCCGCTCCTTCTGTCTT
TATCTTCCCTCCATCTGACGAGCAATTAAAGAGTGGGACAGCCTCGGTGGTGTGTTTGCTCAAT
AACTTCTATCCAAGGGAGGCAAAGGTGCAGTGGAAGGTCGATAACGCTCTCCAGAGTGGGAATT
CCCAGGAGTCCGTGACCGAGCAGGATTCTAAAGATAGCACATACTCACTGTCTTCCACCCTGAC
CCTGTCCAAGGCAGACTACGAGAAGCACAAAGTTTACGCCTGTGAAGTGACACACCAGGGCCTC
AGCTCTCCTGTCACAAAGAGTTTTAATCGGGGCGAGTGT Amino acid Sequence: (SEQ
ID NO: 467)
CISPRGCPDGPYVMYGSSGGSGGSGGSGQNQALRMAGGSGGSLSGRSGNHGSSGTQILLTQSPV
ILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTL
SINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN
NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL
SSPVTKSFNRGEC
[0496] The following materials were used in the studies described
herein.
[0497] Reagents and Strains:
[0498] Human u-PA (Research & Diagnostics Systems, Inc.) was
used without modifications. Human matriptase (Research &
Diagnostics Systems, Inc.) was used without modifications. Human
MMP14 (Research & Diagnostics Systems, Inc.) was activated
following the supplied protocol and used without modifications.
MMP14 Buffer HCM (50 mM HEPES (pH 6.8), 10 mM CaCl.sub.2, 0.5 mM
MgCl.sub.2) was used. u-PA and Matriptase Buffer TBST (50 mM
Tris-HCl, 150 mM NaCl, 0.05% Tween20, pH 7.4) was used.
[0499] The following methods were used to evaluate in Vitro
substrate activity in activatable antibodies.
[0500] Substrate Proteolysis:
[0501] The ability of substrates in the activatable antibodies to
be cleaved by u-PA, matriptase and/or MMP14 was determined as
follows. Samples were incubated overnight for 16 to 24 hours at
37.degree. C. in the presence or absence of protease in PBS pH 7.2.
Protease digests were prepared to maintain an activatable antibody
to protease ratio of 9-to-1. Proteolysis was confirmed by capillary
electrophoresis, ELISA, or SDS-PAGE.
[0502] Substrate Cleavage Kinetics (k.sub.cat/K.sub.m):
[0503] The ability of EGFR activatable antibodies containing
substrates, 2001, 2002, 0001/LP'/1001 or 1001/LP'/0001, to be
cleaved by matriptase and/or MMP14 was determined as follows.
Matriptase protease digests were performed in TBST, 50 mM Tris-HCl,
150 mM NaCl, 0.05% Tween20, pH 7.4. MMP14 protease digests were
performed in HCM, 50 mM HEPES (pH 6.8), 10 mM CaCl.sub.2, 0.5 mM
MgCl.sub.2. Varying concentrations of active site titrated
matriptase or MMP14 were combined with a fixed activatable antibody
concentration to maintain a substrate to protease ratio of at least
50. Samples comprising these substrates were incubated at
37.degree. C. for up to 24 hr. To stop the reaction, 5 .mu.l of the
digest was added to 7 .mu.l of HT Protein Express Sample Buffer
(Caliper LifeSciences) containing 20 mM 2-Mercaptoethanol for 10
minutes at 95.degree. C. After heat denaturation, 32 .mu.l of
ddH.sub.2O was added and samples analyzed on a LabChip GXII per
manufacturer's instructions. The LabChip GXII software was used to
quantify light chain peak area. Product conversion was calculated
by plugging the light chain peak areas into the following equation:
cleaved LC/(cleaved LC+uncleaved LC), LC=light chain peak area.
k.sub.cat/K.sub.m values were determined with the following
equation
k cat K m = - ln ( 1 - C ) / ( t * p ) ##EQU00001##
where C is product conversion, t is time (s), and p is protease
concentration (M), which assumes that the substrate concentration
is below the K.sub.m and in excess of the protease
concentration.
[0504] The following methods can be used to evaluate the in vivo
substrate stability of activatable antibodies described herein.
[0505] This section describes the experimental method for
evaluating in vivo stability of substrates of the embodiments when
they were incorporated into EGFR activatable antibodies and
injected into mice.
[0506] Three nude mice (Crl:NU-Foxn1nu) received a single IP dose
of each EGFR activatable antibodies containing 2001, 2002,
0001/LP'/1001, 1001/LP'/0001, 1001/LP'/0002, 0001/LP'/1002, or
0002/LP'/1002 substrates at 12.5 mg/kg on Day 0. Mice were
euthanized on day 4 (.about.96 hours post-dose) by CO.sub.2
asphyxiation, and blood was collected immediately as plasma-EDTA
and stored at -80.degree. C.
[0507] The EGFR activatable antibodies were purified from plasma by
anti-human IgG immunoprecipitation using magnetic beads. Eluted
EGFR activatable antibodies were prepared for analysis by capillary
electrophoresis as described in the k.sub.cat/K.sub.m section.
Briefly, 5 .mu.l of eluted IgG was added to 7 .mu.l Protein Express
Sample Buffer with 2-mercaptoethanol. The method of quantification
of circulating stability was identical to quantification of product
conversion.
[0508] The following methods are used to evaluate in vivo efficacy
of activatable antibodies.
[0509] This section describes the experimental method for
evaluating that EGFR activatable antibodies comprising
matriptase-cleavable substrates, MMP14-cleavable substrates, or
substrates of the embodiments, i.e., substrates cleavable by
matriptase and MMP14, are efficacious in vivo. Seven EGFR
activatable antibodies comprising substrate sequences of 0001,
0002, 1001, 2001, 2002, 0001/LP'/1001 or 1001/LP'/0001, cleavable
by either or both matriptase and/or MMP14 were administered at 12.5
mg/kg intraperitoneally (i.p.) to H292 xenograft tumor-bearing
(lung cancer) mice on Day 0. Mice were retro-orbitally bled on day
8 (.about.192 hours post-dose). Blood was collected immediately as
plasma-EDTA and stored at -80.degree. C. EGFR activatable
antibodies were purified from plasma by anti-human IgG
immunoprecipitation using magnetic beads. Eluted EGFR activatable
antibodies were prepared for analysis by capillary electrophoresis.
Briefly, 5 .mu.l of eluted IgG was added to 7 .mu.l Protein Express
Sample Buffer with 2-mercaptoethanol. Quantification of circulating
stability was identical to quantification of product
conversion.
[0510] At day 8, the three EGFR activatable antibodies containing
matriptase-cleavable substrates or MMP14-cleavable substrates,
0001, 0002 or 1001, demonstrated mean percent (%) activation values
ranging from 14% to 15% and the four EGFR activatable antibodies
containing substrates, 2001, 2002, 0001/LP'/1001 or 1001/LP'/0001,
of the embodiments, i.e., substrates cleavable by matriptase and
MMP14, demonstrated mean % activation values of 28% to 33%. Mean %
activation is calculated as ((product conversion sum of the test
group)*100%)/(number of animals in the test group).
[0511] All seven EGFR activatable antibodies containing substrate
sequences of 0001, 0002, 1001, 2001, 2002, 0001/LP'/1001 or
1001/LP'/0001 also comprised the masking moiety comprising the
amino acid sequence CISPRGCPDGPYVMY (SEQ ID NO: 168) and anti-EGFR
antibody C225v5 antibody comprising a light chain (SEQ ID NO: 111)
and a heavy chain (SEQ ID NO: 108). The configuration of the light
chain of the activatable antibody was masking
moiety--substrate--light chain of C225v5.
[0512] At day 21, the three EGFR activatable antibodies containing
matriptase-cleavable substrates or MMP14-cleavable substrates,
0001, 0002 or 1001, demonstrated tumor growth inhibition ranging
from 41% to 57% as measured by mean percent (%) inhibition and the
four EGFR activatable antibodies containing substrates, 2001, 2002,
0001/LP'/1001 or 1001/LP'/0001, of the embodiments, i.e.,
substrates cleavable by matriptase and MMP14, demonstrated tumor
growth inhibition ranging from 77% to 80% as measured by mean %
inhibition. Mean % inhibition is calculated as
(mean(C)-mean(C0))-(mean(T)-mean(T0))/(mean(C)-mean(C0))*1000%,
wherein T is the current test group value, T0 is the current test
group initial value, C is the control group value, and C0 is the
control group initial value. The EGFR antibody cetuximab at day 21
demonstrated 86% inhibition in this study.
Example 3
In Situ Imaging of Anti-EGFR Activatable Antibodies
[0513] The present Example describes the use of in situ imaging of
non-labeled anti-EGFR activatable antibodies. The cleavage and
binding was detected using a secondary antibody that specifically
binds to the AB portion of the activatable antibody.
[0514] In situ imaging of the activation and binding of a
non-labeled anti-EGFR activatable antibody 3954-2001-C225v5 on H292
lung cancer tumor tissue was conducted as follows: Frozen tissue
sections were laid over glass slides. A solution containing
non-labeled anti-EGFR activatable antibodies was applied on the
tissue and incubated, e.g., for 1 hour at room temperature (about
22-24.degree. C.) in an incubation buffer of 10 mM Hepes buffer pH
7.4, containing 150 mM NaCl. 10 .mu.M ZnCl.sub.2, 2 mM CaCl.sub.2
and 0.005% Tween 20; activatable antibody at a concentration of
about 1 .mu.g/ml. The conditions of such an incubation can be
adjusted to be conducive to the cleavage agent in the tissue
section by, for example, varying the pH of the solution (e.g.,
within a range of about pH 7 to about pH 8.5), the temperature of
the incubation (e.g., within a range of about 20.degree. C. to
about 40.degree. C., e.g., room temperature or 37.degree. C.), the
incubation time (e.g., within a range of about 15 minutes to about
150 minutes, and/or the activatable antibody concentrations (e.g.,
within a range of about 0.05 .mu.g/ml to about 10 .mu.g/ml). The
tissue was then extensively washed to remove non-bound material.
The presence of activated antibody on the tissue was detected using
a secondary anti-human IgG antibody labeled with AlexaFluor-647.
The conditions of that detection can be adjusted to the detecting
reagent and detection modality (e.g., fluorescently labeled). For
example, when a fluorescent tag was used, the tissue was submitted
to fluorescent microscopy. As shown in FIG. 6, anti-EGFR
activatable antibody 3954-2001-C225v5 demonstrated staining with
comparable intensity and pattern as parental anti-EGFR antibody.
The fluorescent signal of anti-EGFR activatable antibody
3954-2001-C225v5 was significantly inhibited by pre-treatment of
the tissue with a 1:100 dilution of broad spectrum inhibitor
cocktail set III (539134, EMD Millipore, Billerica, Mass.) and 50
mM EDTA.
Example 4
Additional Matrix Metalloprotease (MMP) and Serine Protease (SP)
Activatable Antibodies
[0515] This Example demonstrates the generation and evaluation of
additional substrate sequences that are activated in the presence
of at least one matrix metalloprotease (MMP) and at least one
serine protease.
[0516] The studies described herein used the following substrate
sequences:
TABLE-US-00020 CM1-CM2 Substrate AA sequence SEQ ID NO: 2001
ISSGLLSGRSDNH 1 1004/LP'/0003 AVGLLAPPGGTSTSGRSANPRG 3
1004/LP'/0001 AVGLLAPPGGLSGRSDNH 7 2003 ISSGLLSGRSANPRG 469 2004
AVGLLAPPTSGRSANPRG 470 2005 AVGLLAPPSGRSANPRG 471
[0517] The ability of substrates, 2001, 1004/LP'/0001,
1004/LP'/0003, 2003, 2004, or 2005 to be cleaved by human
matriptase and/or human uPA was determined as described above in
Example 2.
[0518] Substrate 2003 demonstrated approximately a 50-fold increase
in the cleavage kinetics for matriptase as compared to substrate
2001, and substrate 2005 demonstrated approximately a 50-fold
increase in the cleavage kinetics for matriptase as compared to
substrate 1004/LP'/0001.
[0519] Substrates 2003 and 2005 also demonstrated modest increases
in the range of about 3- to 4-fold in uPA kinetics as compared to
2001 and 1004/LP'/0001, respectively. Substrates 2003 and 2005 were
found to be cleaved in the presence of mouse uPA as well.
[0520] Substrates 2003, 2004, and 2005 were incorporated in the
following activatable antibodies:
TABLE-US-00021 Anti-EGFR Heavy Chain: Amino acid Sequence: (SEQ ID
NO: 108) QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV
IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALT
YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Anti-EGFR Light
Chain: Amino acid Sequence: (SEQ ID NO: 111)
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY
ASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGA
GTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC
Anti-EGFR 2003 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 472)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSANPRGGSSGTQI
LLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYAS
ESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGT
KLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN
ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC
Anti-EGFR 2003 Activatable Antibody Light Chain with spacer
sequence: Amino acid Sequence: (SEQ ID NO: 473)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSANPRGG
SSGTQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRL
LIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPT
TFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV
QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV
THQGLSSPVTKSFNRGEC Anti-EGFR 2005 Activatable Antibody Light Chain:
Amino acid Sequence: (SEQ ID NO: 474)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPSGRSANPRGGSSGT
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY
ASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGA
GTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC
Anti-EGFR 2005 Activatable Antibody Light Chain with spacer
sequence: Amino acid Sequence: (SEQ ID NO: 475)
QGQSGQCISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPSGRSANPR
GGSSGTQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSP
RLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNW
PTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC
EVTHQGLSSPVTKSFNRGEC
[0521] The substrates used in all of the anti-EGFR activatable
antibodies shown above were cleaved by human matriptase, by human
uPA, by human matrix metalloprotease 14 (MMP14), and human matrix
metalloprotease 9 (MMP9).
[0522] This section describes the evaluation of various anti-EGFR
activatable antibodies shown above in a H292 tumor efficacy study
using H292 xenograft tumors in nu/nu mice. The H292 tumor efficacy
study is described in Example 2 and is also described in PCT
Publication No. WO 2013/163631.
[0523] In this study, the mice were group and dosed as shown in the
Table below using a control intravenous immunoglobulin (IVIG), the
anti-EGFR antibody cetuximab, the anti-EGFR activatable antibody
referred to herein as anti-EGFR 2001 activatable antibody, which
includes the heavy chain sequence of SEQ ID NO: 108, and the light
chain sequence of SEQ ID NO: 449; the anti-EGFR activatable
antibody referred to herein as anti-EGFR 2003 activatable antibody,
which includes the heavy chain sequence of SEQ ID NO: 108, and the
light chain sequence of SEQ ID NO: 472; or the anti-EGFR
activatable antibody referred to herein as anti-EGFR 2005
activatable antibody, which includes the heavy chain sequence of
SEQ ID NO: 108, and the light chain sequence of SEQ ID NO: 474:
TABLE-US-00022 Dose Group Count Treatment (mg/kg) Schedule 1 8 IVIG
9 Single dose 2 8 Cetuximab 9 Single dose 3 8 Anti-EGFR 2001 9
Single dose Activatable Antibody 4 8 Anti-EGFR 2003 9 Single dose
Activatable Antibody 5 8 Anti-EGFR 2005 9 Single dose Activatable
Antibody
[0524] The efficacy of the substrates used in the anti-EGFR
antibodies shown above was evaluated by measuring tumor volume (TV
mm.sup.3) at various time points post-administration. The results
of this study are shown in FIGS. 8A-8F.
[0525] This section describes the evaluation of various anti-Jagged
activatable antibodies in a toxicology study using methods similar
to those described in Example 2 with regard to the data shown in
FIG. 4.
[0526] In this study, toxicity was measured as a function of body
weight (BW) loss in DBA/1 mice following administration with a
control intravenous immunoglobulin (IVIG), a 20 mg/kg dose of the
anti-Jagged antibody referred to herein as 4D11, which includes the
heavy chain sequence of SEQ ID NO: 67 and the light chain sequence
of SEQ ID NO: 162, a 10 mg/kg dose of the 4D1 antibody, a 5 mg/kg
dose of the 4D1 antibody, the anti-Jagged activatable antibody
referred to herein as anti-Jagged 2001 activatable antibody, which
includes the heavy chain sequence of SEQ ID NO: 67, and the light
chain sequence of SEQ ID NO: 420, the anti-Jagged activatable
antibody referred to herein as anti-Jagged 1004/LP'/0001
activatable antibody, which includes the heavy chain sequence of
SEQ ID NO: 67, and the light chain sequence of SEQ ID NO: 432, the
anti-Jagged activatable antibody referred to herein as anti-Jagged
1004/LP'/0003 activatable antibody, which includes the heavy chain
sequence of SEQ ID NO: 67, and the light chain sequence of SEQ ID
NO: 424, the anti-Jagged activatable antibody referred to herein as
anti-Jagged 2003 activatable antibody, which includes the heavy
chain sequence of SEQ ID NO: 67, and the light chain sequence of
SEQ ID NO: 477 shown below, and the anti-Jagged activatable
antibody referred to herein as anti-Jagged 2005 activatable
antibody, which includes the heavy chain sequence of SEQ ID NO: 67,
and the light chain sequence of SEQ ID NO: 479 shown below.
TABLE-US-00023 Anti-Jagged 2003 activatable antibody Lc with spacer
sequence Amino Acid sequence (SEQ ID NO: 476)
QGQSGQCNIWLVGGDCRGWQGGSSGGSISSGLLSGRSANPRGGGSDIQMT
QSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQ
SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ
SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPV TKSFNRGEC
Anti-Jagged 2003 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 477) CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSANPRGGGSDIQMTQSPSSL
SASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR
FSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVA
APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE
SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC Anti-Jagged
2005 activatable antibody Lc with spacer sequence Amino Acid
sequence (SEQ ID NO: 478)
QGQSGQCNIWLVGGDCRGWQGGSSGGSAVGLLAPPSGRSANPRGGGSDIQ
MTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASS
LQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTK
VEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA
LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC
Anti-Jagged 2005 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 479) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPSGRSANPRGGGSDIOMTQSPS
SLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVP
SRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRT
VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS
QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC
[0527] In the study depicted in FIG. 9, the mice were group and
dosed as shown in the Table below:
TABLE-US-00024 Dose Group Count Treatment (mg/kg) Schedule Route 1
3 IVIG -- Single IP dose 2 3 4D11 20 mg/kg Single IP dose 3 3 4D11
10 mg/kg Single IP dose 4 3 4D11 5 mg/kg Single IP dose 5 3
Anti-Jagged 2001 20 mg/kg Single IP Activatable Antibody dose 6 3
Anti-Jagged 20 mg/kg Single IP 1004/LP'/0001 dose Activatable
Antibody 7 3 Anti-Jagged 2003 20 mg/kg Single IP Activatable
Antibody dose 8 3 Anti-Jagged 2005 20 mg/kg Single IP Activatable
Antibody dose
[0528] The results are shown in FIG. 9 as relative body weight (BW)
change percent (%) at various time points during the study.
[0529] The results are shown in FIG. 10 as relative body weight
(BW) change percent (%) at various time points during the
study.
[0530] As shown in FIGS. 8A-8F, FIG. 9, and FIG. 10, activatable
antibodies including the cleavable substrates of the disclosure are
safe and efficacious. In particular, the 2003 substrate has
demonstrated efficacy comparable to the 2001 substrate and safety
comparable to IVIG, and the 2005 substrate has demonstrated
efficacy comparable to parental and safety comparable to parental
dosed 4-fold lower.
Example 5
Additional Matrix Metalloprotease (MMP) and Serine Protease (SP)
Activatable Antibodies
[0531] This Example demonstrates the generation and evaluation of
additional substrate sequences that are activated in the presence
of at least one matrix metalloprotease (MMP) and at least one
serine protease.
[0532] The studies described herein used the following substrate
sequences:
TABLE-US-00025 CM1-CM2 Amino Acid Substrate Sequence Nucleotide
Sequence 2006 ISSGLLSGRSDDH ATATCGAGTGGATTGCTGTCTGGCAGATCTGACGATCAC
(SEQ ID NO: 483) (SEQ ID NO: 491) 2007 ISSGLLSGRSDIH
ATATCGAGTGGATTGCTGTCTGGCAGATCTGACATACAC (SEQ ID NO: 484) (SEQ ID
NO: 492) 2008 ISSGLLSGRSDQH ATATCGAGTGGATTGCTGTCTGGCAGATCTGACCAACAC
(SEQ ID NO: 485) (SEQ ID NO: 493) 2009 ISSGLLSGRSDTH
ATATCGAGTGGATTGCTGTCTGGCAGATCTGACACTCAC (SEQ ID NO: 486) (SEQ ID
NO: 494) 2010 ISSGLLSGRSDYH ATATCGAGTGGATTGCTGTCTGGCAGATCTGACTATCAC
(SEQ ID NO 487) (SEQ ID NO: 495) 2011 ISSGLLSGRSDNP
ATTAGCTCAGGCCTTCTTAGCGGCCGCAGCGACAATCCC (SEQ ID NO: 488) (SEQ ID
NO: 496) 2012 ISSGLLSGRSANP ATATCGAGTGGATTGCTGTCTGGCAGATCTGCTAATCCC
(SEQ ID NO: 489) (SEQ ID NO: 497) 2013 ISSGLLSGRSANI
ATATCGAGTGGATTGCTGTCTGGCAGATCTGCTAATATA (SEQ ID NO: 490) (SEQ ID
NO: 498) 2014 ISSGLLSGRSDNI ATATCGAGTGGATTGCTGTCTGGCAGATCTGACAATATA
(SEQ ID NO: 555) (SEQ ID NO: 556) 3006 AVGLLAPPGGLSGRSDDH
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 515)
GGCAGATCTGACGATCAC(SEQ ID NO: 523) 3007 AVGLLAPPGGLSGRSDTH
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 516)
GGCAGATCTGACATACAC (SEQ ID NO: 524) 3008 AVGLLAPPGGLSGRSDQH
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 517)
GGCAGATCTGACCAACAC (SEQ ID NO: 525) 3009 AVGLLAPPGGLSGRSDTH
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 518)
GGCAGATCTGACACTCAC (SEQ ID NO: 526) 3010 AVGLLAPPGGLSGRSDYH
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 519)
GGCAGATCTGACTATCAC (SEQ ID NO: 527) 3011 AVGLLAPPGGLSGRSDNP
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 520)
GGCAGATCTGACAATCCC (SEQ ID NO: 528) 3012 AVGLLAPPGGLSGRSANP
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 521)
GGCAGATCTGCTAATCCC (SEQ ID NO: 529) 3013 AVGLLAPPGGLSGRSANI
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCT (SEQ ID NO: 522)
GGCACATCTGCTAATATA (SEQ ID NO: 530) 3014 AVGLLAPPGGLSGRSDNI
GCTGTGGGACTGCTGGCTCCTCCTGGTGGCCTGTCTGGCA (SEQ ID NO: 557)
GATCTGACAATATA (SEQ ID NO: 558)
[0533] Those of ordinary skill in the art will appreciate that the
nucleotide sequences presented herein are exemplary, and the
skilled artisan can also use other codon combinations and/or
degenerate nucleotide sequence(s) to express the same peptide
sequence.
[0534] Substrates 2006-2014 and substrates 3006-3014 were
incorporated in the following activatable antibodies:
TABLE-US-00026 Anti-EGFR Heavy Chain: Amino acid Sequence: (SEQ ID
NO: 108) QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGV
IWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALT
YYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKD
YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY
ICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV
YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL
DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Anti-EGFR Light
Chain: Amino acid Sequence: (SEQ ID NO: 111)
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKY
ASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGA
GTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV
DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC
Anti-EGFR 2006 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 499)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDDHGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2007 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 500)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDIHGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2008 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 501)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDQHGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2009 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 502)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDTHGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2010 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 503)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDYHGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEODSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2011 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 504)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDNPGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2012 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 505)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSANPGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2013 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 506)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSANIGSSGTQILL
TOSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 2014 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 559)
CISPRGCPDGPYVMYGSSGGSGGSGGSGISSGLLSGRSDNIGSSGTQILL
TQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASES
ISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKL
ELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL
QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC
Anti-EGFR 3006 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 531)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDDHGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3007 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 532)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDIHGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3008 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 533)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDQHGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3009 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 534)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDTHGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3010 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 535)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDYHGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3011 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 536)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDNPGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3012 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 537)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSANPGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3013 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 538)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSANIGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC
Anti-EGFR 3014 Activatable Antibody Light Chain: Amino acid
Sequence: (SEQ ID NO: 560)
CISPRGCPDGPYVMYGSSGGSGGSGGSGAVGLLAPPGGLSGRSDNIGSSG
TQILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIK
YASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFG
AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK
VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ
GLSSPVTKSFNRGEC
[0535] All eighteen EGFR activatable antibodies containing
substrate sequences of substrate 2006 (SEQ ID NO: 483), substrate
2007 (SEQ ID NO: 484), substrate 2008 (SEQ ID NO: 485), substrate
2009 (SEQ ID NO: 486), substrate 2010 (SEQ ID NO: 487), substrate
2011 (SEQ ID NO: 488), substrate 2012 (SEQ ID NO: 489), substrate
2013 (SEQ ID NO: 490), 2014 (SEQ ID NO: 555), substrate 3006 (SEQ
ID NO: 515), substrate 3007 (SEQ ID NO: 516), substrate 3008 (SEQ
ID NO: 517), substrate 3009 (SEQ ID NO: 518), substrate 3010 (SEQ
ID NO: 519), substrate 3011 (SEQ ID NO: 520), substrate 3012 (SEQ
ID NO: 521), substrate 3013 (SEQ ID NO: 522), or substrate 3014
(SEQ ID NO: 557) also comprised the masking moiety comprising the
amino acid sequence CISPRGCPDGPYVMY (SEQ ID NO: 168) and anti-EGFR
antibody C225v5 antibody comprising a light chain (SEQ ID NO: 111)
and a heavy chain (SEQ ID NO: 108). The configuration of the light
chain of the activatable antibody was masking
moiety--substrate--light chain of C225v5.
[0536] Cleavage of anti-EGFR activatable antibodies comprising
substrates 2001, 2006-2010 and 2012 by human matriptase using
techniques similar to those described herein exhibited a range of
k.sub.cat/K.sub.m values ranging from 6E+02 to 2E+04. Cleavage of
anti-EGFR activatable antibodies comprising substrates 2001,
2006-2010, 2012 and 2013 by human matrix metalloprotease 14 (MMP14)
using techniques similar to those described herein exhibited a
range of k.sub.cat/K.sub.m values ranging from 1E+04 to 5E+04. In
vivo, these antibodies also exhibited comparable 4-day stability in
both normal and tumor-bearing mice using techniques similar to
those described herein.
[0537] This section describes the evaluation of various anti-EGFR
activatable antibodies shown above in a H292 tumor efficacy study
using H292 xenograft tumors in nu/nu mice. The H292 tumor efficacy
study is described in Example 2 and is also described in PCT
Publication No. WO 2013/163631, the contents of each of which are
hereby incorporated by reference in their entireties.
[0538] In this study, the mice were group and dosed as shown in the
Table below using a control PBS, activatable antibody, which
includes the heavy chain sequence of SEQ ID NO: 108, and the light
chain sequence of SEQ ID NO: 111; the anti-EGFR C225v5-3954-2001
activatable antibody, anti-EGFR C225v5-3954-2006 activatable
antibody, anti-EGFR C225v5-3954-2007 activatable antibody, etc., as
shown in the Table below:
TABLE-US-00027 Dose Group Count Treatment (mg/kg) Schedule 1 8 IVIG
9 Single Dose 2 8 C225v5-3954-2001 9 Single Dose 3 8
C225v5-3954-2007 9 Single Dose 4 8 C225v5-3954-2006 9 Single Dose 5
8 C225v5-3954-2008 9 Single Dose 6 8 C225v5-3954-2009 9 Single Dose
7 8 C225v5-3954-2010 9 Single Dose 8 8 C225v5-3954-2012 9 Single
Dose 9 8 C225v5-3954-2013 9 Single Dose
[0539] The efficacy of the substrates used in the anti-EGFR
antibodies shown above was evaluated by measuring tumor volume (TV
mm.sup.3) at various time points post-administration. The results
of this study are shown in FIGS. 11A-11H and 12.
[0540] This section describes the evaluation of various anti-Jagged
activatable antibodies in a toxicology study using methods similar
to those described in Example 2 with regard to the data shown in
FIG. 4.
[0541] In this study, 20 mg/kg dose of the anti-Jagged antibody
referred to herein as 4D11, which includes the heavy chain sequence
of SEQ ID NO: 67 and the light chain sequence of SEQ ID NO: 162, a
10 mg/kg dose of the 4D11 antibody, a 5 mg/kg dose of the 4D11
antibody, the anti-Jagged activatable antibody referred to herein
as anti-Jagged 2006 activatable antibody, which includes the heavy
chain sequence of SEQ ID NO: 67, and the light chain sequence of
SEQ ID NO: 507-514 shown below.
TABLE-US-00028 Anti-Jagged 2006 activatable antibody Lc Amino Acid
sequence (SEQ ID NO: 507)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDDHGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2007 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 508)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDIHGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2008 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 509)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDQHGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2009 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 510)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDTHGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2010 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 511)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDYHGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2011 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 512)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDNPGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2012 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 513)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSANPGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2013 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 514)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSANIGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
2014 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 561)
CNIWLVGGDCRGWQGGSSGGSISSGLLSGRSDNIGGGSDIQMTQSPSSLS
ASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAA
PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES
VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRG EC Anti-Jagged
3006 activatable antibody Lc Amino Acid sequence (SEQ ID NO: 539)
CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDDHGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLOPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGE C
Anti-Jagged 3007 activatable antibody Lc Amino Acid sequence (SEO
ID NO: 540) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDIHGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3008 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 541) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDQHGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3009 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 542) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDTHGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3010 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 543) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDYHGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3011 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 544) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDNPGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3012 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 545) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSANPGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3013 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 546) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSANIGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
Anti-Jagged 3014 activatable antibody Lc Amino Acid sequence (SEQ
ID NO: 562) CNIWLVGGDCRGWQGGSSGGSAVGLLAPPGGLSGRSDNIGGGSDIQMTQS
PSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSG
VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIK
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG
NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC
[0542] All eighteen anti-Jagged activatable antibodies containing
substrate sequences of substrate 2006 (SEQ ID NO: 483), substrate
2007 (SEQ ID NO: 484), substrate 2008 (SEQ ID NO: 485), substrate
2009 (SEQ ID NO: 486), substrate 2010 (SEQ ID NO: 487), substrate
2011 (SEQ ID NO: 488), substrate 2012 (SEQ ID NO: 489), substrate
2013 (SEQ ID NO: 490), 2014 (SEQ ID NO: 555); substrate 3006 (SEQ
ID NO: 515); substrate 3007 (SEQ ID NO: 516); substrate 3008 (SEQ
ID NO: 517); substrate 3009 (SEQ ID NO: 518); substrate 3010 (SEQ
ID NO: 519); substrate 3011 (SEQ ID NO: 520); substrate 3012 (SEQ
ID NO: 521); substrate 3013 (SEQ ID NO: 522); or substrate 3014
(SEQ ID NO: 557) also comprised the masking moiety comprising the
amino acid sequence and anti-Jagged antibody 4D11 antibody
comprising a light chain (SEQ ID NO: 162) and a heavy chain (SEQ ID
NO: 67). The configuration of the light chain of the activatable
antibody was masking moiety--substrate--light chain of 4D11.
[0543] In this study, the mice were group and dosed as shown in the
Table below:
TABLE-US-00029 Dose Group Count Treatment (mg/kg) Schedule A 3 IVIG
20 Single Dose B 4 4D11 5 Single Dose C 4 4D11 10 Single Dose D 4
4D11 20 Single Dose E 4 4D11-5342-2001 20 Single Dose F 3
4D11-5342-2006 20 Single Dose G 3 4D11-5342-2007 20 Single Dose H 3
4D11-5342-2008 20 Single Dose I 3 4D11-5342-2009 20 Single Dose J 3
4D11-5342-2010 20 Single Dose K 3 4D11-5342-2012 20 Single Dose L 3
4D11-5342-2013 20 Single Dose
[0544] The results are shown in FIG. 13 as relative body weight
(BW) change percent (%) at various time points during the
study.
[0545] As shown in FIGS. 11A-11H, FIG. 12, and FIG. 13, activatable
antibodies including the cleavable substrates of the disclosure are
safe and efficacious.
Example 6
In Vivo Imaging
[0546] 7- to 9-week-old female athymic nu/nu (Charles River
Laboratories) mice were inoculated subcutaneously with
5.times.10.sup.6 NCI-H292 (left hind flank) and FaDu cells (right
hind flank). The NCI-H292 cells (ATCC) and FaDu cells (ATCC) were
suspended 1:1 with Matrigel in serum-free or without Matrigel in
serum free medium, respectively. Clinical observations, body
weights, and digital caliper tumor volume measurements were made
two times weekly once tumors become measureable. Tumor volumes were
calculated with the formula (ab')/2, where a is the longer and b is
the smaller of two perpendicular diameters. H292 and FaDu xenograft
tumor-bearing mice with tumor volumes of 250-500 mm3 were
distributed by tumor size into 3 groups with n=3 per group. The
animals were injected intraperitoneally with 15 mg/kg of AlexaFluor
750 (AF750)-conjugated cetuximab (Cetuximab-AF750) or activatable
antibodies containing 2001 and 1004/LP'/0001 substrates
(Pb2001-AF750 and Pb1004/LP'/0001-SF750). Computed tomography (CT)
scans with subsequent fluorescent images were obtained with an IVIS
Spectrum/CT imaging system (Caliper Life Sciences, PE). A series of
fluorescent surface radiance images were acquired at multiple
transillumination locations encompassing the region of interest at
excitation and emission wavelengths of 745 nm and 800 nm,
respectively (FIG. 14). Three-dimensional reconstruction of the
optical and .mu.CT images and their co-registration were performed
with the Living Image software 4.2 (Caliper Life Sciences).
Obtained imaging data demonstrate accumulation of activatable
antibodies in both xenograft tumors with the fluorescent signal
similar to cetuximab parental antibody.
OTHER EMBODIMENTS
[0547] While the invention has been described in conjunction with
the detailed description thereof, the foregoing description is
intended to illustrate and not limit the scope of the invention,
which is defined by the scope of the appended claims. Other
aspects, advantages, and modifications are within the scope of the
following.
Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID
NOS: 562 <210> SEQ ID NO 1 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 1 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp
Asn His 1 5 10 <210> SEQ ID NO 2 <211> LENGTH: 22
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 2 Ile Ser Ser Gly Leu Leu Ser Ser
Gly Gly Ser Gly Gly Ser Leu Ser 1 5 10 15 Gly Arg Ser Asp Asn His
20 <210> SEQ ID NO 3 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 3 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Thr Ser Thr Ser
Gly Arg 1 5 10 15 Ser Ala Asn Pro Arg Gly 20 <210> SEQ ID NO
4 <211> LENGTH: 22 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 4
Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ala Val 1 5
10 15 Gly Leu Leu Ala Pro Pro 20 <210> SEQ ID NO 5
<211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 5 Val His
Met Pro Leu Gly Phe Leu Gly Pro Gly Gly Thr Ser Thr Ser 1 5 10 15
Gly Arg Ser Ala Asn Pro Arg Gly 20 <210> SEQ ID NO 6
<211> LENGTH: 24 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 6 Thr Ser
Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Val His 1 5 10 15
Met Pro Leu Gly Phe Leu Gly Pro 20 <210> SEQ ID NO 7
<211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 7 Ala Val
Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15
Asn His <210> SEQ ID NO 8 <211> LENGTH: 18 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 8 Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ala
Val Gly Leu Leu Ala 1 5 10 15 Pro Pro <210> SEQ ID NO 9
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 9 Val His
Met Pro Leu Gly Phe Leu Gly Pro Gly Gly Leu Ser Gly Arg 1 5 10 15
Ser Asp Asn His 20 <210> SEQ ID NO 10 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 10 Leu Ser Gly Arg Ser Asp Asn
His Gly Gly Val His Met Pro Leu Gly 1 5 10 15 Phe Leu Gly Pro 20
<210> SEQ ID NO 11 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 11 Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ser Gly Gly
Ser Ile Ser 1 5 10 15 Ser Gly Leu Leu Ser Ser 20 <210> SEQ ID
NO 12 <211> LENGTH: 22 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 12
Leu Ser Gly Arg Ser Gly Asn His Gly Gly Ser Gly Gly Ser Ile Ser 1 5
10 15 Ser Gly Leu Leu Ser Ser 20 <210> SEQ ID NO 13
<211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 13 Ile
Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser 1 5 10
15 Gly Arg Ser Gly Asn His 20 <210> SEQ ID NO 14 <211>
LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 14 Leu Ser Gly Arg Ser
Asp Asn His Gly Gly Ser Gly Gly Ser Gln Asn 1 5 10 15 Gln Ala Leu
Arg Met Ala 20 <210> SEQ ID NO 15 <211> LENGTH: 22
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 15 Gln Asn Gln Ala Leu Arg Met
Ala Gly Gly Ser Gly Gly Ser Leu Ser 1 5 10 15 Gly Arg Ser Asp Asn
His 20 <210> SEQ ID NO 16 <211> LENGTH: 22 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 16 Leu Ser Gly Arg Ser Gly Asn His Gly Gly
Ser Gly Gly Ser Gln Asn 1 5 10 15 Gln Ala Leu Arg Met Ala 20
<210> SEQ ID NO 17 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 17 Gln Asn Gln Ala Leu Arg Met Ala Gly Gly Ser Gly Gly
Ser Leu Ser 1 5 10 15 Gly Arg Ser Gly Asn His 20 <210> SEQ ID
NO 18 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 18
Leu Ser Gly Arg Ser Asp Asn His 1 5 <210> SEQ ID NO 19
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 19 Leu
Ser Gly Arg Ser Gly Asn His 1 5 <210> SEQ ID NO 20
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 20 Ile
Ser Ser Gly Leu Leu Ser Ser 1 5 <210> SEQ ID NO 21
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 21 Gln
Asn Gln Ala Leu Arg Met Ala 1 5 <210> SEQ ID NO 22
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 22 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Gly Asn His 1 5 10 <210>
SEQ ID NO 23 <211> LENGTH: 24 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 23 ttaagcgggc ggtcggacaa ccac 24 <210> SEQ ID NO 24
<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 24
cttagcgggc ggagcggcaa ccac 24 <210> SEQ ID NO 25 <211>
LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 25 atctcctccg
ggctactgag ttct 24 <210> SEQ ID NO 26 <211> LENGTH: 24
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 26 cagaaccagg cgctcagaat ggca 24
<210> SEQ ID NO 27 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 27 atatcatccg gcctccttag cggccgttcc gacaatcac 39
<210> SEQ ID NO 28 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 28 ataagttctg ggctcctgtc gggccggagt ggaaatcac 39
<210> SEQ ID NO 29 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 29 ctgagcgggc ggtccgataa tcatggtggt tcaggaggga gtatttcttc
cggcttactg 60 agtagc 66 <210> SEQ ID NO 30 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 30 atctcctctg
ggttgctttc ttcaggaggt tcagggggga gcctgagcgg acgctccgac 60 aaccat 66
<210> SEQ ID NO 31 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 31 ctctcaggaa gatccggaaa tcatgggggg tctgggggga gtatctcatc
aggtctgctg 60 agcagc 66 <210> SEQ ID NO 32 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 32 atctcaagtg
ggctgttaag ttccggcggc agtggagggt ccctaagcgg ccgcagcggg 60 aatcac 66
<210> SEQ ID NO 33 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 33 ctctctggcc gctccgataa tcatggtgga tccggtggct ctcagaacca
ggcactacgg 60 atggca 66 <210> SEQ ID NO 34 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 34 cagaaccagg
cgctcaggat ggcagggggg agtggcggaa gcctttctgg tcgatccgat 60 aatcac 66
<210> SEQ ID NO 35 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 35 cttagcggac gctctggcaa ccacggagga tctggaggaa gtcagaacca
ggccttgcgc 60 atggcc 66 <210> SEQ ID NO 36 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 36 caaaaccagg
ctctgcgcat ggctgggggg tctggtggga gcctgagcgg gcggtcagga 60 aaccac 66
<210> SEQ ID NO 37 <211> LENGTH: 37 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 37 gtgcagccac cgtacgtttg atttccacct tggtccc 37
<210> SEQ ID NO 38 <211> LENGTH: 97 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 38 caggggggct cgagcggcgg ctctatctct tccggactgc tgtccggcag
atccgacaat 60 cacggcggag gctctgacat ccagatgacc cagtctc 97
<210> SEQ ID NO 39 <211> LENGTH: 124 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 39 caggggggct cgagcggcgg ctctatctct tctggcctgc tgtctagcgg
cggctccggc 60 ggatctctgt ctggcagatc tgacaaccac ggcggaggct
ccgacatcca gatgacccag 120 tctc 124 <210> SEQ ID NO 40
<211> LENGTH: 121 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 40
caggggggct cgagcggagg atctgctgtg ggactgctgg ctcctcctgg cggcacatct
60 acctctggca gatccgccaa ccctcggggc ggaggatctg acatccagat
gacccagtct 120 c 121 <210> SEQ ID NO 41 <211> LENGTH:
121 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 41 caggggggct cgagcggcgg
ctccacatct acctctggca gatccgccaa ccccagaggt 60 ggcggagctg
tgggactgct ggctccacca ggcggatctg acatccagat gacccagtct 120 c 121
<210> SEQ ID NO 42 <211> LENGTH: 127 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 42 caggggggct cgagcggcgg ctctgtgcat atgcccctgg gctttctggg
ccctggcggc 60 acatctacct ctggcagatc cgccaaccct cggggcggag
gatctgacat ccagatgacc 120 cagtctc 127 <210> SEQ ID NO 43
<211> LENGTH: 127 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 43
caggggggct cgagcggcgg ctccacatct acctctggca gatccgccaa ccccagaggc
60 ggcggagtgc atatgcctct gggctttctg ggacctggcg gctctgacat
ccagatgacc 120 cagtctc 127 <210> SEQ ID NO 44 <211>
LENGTH: 109 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 44 caggggggct
cgagcggagg atctgctgtg ggactgctgg ctcctcctgg tggcctgtct 60
ggcagatctg ataaccacgg cggctccgac atccagatga cccagtctc 109
<210> SEQ ID NO 45 <211> LENGTH: 112 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 45 caggggggct cgagcggagg ctctggcctg tctggcagat ccgataacca
tggcggcgct 60 gtgggactgc tggctcctcc tggtggatct gacatccaga
tgacccagtc tc 112 <210> SEQ ID NO 46 <211> LENGTH: 115
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 46 caggggggct cgagcggcgg
ctctgtgcat atgcccctgg gctttctggg acctggcggc 60 ctgtctggca
gatccgataa tcacggcggc tccgacatcc agatgaccca gtctc 115 <210>
SEQ ID NO 47 <211> LENGTH: 118 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 47 caggggggct cgagcggagg ctctggcctg tctggcagat ctgataacca
cggcggcgtg 60 cacatgcccc tgggctttct gggacctggc ggatctgaca
tccagatgac ccagtctc 118 <210> SEQ ID NO 48 <211>
LENGTH: 774 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 48 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc tatctcttcc ggactgctgt ccggcagatc cgacaatcac
120 ggcggaggct ctgacatcca gatgacccag tctccatcct ccctgtctgc
atctgtagga 180 gacagagtca ccatcacttg ccgggcaagt cagagcatta
gcagctattt aaattggtat 240 cagcagaaac cagggaaagc ccctaagctc
ctgatctatg cggcatccag tttgcaaagt 300 ggggtcccat caaggttcag
tggcagtgga tctgggacag atttcactct caccatcagc 360 agtctgcaac
ctgaagattt tgcaacttac tactgtcaac agacggttgt ggcgcctccg 420
ttattcggcc aagggaccaa ggtggaaatc aaacgtacgg tggctgcacc atctgtcttc
480 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt
gtgcctgctg 540 aataacttct atcccagaga ggccaaagta cagtggaagg
tggataacgc cctccaatcg 600 ggtaactccc aggagagtgt cacagagcag
gacagcaagg acagcaccta cagcctcagc 660 agcaccctga cgctgagcaa
agcagactac gagaaacaca aagtctacgc ctgcgaagtc 720 acccatcagg
gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 774 <210>
SEQ ID NO 49 <211> LENGTH: 258 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 49 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu 20 25 30 Leu Ser Gly Arg Ser Asp Asn His Gly
Gly Gly Ser Asp Ile Gln Met 35 40 45 Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly Asp Arg Val Thr 50 55 60 Ile Thr Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr 65 70 75 80 Gln Gln Lys
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser 85 90 95 Ser
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 100 105
110 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
115 120 125 Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe
Gly Gln 130 135 140 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
Pro Ser Val Phe 145 150 155 160 Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val 165 170 175 Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp 180 185 190 Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr 195 200 205 Glu Gln Asp
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 210 215 220 Leu
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 225 230
235 240 Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly 245 250 255 Glu Cys <210> SEQ ID NO 50 <211>
LENGTH: 801 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 50 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc tatctcttct ggcctgctgt ctagcggcgg ctccggcgga
120 tctctgtctg gcagatctga caaccacggc ggaggctccg acatccagat
gacccagtct 180 ccatcctccc tgtctgcatc tgtaggagac agagtcacca
tcacttgccg ggcaagtcag 240 agcattagca gctatttaaa ttggtatcag
cagaaaccag ggaaagcccc taagctcctg 300 atctatgcgg catccagttt
gcaaagtggg gtcccatcaa ggttcagtgg cagtggatct 360 gggacagatt
tcactctcac catcagcagt ctgcaacctg aagattttgc aacttactac 420
tgtcaacaga cggttgtggc gcctccgtta ttcggccaag ggaccaaggt ggaaatcaaa
480 cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca
gttgaaatct 540 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc
ccagagaggc caaagtacag 600 tggaaggtgg ataacgccct ccaatcgggt
aactcccagg agagtgtcac agagcaggac 660 agcaaggaca gcacctacag
cctcagcagc accctgacgc tgagcaaagc agactacgag 720 aaacacaaag
tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 780
agcttcaaca ggggagagtg t 801 <210> SEQ ID NO 51 <211>
LENGTH: 267 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 51 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu 20 25 30 Leu
Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg Ser Asp Asn 35 40
45 His Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
50 55 60 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln 65 70 75 80 Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
Pro Gly Lys Ala 85 90 95 Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
Leu Gln Ser Gly Val Pro 100 105 110 Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile 115 120 125 Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr 130 135 140 Val Val Ala Pro
Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 145 150 155 160 Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 165 170
175 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
180 185 190 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln 195 200 205 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
Ser Lys Asp Ser 210 215 220 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
Ser Lys Ala Asp Tyr Glu 225 230 235 240 Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser 245 250 255 Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 52
<211> LENGTH: 798 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 52
caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag
60 gggggctcga gcggaggatc tgctgtggga ctgctggctc ctcctggcgg
cacatctacc 120 tctggcagat ccgccaaccc tcggggcgga ggatctgaca
tccagatgac ccagtctcca 180 tcctccctgt ctgcatctgt aggagacaga
gtcaccatca cttgccgggc aagtcagagc 240 attagcagct atttaaattg
gtatcagcag aaaccaggga aagcccctaa gctcctgatc 300 tatgcggcat
ccagtttgca aagtggggtc ccatcaaggt tcagtggcag tggatctggg 360
acagatttca ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt
420 caacagacgg ttgtggcgcc tccgttattc ggccaaggga ccaaggtgga
aatcaaacgt 480 acggtggctg caccatctgt cttcatcttc ccgccatctg
atgagcagtt gaaatctgga 540 actgcctctg ttgtgtgcct gctgaataac
ttctatccca gagaggccaa agtacagtgg 600 aaggtggata acgccctcca
atcgggtaac tcccaggaga gtgtcacaga gcaggacagc 660 aaggacagca
cctacagcct cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 720
cacaaagtct acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc
780 ttcaacaggg gagagtgt 798 <210> SEQ ID NO 53 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 53 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Ala Val Gly Leu Leu 20 25 30 Ala
Pro Pro Gly Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg 35 40
45 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
50 55 60 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro 85 90 95 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser 115 120 125 Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val 130 135 140 Val Ala Pro Pro
Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 54 <211>
LENGTH: 798 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 54 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc cacatctacc tctggcagat ccgccaaccc cagaggtggc
120 ggagctgtgg gactgctggc tccaccaggc ggatctgaca tccagatgac
ccagtctcca 180 tcctccctgt ctgcatctgt aggagacaga gtcaccatca
cttgccgggc aagtcagagc 240 attagcagct atttaaattg gtatcagcag
aaaccaggga aagcccctaa gctcctgatc 300 tatgcggcat ccagtttgca
aagtggggtc ccatcaaggt tcagtggcag tggatctggg 360 acagatttca
ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 420
caacagacgg ttgtggcgcc tccgttattc ggccaaggga ccaaggtgga aatcaaacgt
480 acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt
gaaatctgga 540 actgcctctg ttgtgtgcct gctgaataac ttctatccca
gagaggccaa agtacagtgg 600 aaggtggata acgccctcca atcgggtaac
tcccaggaga gtgtcacaga gcaggacagc 660 aaggacagca cctacagcct
cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 720 cacaaagtct
acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 780
ttcaacaggg gagagtgt 798 <210> SEQ ID NO 55 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 55 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Thr Ser Thr Ser Gly 20 25 30 Arg
Ser Ala Asn Pro Arg Gly Gly Gly Ala Val Gly Leu Leu Ala Pro 35 40
45 Pro Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
50 55 60 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro 85 90 95 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser 115 120 125 Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val 130 135 140 Val Ala Pro Pro
Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 56 <211>
LENGTH: 804 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 56 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc tgtgcatatg cccctgggct ttctgggccc tggcggcaca
120 tctacctctg gcagatccgc caaccctcgg ggcggaggat ctgacatcca
gatgacccag 180 tctccatcct ccctgtctgc atctgtagga gacagagtca
ccatcacttg ccgggcaagt 240 cagagcatta gcagctattt aaattggtat
cagcagaaac cagggaaagc ccctaagctc 300 ctgatctatg cggcatccag
tttgcaaagt ggggtcccat caaggttcag tggcagtgga 360 tctgggacag
atttcactct caccatcagc agtctgcaac ctgaagattt tgcaacttac 420
tactgtcaac agacggttgt ggcgcctccg ttattcggcc aagggaccaa ggtggaaatc
480 aaacgtacgg tggctgcacc atctgtcttc atcttcccgc catctgatga
gcagttgaaa 540 tctggaactg cctctgttgt gtgcctgctg aataacttct
atcccagaga ggccaaagta 600 cagtggaagg tggataacgc cctccaatcg
ggtaactccc aggagagtgt cacagagcag 660 gacagcaagg acagcaccta
cagcctcagc agcaccctga cgctgagcaa agcagactac 720 gagaaacaca
aagtctacgc ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca 780
aagagcttca acaggggaga gtgt 804 <210> SEQ ID NO 57 <211>
LENGTH: 268 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 57 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Val His Met Pro Leu 20 25 30 Gly
Phe Leu Gly Pro Gly Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn 35 40
45 Pro Arg Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
50 55 60 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser 65 70 75 80 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys 85 90 95 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val 100 105 110 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 115 120 125 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 130 135 140 Thr Val Val Ala
Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 145 150 155 160 Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 165 170
175 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
180 185 190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 225 230 235 240 Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 245 250 255 Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 58
<211> LENGTH: 804 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 58
caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag
60 gggggctcga gcggcggctc cacatctacc tctggcagat ccgccaaccc
cagaggcggc 120 ggagtgcata tgcctctggg ctttctggga cctggcggct
ctgacatcca gatgacccag 180 tctccatcct ccctgtctgc atctgtagga
gacagagtca ccatcacttg ccgggcaagt 240 cagagcatta gcagctattt
aaattggtat cagcagaaac cagggaaagc ccctaagctc 300 ctgatctatg
cggcatccag tttgcaaagt ggggtcccat caaggttcag tggcagtgga 360
tctgggacag atttcactct caccatcagc agtctgcaac ctgaagattt tgcaacttac
420 tactgtcaac agacggttgt ggcgcctccg ttattcggcc aagggaccaa
ggtggaaatc 480 aaacgtacgg tggctgcacc atctgtcttc atcttcccgc
catctgatga gcagttgaaa 540 tctggaactg cctctgttgt gtgcctgctg
aataacttct atcccagaga ggccaaagta 600 cagtggaagg tggataacgc
cctccaatcg ggtaactccc aggagagtgt cacagagcag 660 gacagcaagg
acagcaccta cagcctcagc agcaccctga cgctgagcaa agcagactac 720
gagaaacaca aagtctacgc ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca
780 aagagcttca acaggggaga gtgt 804 <210> SEQ ID NO 59
<211> LENGTH: 268 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 59 Gln
Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10
15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser Thr Ser Thr Ser Gly
20 25 30 Arg Ser Ala Asn Pro Arg Gly Gly Gly Val His Met Pro Leu
Gly Phe 35 40 45 Leu Gly Pro Gly Gly Ser Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser 50 55 60 Leu Ser Ala Ser Val Gly Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser 65 70 75 80 Gln Ser Ile Ser Ser Tyr Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys 85 90 95 Ala Pro Lys Leu Leu Ile
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 100 105 110 Pro Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 115 120 125 Ile Ser
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 130 135 140
Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 145
150 155 160 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
Ser Asp 165 170 175 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys
Leu Leu Asn Asn 180 185 190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
Lys Val Asp Asn Ala Leu 195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser
Val Thr Glu Gln Asp Ser Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 225 230 235 240 Glu Lys His
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 245 250 255 Ser
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ
ID NO 60 <211> LENGTH: 786 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 60
caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag
60 gggggctcga gcggaggatc tgctgtggga ctgctggctc ctcctggtgg
cctgtctggc 120 agatctgata accacggcgg ctccgacatc cagatgaccc
agtctccatc ctccctgtct 180 gcatctgtag gagacagagt caccatcact
tgccgggcaa gtcagagcat tagcagctat 240 ttaaattggt atcagcagaa
accagggaaa gcccctaagc tcctgatcta tgcggcatcc 300 agtttgcaaa
gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 360
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagacggtt
420 gtggcgcctc cgttattcgg ccaagggacc aaggtggaaa tcaaacgtac
ggtggctgca 480 ccatctgtct tcatcttccc gccatctgat gagcagttga
aatctggaac tgcctctgtt 540 gtgtgcctgc tgaataactt ctatcccaga
gaggccaaag tacagtggaa ggtggataac 600 gccctccaat cgggtaactc
ccaggagagt gtcacagagc aggacagcaa ggacagcacc 660 tacagcctca
gcagcaccct gacgctgagc aaagcagact acgagaaaca caaagtctac 720
gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt caacagggga
780 gagtgt 786 <210> SEQ ID NO 61 <211> LENGTH: 262
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 61 Gln Gly Gln Ser Gly Gln Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly
Gly Ser Ser Gly Gly Ser Ala Val Gly Leu Leu 20 25 30 Ala Pro Pro
Gly Gly Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ser 35 40 45 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 50 55
60 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
65 70 75 80 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 85 90 95 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 115 120 125 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Thr Val Val Ala Pro Pro 130 135 140 Leu Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 145 150 155 160 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 165 170 175 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 180 185
190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
195 200 205 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 225 230 235 240 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 62 <211> LENGTH: 789 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 62 caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag
gggctggcag 60 gggggctcga gcggaggctc tggcctgtct ggcagatccg
ataaccatgg cggcgctgtg 120 ggactgctgg ctcctcctgg tggatctgac
atccagatga cccagtctcc atcctccctg 180 tctgcatctg taggagacag
agtcaccatc acttgccggg caagtcagag cattagcagc 240 tatttaaatt
ggtatcagca gaaaccaggg aaagccccta agctcctgat ctatgcggca 300
tccagtttgc aaagtggggt cccatcaagg ttcagtggca gtggatctgg gacagatttc
360 actctcacca tcagcagtct gcaacctgaa gattttgcaa cttactactg
tcaacagacg 420 gttgtggcgc ctccgttatt cggccaaggg accaaggtgg
aaatcaaacg tacggtggct 480 gcaccatctg tcttcatctt cccgccatct
gatgagcagt tgaaatctgg aactgcctct 540 gttgtgtgcc tgctgaataa
cttctatccc agagaggcca aagtacagtg gaaggtggat 600 aacgccctcc
aatcgggtaa ctcccaggag agtgtcacag agcaggacag caaggacagc 660
acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa acacaaagtc
720 tacgcctgcg aagtcaccca tcagggcctg agctcgcccg tcacaaagag
cttcaacagg 780 ggagagtgt 789 <210> SEQ ID NO 63 <211>
LENGTH: 263 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 63 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser
Asp Asn His Gly Gly Ala Val Gly Leu Leu Ala Pro Pro Gly Gly 35 40
45 Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
50 55 60 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Ser 65 70 75 80 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu 85 90 95 Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser 100 105 110 Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln 115 120 125 Pro Glu Asp Phe Ala Thr
Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro 130 135 140 Pro Leu Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 145 150 155 160 Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 165 170
175 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
180 185 190 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser 195 200 205 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu 210 215 220 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val 225 230 235 240 Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys 245 250 255 Ser Phe Asn Arg Gly
Glu Cys 260 <210> SEQ ID NO 64 <211> LENGTH: 792
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 64 caaggccagt ctggccagtg
caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60 gggggctcga
gcggcggctc tgtgcatatg cccctgggct ttctgggacc tggcggcctg 120
tctggcagat ccgataatca cggcggctcc gacatccaga tgacccagtc tccatcctcc
180 ctgtctgcat ctgtaggaga cagagtcacc atcacttgcc gggcaagtca
gagcattagc 240 agctatttaa attggtatca gcagaaacca gggaaagccc
ctaagctcct gatctatgcg 300 gcatccagtt tgcaaagtgg ggtcccatca
aggttcagtg gcagtggatc tgggacagat 360 ttcactctca ccatcagcag
tctgcaacct gaagattttg caacttacta ctgtcaacag 420 acggttgtgg
cgcctccgtt attcggccaa gggaccaagg tggaaatcaa acgtacggtg 480
gctgcaccat ctgtcttcat cttcccgcca tctgatgagc agttgaaatc tggaactgcc
540 tctgttgtgt gcctgctgaa taacttctat cccagagagg ccaaagtaca
gtggaaggtg 600 gataacgccc tccaatcggg taactcccag gagagtgtca
cagagcagga cagcaaggac 660 agcacctaca gcctcagcag caccctgacg
ctgagcaaag cagactacga gaaacacaaa 720 gtctacgcct gcgaagtcac
ccatcagggc ctgagctcgc ccgtcacaaa gagcttcaac 780 aggggagagt gt 792
<210> SEQ ID NO 65 <211> LENGTH: 264 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 65 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser
Val His Met Pro Leu 20 25 30 Gly Phe Leu Gly Pro Gly Gly Leu Ser
Gly Arg Ser Asp Asn His Gly 35 40 45 Gly Ser Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser 50 55 60 Val Gly Asp Arg Val
Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser 65 70 75 80 Ser Tyr Leu
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu 85 90 95 Leu
Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe 100 105
110 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
115 120 125 Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val
Val Ala 130 135 140 Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys Arg Thr Val 145 150 155 160 Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp Glu Gln Leu Lys 165 170 175 Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn Phe Tyr Pro Arg 180 185 190 Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 195 200 205 Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 210 215 220 Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 225 230
235 240 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
Thr 245 250 255 Lys Ser Phe Asn Arg Gly Glu Cys 260 <210> SEQ
ID NO 66 <211> LENGTH: 795 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 66
caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag
60 gggggctcga gcggaggctc tggcctgtct ggcagatctg ataaccacgg
cggcgtgcac 120 atgcccctgg gctttctggg acctggcgga tctgacatcc
agatgaccca gtctccatcc 180 tccctgtctg catctgtagg agacagagtc
accatcactt gccgggcaag tcagagcatt 240 agcagctatt taaattggta
tcagcagaaa ccagggaaag cccctaagct cctgatctat 300 gcggcatcca
gtttgcaaag tggggtccca tcaaggttca gtggcagtgg atctgggaca 360
gatttcactc tcaccatcag cagtctgcaa cctgaagatt ttgcaactta ctactgtcaa
420 cagacggttg tggcgcctcc gttattcggc caagggacca aggtggaaat
caaacgtacg 480 gtggctgcac catctgtctt catcttcccg ccatctgatg
agcagttgaa atctggaact 540 gcctctgttg tgtgcctgct gaataacttc
tatcccagag aggccaaagt acagtggaag 600 gtggataacg ccctccaatc
gggtaactcc caggagagtg tcacagagca ggacagcaag 660 gacagcacct
acagcctcag cagcaccctg acgctgagca aagcagacta cgagaaacac 720
aaagtctacg cctgcgaagt cacccatcag ggcctgagct cgcccgtcac aaagagcttc
780 aacaggggag agtgt 795 <210> SEQ ID NO 67 <211>
LENGTH: 449 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 67 Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ser Ser Ile Asp Pro Glu Gly Arg Gln Thr Tyr Tyr Ala Asp Ser Val
50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe
Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170
175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro
Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro
Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val
Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295
300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr
Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr
Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420
425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly 435 440 445 Lys <210> SEQ ID NO 68 <211> LENGTH:
1347 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 68 Cys Ala Gly Gly Thr
Ala Cys Ala Gly Cys Thr Gly Ala Ala Ala Cys 1 5 10 15 Ala Gly Thr
Cys Thr Gly Gly Ala Cys Cys Cys Gly Gly Gly Cys Thr 20 25 30 Thr
Gly Thr Ala Cys Ala Gly Cys Cys Thr Ala Gly Thr Cys Ala Gly 35 40
45 Thr Cys Ala Cys Thr Gly Thr Cys Thr Ala Thr Cys Ala Cys Cys Thr
50 55 60 Gly Thr Ala Cys Cys Gly Thr Cys Thr Cys Ala Gly Gly Thr
Thr Thr 65 70 75 80 Thr Ala Gly Cys Cys Thr Gly Ala Cys Ala Ala Ala
Thr Thr Ala Cys 85 90 95 Gly Gly Thr Gly Thr Gly Cys Ala Thr Thr
Gly Gly Gly Thr Ala Cys 100 105 110 Gly Cys Cys Ala Gly Thr Cys Thr
Cys Cys Cys Gly Gly Thr Ala Ala 115 120 125 Gly Gly Gly Gly Cys Thr
Gly Gly Ala Gly Thr Gly Gly Cys Thr Cys 130 135 140 Gly Gly Cys Gly
Thr Gly Ala Thr Cys Thr Gly Gly Thr Cys Cys Gly 145 150 155 160 Gly
Gly Gly Gly Gly Ala Ala Cys Ala Cys Ala Gly Ala Thr Thr Ala 165 170
175 Thr Ala Ala Thr Ala Cys Thr Cys Cys Thr Thr Thr Cys Ala Cys Ala
180 185 190 Thr Cys Thr Ala Gly Ala Cys Thr Gly Thr Cys Cys Ala Thr
Cys Ala 195 200 205 Ala Cys Ala Ala Ala Gly Ala Cys Ala Ala Cys Thr
Cys Cys Ala Ala 210 215 220 Ala Thr Cys Gly Cys Ala Gly Gly Thr Thr
Thr Thr Thr Thr Thr Cys 225 230 235 240 Ala Ala Gly Ala Thr Gly Ala
Ala Thr Thr Cys Cys Cys Thr Gly Cys 245 250 255 Ala Ala Thr Cys Ala
Cys Ala Gly Gly Ala Cys Ala Cys Thr Gly Cys 260 265 270 Cys Ala Thr
Cys Thr Ala Thr Thr Ala Thr Thr Gly Cys Gly Cys Gly 275 280 285 Ala
Gly Gly Gly Cys Cys Cys Thr Gly Ala Cys Thr Thr Ala Thr Thr 290 295
300 Ala Thr Gly Ala Cys Thr Ala Thr Gly Ala Gly Thr Thr Cys Gly Cys
305 310 315 320 Thr Thr Ala Thr Thr Gly Gly Gly Gly Cys Cys Ala Gly
Gly Gly Gly 325 330 335 Ala Cys Gly Cys Thr Thr Gly Thr Gly Ala Cys
Cys Gly Thr Ala Ala 340 345 350 Gly Cys Gly Cys Thr Gly Cys Thr Ala
Gly Thr Ala Cys Cys Ala Ala 355 360 365 Gly Gly Gly Cys Cys Cys Cys
Ala Gly Thr Gly Thr Gly Thr Thr Cys 370 375 380 Cys Cys Cys Cys Thr
Thr Gly Cys Cys Cys Cys Cys Ala Gly Cys Ala 385 390 395 400 Gly Thr
Ala Ala Gly Thr Cys Cys Ala Cys Cys Thr Cys Ala Gly Gly 405 410 415
Thr Gly Gly Cys Ala Cys Ala Gly Cys Thr Gly Cys Cys Cys Thr Thr 420
425 430 Gly Gly Gly Thr Gly Cys Cys Thr Thr Gly Thr Gly Ala Ala Gly
Gly 435 440 445 Ala Thr Thr Ala Cys Thr Thr Cys Cys Cys Ala Gly Ala
Ala Cys Cys 450 455 460 Ala Gly Thr Gly Ala Cys Cys Gly Thr Gly Ala
Gly Cys Thr Gly Gly 465 470 475 480 Ala Ala Thr Thr Cys Cys Gly Gly
Ala Gly Cys Cys Cys Thr Thr Ala 485 490 495 Cys Cys Ala Gly Cys Gly
Gly Thr Gly Thr Gly Cys Ala Thr Ala Cys 500 505 510 Cys Thr Thr Thr
Cys Cys Gly Gly Cys Cys Gly Thr Cys Cys Thr Gly 515 520 525 Cys Ala
Ala Ala Gly Cys Ala Gly Cys Gly Gly Ala Cys Thr Thr Thr 530 535 540
Ala Cys Ala Gly Thr Cys Thr Gly Thr Cys Thr Ala Gly Cys Gly Thr 545
550 555 560 Gly Gly Thr Cys Ala Cys Cys Gly Thr Gly Cys Cys Cys Ala
Gly Cys 565 570 575 Ala Gly Cys Ala Gly Cys Cys Thr Gly Gly Gly Thr
Ala Cys Ala Cys 580 585 590 Ala Gly Ala Cys Gly Thr Ala Thr Ala Thr
Thr Thr Gly Cys Ala Ala 595 600 605 Cys Gly Thr Thr Ala Ala Thr Cys
Ala Cys Ala Ala Ala Cys Cys Cys 610 615 620 Thr Cys Ala Ala Ala Cys
Ala Cys Ala Ala Ala Gly Gly Thr Gly Gly 625 630 635 640 Ala Cys Ala
Ala Gly Ala Ala Ala Gly Thr Gly Gly Ala Gly Cys Cys 645 650 655 Thr
Ala Ala Ala Thr Cys Ala Thr Gly Thr Gly Ala Thr Ala Ala Gly 660 665
670 Ala Cys Ala Cys Ala Thr Ala Cys Ala Thr Gly Cys Cys Cys Thr Cys
675 680 685 Cys Cys Thr Gly Cys Cys Cys Thr Gly Cys Ala Cys Cys Gly
Gly Ala 690 695 700 Gly Cys Thr Cys Thr Thr Ala Gly Gly Thr Gly Gly
Ala Cys Cys Thr 705 710 715 720 Thr Cys Ala Gly Thr Cys Thr Thr Thr
Thr Thr Ala Thr Thr Thr Cys 725 730 735 Cys Ala Cys Cys Thr Ala Ala
Ala Cys Cys Cys Ala Ala Ala Gly Ala 740 745 750 Thr Ala Cys Ala Cys
Thr Thr Ala Thr Gly Ala Thr Cys Thr Cys Ala 755 760 765 Cys Gly Gly
Ala Cys Ala Cys Cys Cys Gly Ala Gly Gly Thr Gly Ala 770 775 780 Cys
Cys Thr Gly Cys Gly Thr Thr Gly Thr Cys Gly Thr Gly Gly Ala 785 790
795 800 Thr Gly Thr Cys Thr Cys Ala Cys Ala Cys Gly Ala Ala Gly Ala
Cys 805 810 815 Cys Cys Thr Gly Ala Ala Gly Thr Gly Ala Ala Ala Thr
Thr Cys Ala 820 825 830 Ala Thr Thr Gly Gly Thr Ala Thr Gly Thr Thr
Gly Ala Cys Gly Gly 835 840 845 Thr Gly Thr Thr Gly Ala Gly Gly Thr
Gly Cys Ala Thr Ala Ala Cys 850 855 860 Gly Cys Ala Ala Ala Gly Ala
Cys Cys Ala Ala Gly Cys Cys Ala Cys 865 870 875 880 Gly Cys Gly Ala
Gly Gly Ala Gly Cys Ala Gly Thr Ala Thr Ala Ala 885 890 895 Thr Ala
Gly Cys Ala Cys Cys Thr Ala Thr Ala Gly Gly Gly Thr Ala 900 905 910
Gly Thr Cys Ala Gly Cys Gly Thr Ala Cys Thr Gly Ala Cys Thr Gly 915
920 925 Thr Thr Cys Thr Gly Cys Ala Thr Cys Ala Gly Gly Ala Thr Thr
Gly 930 935 940 Gly Cys Thr Gly Ala Ala Cys Gly Gly Thr Ala Ala Ala
Gly Ala Gly 945 950 955 960 Thr Ala Cys Ala Ala Ala Thr Gly Cys Ala
Ala Gly Gly Thr Cys Thr 965 970 975 Cys Ala Ala Ala Cys Ala Ala Gly
Gly Cys Thr Cys Thr Cys Cys Cys 980 985 990 Thr Gly Cys Cys Cys Cys
Gly Ala Thr Cys Gly Ala Gly Ala Ala Gly 995 1000 1005 Ala Cys Ala
Ala Thr Thr Thr Cys Thr Ala Ala Gly Gly Cys Cys 1010 1015 1020 Ala
Ala Ala Gly Gly Gly Cys Ala Gly Cys Cys Cys Cys Gly Gly 1025 1030
1035 Gly Ala Ala Cys Cys Ala Cys Ala Ala Gly Thr Cys Thr Ala Thr
1040 1045 1050 Ala Cys Cys Cys Thr Gly Cys Cys Ala Cys Cys Cys Ala
Gly Thr 1055 1060 1065 Cys Gly Gly Gly Ala Thr Gly Ala Ala Cys Thr
Ala Ala Cys Ala 1070 1075 1080 Ala Ala Ala Ala Ala Thr Cys Ala Gly
Gly Thr Gly Thr Cys Thr 1085 1090 1095 Cys Thr Ala Ala Cys Cys Thr
Gly Cys Cys Thr Gly Gly Thr Gly 1100 1105 1110 Ala Ala Gly Gly Gly
Ala Thr Thr Thr Thr Ala Cys Cys Cys Thr 1115 1120 1125 Thr Cys Cys
Gly Ala Thr Ala Thr Ala Gly Cys Thr Gly Thr Gly 1130 1135 1140 Gly
Ala Gly Thr Gly Gly Gly Ala Gly Thr Cys Thr Ala Ala Thr 1145 1150
1155 Gly Gly Cys Cys Ala Ala Cys Cys Ala Gly Ala Gly Ala Ala Thr
1160 1165 1170 Ala Ala Thr Thr Ala Cys Ala Ala Gly Ala Cys Thr Ala
Cys Cys 1175 1180 1185 Cys Cys Cys Cys Cys Cys Gly Thr Thr Cys Thr
Thr Gly Ala Cys 1190 1195 1200 Ala Gly Thr Gly Ala Thr Gly Gly Cys
Thr Cys Gly Thr Thr Cys 1205 1210 1215 Thr Thr Cys Thr Thr Ala Thr
Ala Cys Thr Cys Ala Ala Ala Ala 1220 1225 1230 Thr Thr Ala Ala Cys
Ala Gly Thr Cys Gly Ala Cys Ala Ala Ala 1235 1240 1245 Thr Cys Cys
Cys Gly Ala Thr Gly Gly Cys Ala Ala Cys Ala Gly 1250 1255 1260 Gly
Gly Cys Ala Ala Thr Gly Thr Gly Thr Thr Thr Ala Gly Cys 1265 1270
1275 Thr Gly Thr Ala Gly Cys Gly Thr Gly Ala Thr Gly Cys Ala Thr
1280 1285 1290 Gly Ala Ala Gly Cys Cys Cys Thr Gly Cys Ala Cys Ala
Ala Cys 1295 1300 1305 Cys Ala Thr Thr Ala Cys Ala Cys Ala Cys Ala
Gly Ala Ala Gly 1310 1315 1320 Thr Cys Thr Cys Thr Gly Thr Cys Cys
Thr Thr Gly Thr Cys Ala 1325 1330 1335 Cys Cys Thr Gly Gly Cys Ala
Ala Gly 1340 1345 <210> SEQ ID NO 69 <211> LENGTH: 447
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 69 Gln Val Gln Leu Lys Gln Ser
Gly Pro Gly Leu Val Gln Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr
Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30 Gly Val His
Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly
Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55
60 Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80 Lys Ser Leu Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala
Arg Ala 85 90 95 Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly
Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ala Ala Ser Thr Lys Gly
Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser
Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe
Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185
190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val
Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310
315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro 340 345 350 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr
Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
445 <210> SEQ ID NO 70 <211> LENGTH: 645 <212>
TYPE: DNA <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 70 acccaaatcc tcctgaccca gtcccctgtt
atcctttctg tgtcgcccgg ggagcgcgtt 60 agctttagct gccgcgccag
tcagtcaatc ggaacaaaca tccattggta ccagcagcgt 120 acgaacggca
gtccaaggct gctgatcaaa tacgcaagtg aatctatatc ggggattccg 180
tctcggttca gcggatccgg aagcgggact gactttacgc tctccataaa tagcgtcgaa
240 agtgaggaca ttgcagacta ttactgtcag cagaataaca actggccgac
cacatttggg 300 gccggaacca agttggaact gaagcgcact gtggcagctc
ctagtgtttt tattttcccc 360 ccttctgacg agcaactgaa aagtggtaca
gcttcagtag tttgtttgct caataatttc 420 tacccacggg aagcaaaggt
gcagtggaaa gtcgacaacg cattacagag cggcaactct 480 caagaaagcg
tgacggagca ggatagcaag gactcaacat attccttgtc ttccactctc 540
actctgtcaa aggctgatta tgagaagcat aaggtgtatg cgtgcgaagt gacacaccag
600 ggattatcaa gcccagtgac caagtccttt aaccgtggcg aatgc 645
<210> SEQ ID NO 71 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 71 Leu Ser Gly Arg Ser Asp Asn Ile 1 5 <210> SEQ ID
NO 72 <211> LENGTH: 783 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 72
cagggccaga gcggccaatg catctccccc cgcggttgtc ccgacgggcc gtacgtgatg
60 tacggcagct ccggcggcag tgggggtagc ggtgggtccg ggctgagtgg
ccggtccgac 120 aatcacggga gctcgggaac acagattctg ctgacgcaat
ctcccgtgat cctctcggtc 180 tcacccggcg aacgggtctc gttcagctgc
agagcgtccc aatcaatcgg gaccaatatt 240 cactggtacc agcaaaggac
taatgggtct ccccggctgc tgataaaata cgcctccgag 300 tctatctcgg
gcatcccatc ccgatttagt ggtagcggaa gcggcactga tttcaccttg 360
tctattaaca gcgtagaatc tgaggacatt gcagactatt actgtcagca gaataacaat
420 tggcctacaa ctttcggcgc cgggaccaaa ctagagttaa agcgtactgt
ggctgccccc 480 agcgttttta tttttccgcc cagcgacgaa cagctgaagt
caggcacagc ctctgtggtg 540 tgtctcctga ataacttcta ccccagagag
gccaaagttc agtggaaagt ggacaatgcc 600 ttgcagtccg gaaacagtca
agagtccgtg accgagcagg acagtaagga tagcacgtat 660 agcctctcta
gtactttaac actgtccaag gccgactacg agaagcacaa ggtgtacgca 720
tgcgaagtga cccatcaggg gctttcctcc cccgtcacca agtctttcaa tcgcggggag
780 tgt 783 <210> SEQ ID NO 73 <211> LENGTH: 261
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 73 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu
Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 74 <211> LENGTH: 783 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 74 caaggtcagt ccggacagtg tatttcccct agaggttgcc ctgacgggcc
gtatgtcatg 60 tacggtagtt ctggcggtag tggcggatct ggcggcagtg
ggctgagcgg acgtagcggg 120 aatcacggct catccgggac gcagatactg
ctgacccagt cccccgtgat cctgtccgtg 180 tcaccgggcg aaagggtcag
tttctcttgc cgagcatcac agtccatagg tacgaatatc 240 cattggtacc
agcagcggac caatgggagc ccaagactgc tcattaagta cgcatctgag 300
agtatctcag gcattccaag caggttttcc ggcagtggga gcggcactga cttcaccctc
360 agcattaaca gcgtggaaag cgaagacatt gcagattact actgccaaca
gaacaataac 420 tggcctacta cattcggggc aggaactaag ttggagctca
aacgtaccgt cgctgctcct 480 agcgtattta ttttccctcc tagcgatgaa
cagttgaaat ctggtaccgc tagtgttgtg 540 tgcttactga acaactttta
tccccgggag gccaaggtac aatggaaggt ggacaatgcc 600 ctccaatcag
ggaacagcca ggagtctgtt accgagcagg actccaagga cagcacctac 660
agcctgagct ctacccttac attgagcaag gctgattatg agaagcataa ggtctacgct
720 tgtgaggtga cccatcaggg gctcagcagc ccggtgacaa aaagctttaa
ccggggggaa 780 tgc 783 <210> SEQ ID NO 75 <211> LENGTH:
261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 75 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu
Ser Gly Arg Ser Gly Asn His Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 76 <211> LENGTH: 783 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 76 caggggcagt ctgggcagtg tattagcccc agggggtgcc ccgacgggcc
ttacgtgatg 60 tatggcagct ccggtggcag cggaggctct ggcgggagtg
ggatcagttc cggcctgctg 120 agctccgggt caagcgggac ccagatcttg
ctcacccaat caccagtgat cctaagcgtg 180 agccctggcg aacgggtcag
cttctcttgc cgggcatctc agagtattgg cactaacata 240 cactggtacc
agcagcgaac caatgggtcc ccccgccttc taatcaaata tgctagcgaa 300
tccatttcag gaattcctag ccgatttagc ggcagcggat caggcactga cttcactctg
360 tcaatcaact cagttgaaag cgaggacatt gcagactact attgccagca
gaataataat 420 tggcccacta catttggagc tggaacaaaa ttggagctta
agaggacagt ggctgcgcct 480 agtgtattta tctttccccc ctctgacgaa
cagttgaaat cgggaaccgc atccgtcgtc 540 tgtttactga acaacttcta
tcccagagag gccaaagtgc agtggaaagt ggataatgct 600 ttgcagtctg
gcaacagcca ggaaagcgtg acggagcagg actcaaagga tagtacatac 660
tccctgtcct ccaccctgac tctgagtaag gccgactacg agaagcacaa ggtctacgcc
720 tgcgaagtga cgcaccaagg gctatcgagc ccggtcacca agtctttcaa
tcgtggagaa 780 tgc 783 <210> SEQ ID NO 77 <211> LENGTH:
261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 77 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile
Ser Ser Gly Leu Leu Ser Ser Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 78 <211> LENGTH: 783 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 78 caggggcaat caggacaatg catcagccct aggggctgcc cagacggccc
atatgtgatg 60 tacggtagct ctgggggctc aggaggcagc gggggaagcg
gacaaaacca ggccttacga 120 atggctggca gctctggcac ccagatattg
ctgacgcaga gtccagttat ccttagtgtc 180 agccctggtg aacgggtttc
atttagttgc cgtgcctccc agtctattgg aacgaacatt 240 cattggtacc
agcaaaggac caacggttca cccaggttgc ttatcaagta tgcttcagag 300
tcaatctccg ggattccctc aaggttttca ggctctggct caggtaccga ttttacgctg
360 agcatcaact ccgtggagag tgaggacatt gctgattatt actgtcagca
gaataacaat 420 tggccgacaa ctttcggcgc cggcacaaag ctggaactta
agcgtactgt ggctgcgcca 480 tctgtcttca tttttccgcc ctcggacgag
cagttgaagt cagggaccgc ctctgtcgtg 540 tgccttctca ataacttcta
tcccagagag gctaaagtcc agtggaaagt tgataatgca 600 cttcagagcg
ggaatagcca ggagagcgtg acggaacagg actctaagga ctccacctat 660
tctctctcat ccacccttac tctctctaaa gccgactacg aaaagcataa ggtttatgct
720 tgcgaagtca ctcatcaagg gctatctagt ccggtcacta aaagcttcaa
cagaggtgaa 780 tgt 783 <210> SEQ ID NO 79 <211> LENGTH:
261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 79 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Gln
Asn Gln Ala Leu Arg Met Ala Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 80 <211> LENGTH: 798 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 80 caaggccagt ctggacaatg tatcagcccc cgtggctgtc cagacggtcc
ttacgttatg 60 tatggatcta gcgggggctc tggagggtct ggcggctctg
gaatctctag tggacttctc 120 tccggaagaa gcgataatca tggatccagc
gggacacaaa tcctgttgac acagtcccca 180 gtgatcctgt cagtctcgcc
cggagaaagg gtgtctttct cttgtagggc tagtcagtct 240 atcggaacta
acatccattg gtaccagcag cggacaaatg ggagcccgag gcttctgatc 300
aagtatgctt cagagagtat aagcggcatc ccctcaagat ttagtggcag cgggtccggg
360 acagatttca ccttgtcaat caattctgtc gaatccgaag acattgcaga
ctactattgc 420 cagcaaaaca acaactggcc caccactttc ggtgctggaa
ccaaactcga gctgaaacgc 480 actgtggcag ctccttcagt gttcatcttc
ccacctagcg acgagcagtt gaaatcgggg 540 acagcctcag tggtgtgtct
actgaacaac ttttaccccc gggaagccaa agtgcagtgg 600 aaggtcgaca
atgcgctgca atcagggaac agtcaggagt cagttacaga gcaggactct 660
aaggacagta catattcttt gagttccacc ttgacattaa gcaaggcaga ctacgagaaa
720 cacaaggtgt acgcatgtga agttacacac cagggccttt cctccccagt
tacgaaaagc 780 ttcaacagag gcgaatgc 798 <210> SEQ ID NO 81
<211> LENGTH: 266 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 81 Gln
Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10
15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly
20 25 30 Ser Gly Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn
His Gly 35 40 45 Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val Ile Leu Ser 50 55 60 Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala Ser Gln Ser 65 70 75 80 Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn Gly Ser Pro 85 90 95 Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser 100 105 110 Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn 115 120 125 Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn 130 135 140
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 145
150 155 160 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
Glu Gln 165 170 175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn Phe Tyr 180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
82 <211> LENGTH: 798 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 82
caaggtcaga gtggccaatg catatcgccc agaggatgtc ctgacggacc ctacgtgatg
60 tacgggagtt ctggggggag tggaggctct ggcgggtcag ggattagttc
cggcctcttg 120 tctggacgct ccggaaatca cggatcatct gggacccaga
tcctcctgac ccagtctccc 180 gtcattctgt ctgtttctcc aggcgagcgg
gtttcattta gctgtagggc cagtcagagc 240 attggcacca acatccattg
gtaccagcag agaactaatg gcagtcccag actgctcatt 300 aaatatgcaa
gcgaatcaat ttccgggatt ccttctcgct tctcgggatc tggatctggc 360
accgacttca cgctgtccat caacagcgtg gagagtgagg acatcgccga ttactactgc
420 cagcagaaca acaactggcc aacaactttt ggcgccggga ccaagcttga
gttaaagaga 480 accgtagctg caccctctgt tttcattttc ccaccctcag
acgagcagct taagtcagga 540 actgccagtg tggtgtgcct gctgaacaac
ttctacccga gagaggctaa agtccagtgg 600 aaggtagaca atgcccttca
gtctggcaac tctcaggaga gtgtcacaga gcaggattct 660 aaggactcca
cgtacagtct gagttccacc ctcaccctca gtaaggcaga ctacgagaag 720
cacaaagtct acgcatgtga ggttactcac caggggctca gctctcccgt gacgaagtca
780 tttaacagag gtgagtgc 798 <210> SEQ ID NO 83 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 83 Gln Gly Gln Ser Gly
Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val
Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser
Gly Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Gly Asn His Gly 35 40
45 Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser
50 55 60 Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
Asn Gly Ser Pro 85 90 95 Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser
Ile Ser Gly Ile Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Ser Ile Asn 115 120 125 Ser Val Glu Ser Glu Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn 130 135 140 Asn Trp Pro Thr
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 84 <211>
LENGTH: 825 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 84 cagggacagt
cgggacagtg catttctccg agaggctgcc ctgacggccc atacgtaatg 60
tacggatcat ccggtggcag tggagggtcc gggggatccg gtctaagcgg cagaagtgat
120 aatcatggag gctctggcgg gagcatcagc tccggattgc tttccagcgg
aagttctggc 180 actcaaattc tgctgacaca aagccctgtg atcttgtcag
tctcacctgg cgagcgggtg 240 agcttttcat gccgggcttc ccagagcatc
ggtacaaata ttcactggta tcagcagaga 300 accaatggca gtccgcggtt
gctgattaag tatgcgagcg agagcatatc aggcatacca 360 agcagattta
gcgggagtgg ctctgggacc gattttacac tcagtataaa ttcagtggag 420
agcgaggata tagccgacta ctactgccag caaaacaata actggcccac caccttcggc
480 gcagggacca agcttgaact gaagcgtaca gttgccgccc caagcgtatt
tattttccct 540 ccaagcgacg aacagctgaa aagcggtacc gcaagcgttg
tgtgcctgct gaataacttt 600 tacccaaggg aagctaaggt gcagtggaag
gttgacaatg cgctgcagtc aggcaactcc 660 caggaatcgg taacagagca
ggactccaag gattcaactt atagtcttag tagtaccctt 720 actctttcca
aagctgatta tgaaaaacac aaagtgtatg catgcgaggt gacccaccaa 780
ggactgtcat ctcctgtcac caagtccttc aaccggggag agtgt 825 <210>
SEQ ID NO 85 <211> LENGTH: 275 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 85 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Asp Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Ile Ser Ser Gly Leu Leu Ser
Ser Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 86
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 86
caaggtcaga gcggccagtg cattagtcct cgcggttgcc ctgatggacc atacgtaatg
60 tatggaagct ctggtggatc cgggggctct ggcggatcag gaatctccag
cgggctgctc 120 tcatcaggtg gcagcggggg ctcattaagc ggccgaagtg
acaatcacgg ctcgtccggt 180 acacagattc tgctcactca gtcacccgtt
atactgtctg tgtcgcctgg agagcgtgtc 240 agcttttcat gtagagcctc
gcagtcaata ggcacgaata tacactggta ccagcagaga 300 actaatggaa
gcccaaggtt gctcatcaaa tacgcatctg agtcgattag cggcattccg 360
tccaggttta gtggcagtgg aagcggcacc gatttcactt tgtctattaa ctctgtggaa
420 agcgaggaca tcgccgatta ttattgtcag cagaataaca attggcccac
caccttcggt 480 gccggtacta agctggagct gaaacgtaca gttgccgctc
cctctgtgtt tattttccct 540 ccctcggatg agcaactcaa atcagggaca
gcgagtgtcg tatgtctcct gaacaatttt 600 tacccacgtg aagctaaagt
tcagtggaag gtggacaacg ctctgcagtc cggcaacagt 660 caggaaagcg
taactgaaca ggactcaaag gatagcactt actccttgag cagcactctc 720
actctttcca aggctgatta tgagaagcac aaggtgtacg cgtgtgaagt cacccatcag
780 ggactgtcaa gtccggtgac taaatcattt aacaggggcg aatgc 825
<210> SEQ ID NO 87 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 87 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile Ser Ser Gly Leu Leu Ser
Ser Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Asp Asn
His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 88
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 88
cagggccaga gtgggcagtg tatttcccct cgcggatgtc ccgacggtcc atacgtaatg
60 tatgggtcaa gcgggggatc aggaggaagt ggaggctccg gactcagcgg
tcgctccggc 120 aatcacgggg ggtctggcgg atcaataagt tcgggcctcc
tgagctccgg ttcatctggc 180 actcagatcc tgctcacgca gtcgccggta
atactgagtg tctcaccagg cgagcgtgtc 240 agcttcagct gtcgcgcctc
acagtcaatc ggcacaaata tccattggta ccagcaaagg 300 accaatggca
gccctaggct gctgataaaa tacgcatccg agtcaatttc agggattcca 360
tcgagattct cgggcagcgg aagtgggacc gactttactc tctccatcaa cagcgtcgag
420 tcggaggaca tcgcggacta ctactgccag cagaataaca attggccaac
aacattcggc 480 gcaggaacaa agctagagct caagaggaca gtggctgcac
ccagtgtatt catcttccca 540 cctagcgacg agcaactgaa gagcgggacg
gcttccgtcg tttgtctatt aaataatttc 600 tatccccgtg aggctaaagt
tcagtggaag gttgataatg cgttgcagtc cggcaactcc 660 caggaatccg
tcacagagca ggattctaag gattcaacct atagcttaag ctctacactt 720
acgctttcta aagccgatta tgaaaaacac aaggtgtacg cttgtgaggt tacccaccag
780 ggcctgagca gccccgtgac caagtcgttc aaccggggcg agtgt 825
<210> SEQ ID NO 89 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 89 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Gly Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Ile Ser Ser Gly Leu Leu Ser
Ser Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 90
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 90
caaggacaga gcggacagtg tatctcacct cgcggctgcc ccgacggccc ttacgtcatg
60 tacggctcct cgggtgggtc cgggggaagt ggcgggtctg gcattagttc
agggctctta 120 tcttccggcg gaagcggggg atctctttcc gggcggagtg
gcaatcacgg cagtagcgga 180 actcagatcc tactcactca gtcaccagtg
atcctgtctg tcagtccagg ggagagagtg 240 tctttcagtt gtagagcttc
ccagtctatt gggacaaaca ttcactggta tcaacagcga 300 actaatggat
cgccaagact cctgattaaa tatgcttctg agagcatctc tggaattcca 360
tcaagattct cagggagtgg tagcggcacc gattttacgt tatcgatcaa ttccgttgag
420 agcgaagata tcgcggacta ttactgtcag cagaacaata actggcctac
aacgttcggg 480 gcagggacga aattggagct gaagcggacc gtcgccgcgc
caagcgtgtt catcttcccc 540 cctagcgacg agcaattgaa aagcggcacc
gcaagtgtgg tttgcctgct gaacaacttt 600 tatcctcgcg aggcgaaagt
gcagtggaaa gtcgacaatg cactccagtc agggaacagc 660 caagagtccg
ttactgaaca agactctaaa gatagtactt atagcttatc cagcacactg 720
acgctcagta aggccgatta tgaaaaacat aaggtgtatg cgtgtgaggt tacccatcaa
780 ggattgtcat cacccgtcac caaatccttt aacagaggag aatgt 825
<210> SEQ ID NO 91 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 91 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile Ser Ser Gly Leu Leu Ser
Ser Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Gly Asn
His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 92
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 92
cagggtcaaa gtggacagtg tatctcgccc cgcggctgcc cagacggccc atatgtgatg
60 tatggttctt ccggtggatc cggcggatca ggtgggtctg gcctctcagg
tcgttccgac 120 aaccacggcg gctcaggtgg gtctcagaat caggcactgc
ggatggccgg atcttctggc 180 acccagatat tgctcacaca gtcaccagtt
attctgtccg tatctccagg agaacgggta 240 tctttctctt gtagggcaag
ccagtccatc ggaacaaaca tccattggta ccagcagcgg 300 accaatggca
gtccacggct tctgatcaag tatgctagtg aaagcattag cgggattcca 360
agccgatttt ctgggtcggg tagtggaacc gacttcaccc tgagcattaa ctctgtcgaa
420 tccgaagata ttgctgacta ttactgtcag cagaacaaca attggccgac
tacgtttggc 480 gccggaacca aattagaact taagagaacc gtggccgctc
cctctgtctt cattttcccg 540 ccttccgacg aacagctgaa gagcggaact
gcctccgtgg tgtgcctgtt gaataacttt 600 tatccaaggg aagcaaaggt
gcagtggaaa gtggacaatg ctctgcagtc tggcaatagc 660 caggagtccg
tgactgaaca ggacagtaaa gactcaacct actcactgag cagtactctc 720
acattatcca aagccgatta tgaaaagcat aaggtttatg catgcgaggt tacccaccag
780 ggactgagct cccccgtgac caaaagcttc aataggggtg agtgc 825
<210> SEQ ID NO 93 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 93 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Asp Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Gln Asn Gln Ala Leu Arg Met
Ala Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 94
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 94
caggggcagt ccggacaatg catcagcccc cgaggctgcc ctgatggccc ctacgtgatg
60 tacgggtcca gcggtggcag cgggggctca ggggggagcg ggcagaatca
ggccctgaga 120 atggcgggtg gatccggggg gtccctttct ggcaggtccg
ataaccacgg ttctagtgga 180 acacagattt tgctgacaca aagtcccgtc
atcctctctg tgtctcccgg tgagcgggtc 240 agtttttcct gccgagcgtc
ccagagcatc gggacaaata tccattggta ccagcagaga 300 acgaacggct
ctcctagact gctcatcaag tacgcctcgg aaagtatttc cggcattccc 360
tcccgtttca gcggctccgg aagtggtaca gattttaccc tgagtattaa ttccgtcgaa
420 tctgaggaca tagccgacta ctattgccaa cagaataaca attggccaac
aacttttggc 480 gccgggacta agctggagct gaaacggacc gtcgcagcac
caagtgtttt catcttccca 540 ccaagtgacg agcagctgaa atccggaaca
gcgagcgtgg tgtgcctact caataacttc 600 tatccacgcg aagccaaggt
gcagtggaaa gtggacaacg ctctgcagtc cggcaatagc 660 caggaaagcg
tgacagagca agattctaag gacagtacgt attcactgtc cagtacgctc 720
accttaagca aggctgacta cgaaaaacac aaggtctacg cctgtgaggt cacacatcag
780 ggcctctcca gtccggttac aaaaagtttc aatcgcgggg aatgt 825
<210> SEQ ID NO 95 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 95 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Gln Asn Gln Ala Leu Arg Met
Ala Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Asp Asn
His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 96
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 96
caaggccaat ccggtcagtg catcagtccc agaggctgcc ctgacgggcc ctacgtgatg
60 tatggtagct cagggggctc cggcggctcc ggcggaagcg gacttagcgg
ccgtagcggc 120 aaccatgggg gttctggagg atcccagaat caggctctgc
gcatggctgg aagcagcggt 180 acccagatcc tgctcaccca atcacccgtc
atcttgtctg tgagtcctgg cgaaagggtg 240 tcgttctctt gtcgcgcgtc
ccagtccatt gggaccaaca ttcattggta ccagcagagg 300 actaacggga
gcccccgcct gctgatcaaa tacgccagtg aatctatctc tggaatccca 360
tcacgatttt cagggtccgg tagtgggacc gacttcactt tgagtattaa cagtgtggaa
420 tccgaggaca tagccgacta ttactgtcag cagaacaata actggccaac
aacctttggc 480 gccgggacaa agttagagct taagcggact gttgcagccc
cctccgtttt tatcttcccg 540 cccagtgatg aacagctgaa aagcggtacc
gcctccgtag tgtgccttct caataatttt 600 taccccagag aagctaaagt
acagtggaaa gtcgacaacg ccctccagag cggcaacagt 660 caggagtccg
tcaccgagca ggattctaaa gactcaacat atagcctttc gtccacccta 720
acactttcaa aagcagacta tgaaaaacat aaggtgtatg cctgcgaggt cacacaccag
780 gggctcagct ctccagttac taagtcattc aaccgcggag agtgt 825
<210> SEQ ID NO 97 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 97 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Gly Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Gln Asn Gln Ala Leu Arg Met
Ala Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 98
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 98
cagggccaat caggtcagtg cattagcccc cgagggtgtc ccgatgggcc ctacgtaatg
60 tacggatcat cgggcggatc tgggggctcc ggtggctctg gtcagaatca
agctctgcgc 120 atggccggag gtagcggtgg aagcctgagc ggccgaagtg
gaaaccacgg ctcctctggc 180 actcagattc ttctcacgca gtcgcccgtg
atcttgtccg tgagcccagg cgagcgggtg 240 agcttctctt gccgggccag
ccaaagtata ggtacaaata ttcactggta ccaacagcga 300 accaacgggt
cgcctaggtt gctcataaag tacgcatccg agagtataag cggcatacca 360
tctaggttct caggtagcgg cagcgggacc gattttaccc tcagcattaa ttcggttgaa
420 tctgaagata tcgccgatta ttattgtcag cagaataaca attggcctac
tactttcggc 480 gccggaacaa agctggaact taagcgcaca gtggccgctc
cttctgtctt tatcttccct 540 ccatctgacg agcaattaaa gagtgggaca
gcctcggtgg tgtgtttgct caataacttc 600 tatccaaggg aggcaaaggt
gcagtggaag gtcgataacg ctctccagag tgggaattcc 660 caggagtccg
tgaccgagca ggattctaaa gatagcacat actcactgtc ttccaccctg 720
accctgtcca aggcagacta cgagaagcac aaagtttacg cctgtgaagt gacacaccag
780 ggcctcagct ctcctgtcac aaagagtttt aatcggggcg agtgt 825
<210> SEQ ID NO 99 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 99 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Gln Asn Gln Ala Leu Arg Met
Ala Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Gly Asn
His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 100
<211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 100 Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10
15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu
Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr
Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg
Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145
150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265
270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala
Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390
395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 101
<211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 101 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys
Gln Gln Gly Asn Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145
150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210
<210> SEQ ID NO 102 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 102 Tyr Gly Ser Cys Ser Trp Asn Tyr Val His Ile Phe Met
Asp Cys 1 5 10 15 <210> SEQ ID NO 103 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 103 Gln Gly Asp Phe Asp Ile Pro
Phe Pro Ala His Trp Val Pro Ile Thr 1 5 10 15 <210> SEQ ID NO
104 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 104
Met Gly Val Pro Ala Gly Cys Val Trp Asn Tyr Ala His Ile Phe Met 1 5
10 15 Asp Cys <210> SEQ ID NO 105 <211> LENGTH: 21
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 105 Gln Gly Gln Ser Gly Gln Tyr
Gly Ser Cys Ser Trp Asn Tyr Val His 1 5 10 15 Ile Phe Met Asp Cys
20 <210> SEQ ID NO 106 <211> LENGTH: 21 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 106 Gln Gly Gln Ser Gly Gln Gly Asp Phe Asp
Ile Pro Phe Pro Ala His 1 5 10 15 Trp Val Pro Ile Thr 20
<210> SEQ ID NO 107 <211> LENGTH: 24 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 107 Gln Gly Gln Ser Gly Gln Met Gly Val Pro Ala Gly Cys
Val Trp Asn 1 5 10 15 Tyr Ala His Ile Phe Met Asp Cys 20
<210> SEQ ID NO 108 <211> LENGTH: 449 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 108 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 109 <211> LENGTH: 449 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 109 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 110 <211> LENGTH: 449 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 110 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Ala Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 111 <211> LENGTH: 214 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 111 Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn 20 25 30 Ile His Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 65 70 75 80 Glu Asp Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 85 90 95 Thr
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 100 105
110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg
Gly Glu Cys 210 <210> SEQ ID NO 112 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 112 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 113 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 113 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 114 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 114 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 115 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 115
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro
Tyr His Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 116 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 116 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 117 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 117 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Phe Phe Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 118 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 118 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 119 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 119
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys His Ile Gly
Arg Thr Asn Pro Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 120 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 120 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 121 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 121 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 122 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 122
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 123
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 123 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Tyr
Tyr Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 124 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 124 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 125 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 125 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Phe Phe Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 126 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 126 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 127 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 127
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly
Gly Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 128 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 128 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 129 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 129 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Glu Met Gly Trp Gln Thr Leu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 130 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 130
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 131
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 131 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 132 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 132 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 133 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 133 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Phe Tyr Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 134 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 134 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 135 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 135
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro
Phe Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 136 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 136 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 137 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 137 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Glu Met Gly Trp Gln Thr Leu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Ala 85 90 95 Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
138 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 138
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 139
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 139 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 140 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 140 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 141 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 141 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Pro Glu Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 142 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 142
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 143
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 143 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro His
Asn Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 144 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 144 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 145 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 145 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 146 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 146
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 147
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 147 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Phe
Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 148 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 148 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 149 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 149 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Glu Met Gly Trp Gln Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 150 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 150
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Leu Asp Ala Pro Pro 85 90 95 Gln Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 151
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 151 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 152 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 152 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala
Pro Pro 85 90 95 Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 153 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 153 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Pro Glu Gly Arg Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 154 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 154 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 155 <211> LENGTH: 116 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 155
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Glu Met Gly Trp Gln Thr Lys
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala
Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser
Ser 115 <210> SEQ ID NO 156 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 156 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Asp Ala
Pro Leu 85 90 95 Met Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 157 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 157 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Pro Met Gly Gln Leu Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 158 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 158 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 159 <211> LENGTH: 116 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 159
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Asp Glu Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala
Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser
Ser 115 <210> SEQ ID NO 160 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 160 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 161 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 161 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Glu Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 162 <211> LENGTH: 214 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 162
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro 85 90 95 Leu Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135
140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210
<210> SEQ ID NO 163 <211> LENGTH: 449 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 163 Glu Val His Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Asp Pro Glu Gly
Arg Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 164 <211> LENGTH: 214 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(182)..(182) <223> OTHER INFORMATION: X is any amino acid
<400> SEQUENCE: 164 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro 85
90 95 Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr
Leu Xaa Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205
Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 165 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 165 Cys Ile Ser Pro
Arg Gly 1 5 <210> SEQ ID NO 166 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 166 Cys Ile Ser Pro Arg Gly Cys 1
5 <210> SEQ ID NO 167 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 167 Cys Ile Ser Pro Arg Gly Cys Gly 1 5 <210> SEQ
ID NO 168 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 168
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr 1 5 10
15 <210> SEQ ID NO 169 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 169 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met 1 5 10 <210> SEQ ID NO 170 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 170 Cys Ile Ser Pro
Arg Gly Cys Glu Pro Gly Thr Tyr Val Pro Thr 1 5 10 15 <210>
SEQ ID NO 171 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 171 Cys Ile Ser Pro Arg Gly Cys Pro Gly Gln Ile Trp His
Pro Pro 1 5 10 15 <210> SEQ ID NO 172 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 172 Gly Ser His Cys Leu Ile Pro
Ile Asn Met Gly Ala Pro Ser Cys 1 5 10 15 <210> SEQ ID NO 173
<211> LENGTH: 32 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 173 Cys
Ile Ser Pro Arg Gly Cys Gly Gly Ser Ser Ala Ser Gln Ser Gly 1 5 10
15 Gln Gly Ser His Cys Leu Ile Pro Ile Asn Met Gly Ala Pro Ser Cys
20 25 30 <210> SEQ ID NO 174 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 174 Cys Asn His His Tyr Phe Tyr
Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 175 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 175 Ala Asp His Val Phe Trp Gly Ser Tyr Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 176
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 176 Cys
His His Val Tyr Trp Gly His Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 177 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 177 Cys Pro His Phe Thr Thr Thr
Ser Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 178 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 178 Cys Asn His His Tyr His Tyr Tyr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 179
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 179 Cys
Pro His Val Ser Phe Gly Ser Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 180 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 180 Cys Pro Tyr Tyr Thr Leu Ser
Tyr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 181 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 181 Cys Asn His Val Tyr Phe Gly Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 182
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 182 Cys
Asn His Phe Thr Leu Thr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 183 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 183 Cys His His Phe Thr Leu Thr
Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 184 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 184 Tyr Asn Pro Cys Ala Thr Pro Met Cys Cys Ile Ser Pro
Arg Gly Cys 1 5 10 15 Pro Gly <210> SEQ ID NO 185 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 185 Cys Asn His His
Tyr Phe Tyr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 186 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 186 Cys Asn His His Tyr His Tyr Tyr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 187 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 187 Cys Asn His Val
Tyr Phe Gly Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 188 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 188 Cys His His Val Tyr Trp Gly His Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 189 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 189 Cys Pro His Phe
Thr Thr Thr Ser Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 190 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 190 Cys Asn His Phe Thr Leu Thr Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 191 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 191 Cys His His Phe
Thr Leu Thr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 192 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 192 Cys Pro Tyr Tyr Thr Leu Ser Tyr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 193 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 193 Cys Pro His Val
Ser Phe Gly Ser Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 194 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 194 Ala Asp His Val Phe Trp Gly Ser Tyr Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 195 <211>
LENGTH: 17 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 195 Tyr Asn Pro Cys
Ala Thr Pro Met Cys Cys Ile Ser Pro Arg Gly Cys 1 5 10 15 Gly
<210> SEQ ID NO 196 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 196 Cys His His Val Tyr Trp Gly His Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 197 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (2)..(2) <223> OTHER
INFORMATION: X is N or P <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: X is H, V, or F <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>
OTHER INFORMATION: X is Y or T <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6) <223>
OTHER INFORMATION: X is F, W, T, or L <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: X is Y, G, T, or S <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(8)..(8) <223> OTHER INFORMATION: X is T, S, Y, or H
<400> SEQUENCE: 197 Cys Xaa His Xaa Xaa Xaa Xaa Xaa Cys Gly
Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 198
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 198 Cys
Ile Ser Pro Arg Gly Cys Gly Gln Pro Ile Pro Ser Val Lys 1 5 10 15
<210> SEQ ID NO 199 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 199 Cys Ile Ser Pro Arg Gly Cys Thr Gln Pro Tyr His Val
Ser Arg 1 5 10 15 <210> SEQ ID NO 200 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 200 Cys Ile Ser Pro Arg Gly Cys
Asn Ala Val Ser Gly Leu Gly Ser 1 5 10 15 <210> SEQ ID NO 201
<211> LENGTH: 21 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 201 Gln
Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10
15 Arg Gly Trp Gln Gly 20 <210> SEQ ID NO 202 <211>
LENGTH: 26 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 202 Gln Gly Gln Ser
Gly Gln Gly Gln Gln Gln Trp Cys Asn Ile Trp Ile 1 5 10 15 Asn Gly
Gly Asp Cys Arg Gly Trp Asn Gly 20 25 <210> SEQ ID NO 203
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 203 Pro
Trp Cys Met Gln Arg Gln Asp Phe Leu Arg Cys Pro Gln Pro 1 5 10 15
<210> SEQ ID NO 204 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 204 Gln Leu Gly Leu Pro Ala Tyr Met Cys Thr Phe Glu Cys
Leu Arg 1 5 10 15 <210> SEQ ID NO 205 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 205 Cys Asn Leu Trp Val Ser Gly
Gly Asp Cys Gly Gly Leu Gln Gly 1 5 10 15 <210> SEQ ID NO 206
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 206 Ser
Cys Ser Leu Trp Thr Ser Gly Ser Cys Leu Pro His Ser Pro 1 5 10 15
<210> SEQ ID NO 207 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 207 Tyr Cys Leu Gln Leu Pro His Tyr Met Gln Ala Met Cys
Gly Arg 1 5 10 15 <210> SEQ ID NO 208 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 208 Cys Phe Leu Tyr Ser Cys Thr
Asp Val Ser Tyr Trp Asn Asn Thr 1 5 10 15 <210> SEQ ID NO 209
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 209 Pro
Trp Cys Met Gln Arg Gln Asp Tyr Leu Arg Cys Pro Gln Pro 1 5 10 15
<210> SEQ ID NO 210 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 210 Cys Asn Leu Trp Ile Ser Gly Gly Asp Cys Arg Gly Leu
Ala Gly 1 5 10 15 <210> SEQ ID NO 211 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 211 Cys Asn Leu Trp Val Ser Gly
Gly Asp Cys Arg Gly Val Gln Gly 1 5 10 15 <210> SEQ ID NO 212
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 212 Cys
Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Gly Leu Arg Gly 1 5 10 15
<210> SEQ ID NO 213 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 213 Cys Asn Leu Trp Ile Ser Gly Gly Asp Cys Arg Gly Leu
Pro Gly 1 5 10 15 <210> SEQ ID NO 214 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 214 Cys Asn Leu Trp Val Ser Gly
Gly Asp Cys Arg Asp Ala Pro Trp 1 5 10 15 <210> SEQ ID NO 215
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 215 Cys
Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Asp Leu Leu Gly 1 5 10 15
<210> SEQ ID NO 216 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 216 Cys Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Gly Leu
Gln Gly 1 5 10 15 <210> SEQ ID NO 217 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 217 Cys Asn Leu Trp Leu His Gly
Gly Asp Cys Arg Gly Trp Gln Gly 1 5 10 15 <210> SEQ ID NO 218
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 218 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly 1 5 10 15
<210> SEQ ID NO 219 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 219 Cys Thr Thr Trp Phe Cys Gly Gly Asp Cys Gly Val Met
Arg Gly 1 5 10 15 <210> SEQ ID NO 220 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 220 Cys Asn Ile Trp Gly Pro Ser
Val Asp Cys Gly Ala Leu Leu Gly 1 5 10 15 <210> SEQ ID NO 221
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 221 Cys
Asn Ile Trp Val Asn Gly Gly Asp Cys Arg Ser Phe Glu Gly 1 5 10 15
<210> SEQ ID NO 222 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 222 Tyr Cys Leu Asn Leu Pro Arg Tyr Met Gln Asp Met Cys
Trp Ala 1 5 10 15 <210> SEQ ID NO 223 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 223 Tyr Cys Leu Ala Leu Pro His
Tyr Met Gln Ala Asp Cys Ala Arg 1 5 10 15 <210> SEQ ID NO 224
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 224 Cys
Phe Leu Tyr Ser Cys Gly Asp Val Ser Tyr Trp Gly Ser Ala 1 5 10 15
<210> SEQ ID NO 225 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 225 Cys Tyr Leu Tyr Ser Cys Thr Asp Ser Ala Phe Trp Asn
Asn Arg 1 5 10 15 <210> SEQ ID NO 226 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 226 Cys Tyr Leu Tyr Ser Cys Asn
Asp Val Ser Tyr Trp Ser Asn Thr 1 5 10 15 <210> SEQ ID NO 227
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 227 Cys
Phe Leu Tyr Ser Cys Thr Asp Val Ser Tyr Trp 1 5 10 <210> SEQ
ID NO 228 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 228
Cys Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp Asn Ser Ala 1 5 10
15 <210> SEQ ID NO 229 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 229 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ser
Tyr Trp Gly Asp Thr 1 5 10 15 <210> SEQ ID NO 230 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 230 Cys Phe Leu Tyr
Ser Cys Thr Asp Val Ser Tyr Trp Gly Asn Ser 1 5 10 15 <210>
SEQ ID NO 231 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 231 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp Asn
Asn Thr 1 5 10 15 <210> SEQ ID NO 232 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 232 Cys Phe Leu Tyr Ser Cys Gly
Asp Val Ser Tyr Trp Gly Asn Pro Gly 1 5 10 15 Leu Ser <210>
SEQ ID NO 233 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 233 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp Ser
Gly Leu 1 5 10 15 <210> SEQ ID NO 234 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 234 Cys Tyr Leu Tyr Ser Cys Thr
Asp Gly Ser Tyr Trp Asn Ser Thr 1 5 10 15 <210> SEQ ID NO 235
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 235 Cys
Phe Leu Tyr Ser Cys Ser Asp Val Ser Tyr Trp Gly Asn Ile 1 5 10 15
<210> SEQ ID NO 236 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 236 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp 1 5
10 <210> SEQ ID NO 237 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 237 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ser
Tyr Trp Gly Ser Thr 1 5 10 15 <210> SEQ ID NO 238 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 238 Cys Phe Leu Tyr
Ser Cys Thr Asp Val Ala Tyr Trp Gly Asp Thr 1 5 10 15 <210>
SEQ ID NO 239 <211> LENGTH: 20 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 239 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Gly
Trp Val Asp 1 5 10 15 Pro Leu Gln Gly 20 <210> SEQ ID NO 240
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 240 Gly
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Ile Gly 1 5 10
15 Asp Thr Asn Gly 20 <210> SEQ ID NO 241 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 241 Gly Cys Asn Ile Trp Leu Val
Gly Gly Asp Cys Arg Gly Trp Ile Glu 1 5 10 15 Asp Ser Asn Gly 20
<210> SEQ ID NO 242 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 242 Gly Cys Asn Ile Trp Ala Asn Gly Gly Asp Cys Arg Gly
Trp Ile Asp 1 5 10 15 Asn Ile Asp Gly 20 <210> SEQ ID NO 243
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 243 Gly
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Leu Gly 1 5 10
15 Glu Ala Val Gly 20 <210> SEQ ID NO 244 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 244 Gly Cys Asn Ile Trp Leu Val
Gly Gly Asp Cys Arg Gly Trp Leu Glu 1 5 10 15 Glu Ala Val Gly 20
<210> SEQ ID NO 245 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 245 Gly Gly Pro Ala Leu Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Gly Trp Ser Gly 20 <210> SEQ ID NO 246
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 246 Gly
Ala Pro Val Phe Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg 1 5 10
15 Gly Trp Met Gly 20 <210> SEQ ID NO 247 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 247 Gly Gln Gln Gln Trp Cys Asn
Ile Trp Ile Asn Gly Gly Asp Cys Arg 1 5 10 15 Gly Trp Asn Gly 20
<210> SEQ ID NO 248 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 248 Gly Lys Ser Glu Phe Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Gly Trp Ile Gly 20 <210> SEQ ID NO 249
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 249 Gly
Thr Pro Gly Gly Cys Asn Ile Trp Ala Asn Gly Gly Asp Cys Arg 1 5 10
15 Gly Trp Glu Gly 20 <210> SEQ ID NO 250 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 250 Gly Ala Ser Gln Tyr Cys Asn
Leu Trp Ile Asn Gly Gly Asp Cys Arg 1 5 10 15 Gly Trp Arg Gly 20
<210> SEQ ID NO 251 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 251 Gly Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Pro
Trp Val Glu 1 5 10 15 Gly Gly <210> SEQ ID NO 252 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 252 Gly Cys Asn Ile
Trp Ala Val Gly Gly Asp Cys Arg Pro Phe Val Asp 1 5 10 15 Gly Gly
<210> SEQ ID NO 253 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 253 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Ala
Trp Val Asp 1 5 10 15 Thr Gly <210> SEQ ID NO 254 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 254 Gly Cys Asn Ile
Trp Ile Val Gly Gly Asp Cys Arg Pro Phe Ile Asn 1 5 10 15 Asp Gly
<210> SEQ ID NO 255 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 255 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Pro
Val Val Phe 1 5 10 15 Gly Gly <210> SEQ ID NO 256 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 256 Gly Cys Asn Ile
Trp Leu Ser Gly Gly Asp Cys Arg Met Phe Met Asn 1 5 10 15 Glu Gly
<210> SEQ ID NO 257 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 257 Gly Cys Asn Ile Trp Val Asn Gly Gly Asp Cys Arg Ser
Phe Val Tyr 1 5 10 15 Ser Gly <210> SEQ ID NO 258 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 258 Gly Cys Asn Ile
Trp Leu Asn Gly Gly Asp Cys Arg Gly Trp Glu Ala 1 5 10 15 Ser Gly
<210> SEQ ID NO 259 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 259 Gly Cys Asn Ile Trp Ala His Gly Gly Asp Cys Arg Gly
Phe Ile Glu 1 5 10 15 Pro Gly <210> SEQ ID NO 260 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 260 Gly Cys Asn Ile
Trp Leu Asn Gly Gly Asp Cys Arg Thr Phe Val Ala 1 5 10 15 Ser Gly
<210> SEQ ID NO 261 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 261 Gly Cys Asn Ile Trp Ala His Gly Gly Asp Cys Arg Gly
Phe Ile Glu 1 5 10 15 Pro Gly <210> SEQ ID NO 262 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 262 Gly Phe Leu Glu
Asn Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg 1 5 10 15 Thr Gly
<210> SEQ ID NO 263 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 263 Gly Ile Tyr Glu Asn Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Met Gly <210> SEQ ID NO 264 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 264 Gly Ile Pro Asp
Asn Cys Asn Ile Trp Ile Asn Gly Gly Asp Cys Arg 1 5 10 15 Tyr Gly
<210> SEQ ID NO 265 <211> LENGTH: 21 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 265 Gln Gly Gln Ser Gly Gln Tyr Gly Ser Cys Ser Trp Asn
Tyr Val His 1 5 10 15 Ile Phe Met Asp Cys 20 <210> SEQ ID NO
266 <211> LENGTH: 21 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 266
Gln Gly Gln Ser Gly Gln Gly Asp Phe Asp Ile Pro Phe Pro Ala His 1 5
10 15 Trp Val Pro Ile Thr 20 <210> SEQ ID NO 267 <211>
LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 267 Gln Gly Gln Ser
Gly Gln Met Gly Val Pro Ala Gly Cys Val Trp Asn 1 5 10 15 Tyr Ala
His Ile Phe Met Asp Cys 20 <210> SEQ ID NO 268 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 268 Tyr Arg Ser Cys
Asn Trp Asn Tyr Val Ser Ile Phe Leu Asp Cys 1 5 10 15 <210>
SEQ ID NO 269 <211> LENGTH: 16 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 269 Pro Gly Ala Phe Asp Ile Pro Phe Pro Ala His Trp Val
Pro Asn Thr 1 5 10 15 <210> SEQ ID NO 270 <211> LENGTH:
15 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 270 Glu Ser Ser Cys Val Trp Asn
Tyr Val His Ile Tyr Met Asp Cys 1 5 10 15 <210> SEQ ID NO 271
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 271 Tyr
Pro Gly Cys Lys Trp Asn Tyr Asp Arg Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 272 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 272 Tyr Arg Thr Cys Ser Trp Asn Tyr Val Gly Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 273 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 273 Tyr Gly Ser Cys Ser Trp Asn
Tyr Val His Ile Phe Met Asp Cys 1 5 10 15 <210> SEQ ID NO 274
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 274 Tyr
Gly Ser Cys Ser Trp Asn Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 275 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 275 Tyr Gly Ser Cys Asn Trp Asn Tyr Val His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 276 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 276 Tyr Thr Ser Cys Asn Trp Asn
Tyr Val His Ile Phe Met Asp Cys 1 5 10 15 <210> SEQ ID NO 277
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 277 Tyr
Pro Gly Cys Lys Trp Asn Tyr Asp Arg Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 278 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 278 Trp Arg Ser Cys Asn Trp Asn Tyr Ala His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 279 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 279 Trp Ser Asn Cys His Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 280
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 280 Asp
Arg Ser Cys Thr Trp Asn Tyr Val Arg Ile Ser Tyr Asp Cys 1 5 10 15
<210> SEQ ID NO 281 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 281 Ser Gly Ser Cys Lys Trp Asp Tyr Val His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 282 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 282 Ser Arg Ser Cys Ile Trp Asn
Tyr Ala His Ile His Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 283
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 283 Ser
Met Ser Cys Tyr Trp Gln Tyr Glu Arg Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 284 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 284 Tyr Arg Ser Cys Asn Trp Asn Tyr Val Ser Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 285 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 285 Ser Gly Ser Cys Lys Trp Asp
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 286
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 286 Tyr
Lys Ser Cys His Trp Asp Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 287 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 287 Tyr Gly Ser Cys Thr Trp Asn Tyr Val His Ile Phe Met
Glu Cys 1 5 10 15 <210> SEQ ID NO 288 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 288 Phe Ser Ser Cys Asn Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 289
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 289 Trp
Arg Ser Cys Asn Trp Asn Tyr Ala His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 290 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 290 Tyr Gly Ser Cys Gln Trp Asn Tyr Val His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 291 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 291 Tyr Arg Ser Cys Asn Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 292
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 292 Asn
Met Ser Cys His Trp Asp Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 293 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 293 Phe Gly Pro Cys Thr Trp Asn Tyr Ala Arg Ile Ser Trp
Asp Cys 1 5 10 15 <210> SEQ ID NO 294 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (1)..(2) <223> OTHER INFORMATION: X is
any amino acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: X is any amino acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: X is any amino acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: X is any amino acid <400>
SEQUENCE: 294 Xaa Xaa Ser Cys Xaa Trp Xaa Tyr Val His Ile Phe Xaa
Asp Cys 1 5 10 15 <210> SEQ ID NO 295 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 295 Met Gly Val Pro Ala Gly Cys
Val Trp Asn Tyr Ala His Ile Phe Met 1 5 10 15 Asp Cys <210>
SEQ ID NO 296 <211> LENGTH: 18 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 296 Arg Asp Thr Gly Gly Gln Cys Arg Trp Asp Tyr Val His
Ile Phe Met 1 5 10 15 Asp Cys <210> SEQ ID NO 297 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 297 Ala Gly Val Pro
Ala Gly Cys Thr Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 298 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 298 Val Gly Val Pro Asn Gly Cys Val Trp Asn Tyr Ala His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 299 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 299 Asp Gly Gly Pro
Ala Gly Cys Ser Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 300 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 300 Ala Val Gly Pro Ala Gly Cys Trp Trp Asn Tyr Val His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 301 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 301 Cys Thr Trp Asn
Tyr Val His Ile Phe Met Asp Cys Gly Glu Gly Glu 1 5 10 15 Gly Pro
<210> SEQ ID NO 302 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 302 Gly Gly Val Pro Glu Gly Cys Thr Trp Asn Tyr Ala His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 303 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 303 Ala Glu Val Pro
Ala Gly Cys Trp Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 304 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 304 Ala Gly Val Pro Ala Gly Cys Thr Trp Asn Tyr Val His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 305 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 305 Ser Gly Ala Ser
Gly Gly Cys Lys Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Asp Cys
<210> SEQ ID NO 306 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 306 Thr Pro Gly Cys Arg Trp Asn Tyr Val His Ile Phe Met
Glu Cys Glu 1 5 10 15 Ala Leu <210> SEQ ID NO 307 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 307 Val Gly Val Pro
Asn Gly Cys Val Trp Asn Tyr Ala His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 308 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 308 Pro Gly Ala Phe Asp Ile Pro Phe Pro Ala His Trp Val
Pro Asn Thr 1 5 10 15 <210> SEQ ID NO 309 <211> LENGTH:
16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 309 Arg Gly Ala Cys Asp Ile Pro
Phe Pro Ala His Trp Ile Pro Asn Thr 1 5 10 15 <210> SEQ ID NO
310 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 310
Gln Gly Asp Phe Asp Ile Pro Phe Pro Ala His Trp Val Pro Ile Thr 1 5
10 15 <210> SEQ ID NO 311 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: X is any amino
acid <400> SEQUENCE: 311 Xaa Gly Ala Phe Asp Ile Pro Phe Pro
Ala His Trp Val Pro Asn Thr 1 5 10 15 <210> SEQ ID NO 312
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 312 Arg
Gly Asp Gly Asn Asp Ser Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Arg Thr <210> SEQ ID NO 313 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 313 Ser Gly Val Gly Arg Asp Arg
Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10 15 Pro Arg Thr
<210> SEQ ID NO 314 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 314 Trp Ala Gly Gly Asn Asp Cys Asp Ile Pro Phe Pro Ala
His Trp Ile 1 5 10 15 Pro Asn Thr <210> SEQ ID NO 315
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 315 Trp
Gly Asp Gly Met Asp Val Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Val Thr <210> SEQ ID NO 316 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 316 Ala Gly Ser Gly Asn Asp Ser
Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10 15 Pro Arg Thr
<210> SEQ ID NO 317 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 317 Glu Ser Arg Ser Gly Tyr Ala Asp Ile Pro Phe Pro Ala
His Trp Val 1 5 10 15 Pro Arg Thr <210> SEQ ID NO 318
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 318 Arg
Glu Cys Gly Arg Cys Gly Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Arg Thr <210> SEQ ID NO 319 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 319 Pro Arg Phe Lys Ile Ile Gly
Gly 1 5 <210> SEQ ID NO 320 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 320 Pro Arg Phe Arg Ile Ile Gly Gly 1 5
<210> SEQ ID NO 321 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 321 Ser Ser Arg His Arg Arg Ala Leu Asp 1 5 <210>
SEQ ID NO 322 <211> LENGTH: 14 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 322 Arg Lys Ser Ser Ile Ile Ile Arg Met Arg Asp Val Val
Leu 1 5 10 <210> SEQ ID NO 323 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 323 Ser Ser Ser Phe Asp Lys Gly
Lys Tyr Lys Lys Gly Asp Asp Ala 1 5 10 15 <210> SEQ ID NO 324
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 324 Ser
Ser Ser Phe Asp Lys Gly Lys Tyr Lys Arg Gly Asp Asp Ala 1 5 10 15
<210> SEQ ID NO 325 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 325 Ile Glu Gly Arg 1 <210> SEQ ID NO 326
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 326 Ile
Asp Gly Arg 1 <210> SEQ ID NO 327 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 327 Gly Gly Ser Ile Asp Gly Arg 1
5 <210> SEQ ID NO 328 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 328 Pro Leu Gly Leu Trp Ala 1 5 <210> SEQ ID NO 329
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 329 Gly
Pro Gln Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 330
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 330 Gly
Pro Gln Gly Leu Leu Gly Ala 1 5 <210> SEQ ID NO 331
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 331 Gly
Ile Ala Gly Gln 1 5 <210> SEQ ID NO 332 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 332 Gly Pro Leu Gly Ile Ala Gly
Ile 1 5 <210> SEQ ID NO 333 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 333 Gly Pro Glu Gly Leu Arg Val Gly 1 5
<210> SEQ ID NO 334 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 334 Tyr Gly Ala Gly Leu Gly Val Val 1 5 <210> SEQ
ID NO 335 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 335
Ala Gly Leu Gly Val Val Glu Arg 1 5 <210> SEQ ID NO 336
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 336 Ala
Gly Leu Gly Ile Ser Ser Thr 1 5 <210> SEQ ID NO 337
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 337 Glu
Pro Gln Ala Leu Ala Met Ser 1 5 <210> SEQ ID NO 338
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 338 Gln
Ala Leu Ala Met Ser Ala Ile 1 5 <210> SEQ ID NO 339
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 339 Ala
Ala Tyr His Leu Val Ser Gln 1 5 <210> SEQ ID NO 340
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 340 Met
Asp Ala Phe Leu Glu Ser Ser 1 5 <210> SEQ ID NO 341
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 341 Glu
Ser Leu Pro Val Val Ala Val 1 5 <210> SEQ ID NO 342
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 342 Ser
Ala Pro Ala Val Glu Ser Glu 1 5 <210> SEQ ID NO 343
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 343 Asp
Val Ala Gln Phe Val Leu Thr 1 5 <210> SEQ ID NO 344
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 344 Val
Ala Gln Phe Val Leu Thr Glu 1 5 <210> SEQ ID NO 345
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 345 Ala
Gln Phe Val Leu Thr Glu Gly 1 5 <210> SEQ ID NO 346
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 346 Pro
Val Gln Pro Ile Gly Pro Gln 1 5 <210> SEQ ID NO 347
<211> LENGTH: 273 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 347 Gly
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Ser Gly 1 5 10
15 Gly Gly Gly Ser Gly Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
20 25 30 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
Arg Ala 35 40 45 Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
Gln Gln Lys Pro 50 55 60 Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly
Ala Ser Ser Arg Ala Thr 65 70 75 80 Gly Ile Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Thr Ile Ser Arg Leu
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 100 105 110 Gln Gln Tyr Gly
Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val 115 120 125 Glu Ile
Lys Arg Ser Gly Gly Ser Thr Ile Thr Ser Tyr Asn Val Tyr 130 135 140
Tyr Thr Lys Leu Ser Ser Ser Gly Thr Gln Val Gln Leu Val Gln Thr 145
150 155 160 Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser
Cys Ala 165 170 175 Ala Ser Gly Ser Thr Phe Ser Ser Tyr Ala Met Ser
Trp Val Arg Gln 180 185 190 Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
Ala Ile Ser Gly Ser Gly 195 200 205 Gly Ser Thr Tyr Tyr Ala Asp Ser
Val Lys Gly Arg Phe Thr Ile Ser 210 215 220 Arg Asp Asn Ser Lys Asn
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 225 230 235 240 Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Ala Thr Asn Ser Leu Tyr Trp 245 250 255 Tyr
Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 260 265
270 Ser <210> SEQ ID NO 348 <400> SEQUENCE: 348 000
<210> SEQ ID NO 349 <211> LENGTH: 264 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 349 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly
Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu
Gln Gln Ser Gly Ala 20 25 30 Glu Leu Ala Arg Pro Gly Ala Ser Val
Lys Met Ser Cys Lys Ala Ser 35 40 45 Gly Tyr Thr Phe Thr Arg Tyr
Thr Met His Trp Val Lys Gln Arg Pro 50 55 60 Gly Gln Gly Leu Glu
Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr 65 70 75 80 Thr Asn Tyr
Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp 85 90 95 Lys
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu 100 105
110 Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys
115 120 125 Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser
Gly Gly 130 135 140 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
Ser Gln Ile Val 145 150 155 160 Leu Thr Gln Ser Pro Ala Ile Met Ser
Ala Ser Pro Gly Glu Lys Val 165 170 175 Thr Met Thr Cys Ser Ala Ser
Ser Ser Val Ser Tyr Met Asn Trp Tyr 180 185 190 Gln Gln Lys Ser Gly
Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser 195 200 205 Lys Leu Ala
Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly 210 215 220 Thr
Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala 225 230
235 240 Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly
Ser 245 250 255 Gly Thr Lys Leu Glu Ile Asn Arg 260 <210> SEQ
ID NO 350 <211> LENGTH: 6 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 350
Gly Gly Ser Gly Gly Ser 1 5 <210> SEQ ID NO 351 <211>
LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 351 Ala Gln Asn Leu
Leu Gly Met Val 1 5 <210> SEQ ID NO 352 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 352 Ser Thr Phe Pro Phe Gly Met
Phe 1 5 <210> SEQ ID NO 353 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 353 Pro Val Gly Tyr Thr Ser Ser Leu 1 5
<210> SEQ ID NO 354 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 354 Asp Trp Leu Tyr Trp Pro Gly Ile 1 5 <210> SEQ
ID NO 355 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 355
Met Ile Ala Pro Val Ala Tyr Arg 1 5 <210> SEQ ID NO 356
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 356 Arg
Pro Ser Pro Met Trp Ala Tyr 1 5 <210> SEQ ID NO 357
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 357 Trp
Ala Thr Pro Arg Pro Met Arg 1 5 <210> SEQ ID NO 358
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 358 Phe
Arg Leu Leu Asp Trp Gln Trp 1 5 <210> SEQ ID NO 359
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 359 Leu
Lys Ala Ala Pro Arg Trp Ala 1 5 <210> SEQ ID NO 360
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 360 Gly
Pro Ser His Leu Val Leu Thr 1 5 <210> SEQ ID NO 361
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 361 Leu
Pro Gly Gly Leu Ser Pro Trp 1 5 <210> SEQ ID NO 362
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 362 Met
Gly Leu Phe Ser Glu Ala Gly 1 5 <210> SEQ ID NO 363
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 363 Ser
Pro Leu Pro Leu Arg Val Pro 1 5 <210> SEQ ID NO 364
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 364 Arg
Met His Leu Arg Ser Leu Gly 1 5 <210> SEQ ID NO 365
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 365 Leu
Ala Ala Pro Leu Gly Leu Leu 1 5 <210> SEQ ID NO 366
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 366 Ala
Val Gly Leu Leu Ala Pro Pro 1 5 <210> SEQ ID NO 367
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 367 Leu
Leu Ala Pro Ser His Arg Ala 1 5 <210> SEQ ID NO 368
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 368 Pro
Ala Gly Leu Trp Leu Asp Pro 1 5 <210> SEQ ID NO 369
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 369 Ile
Ser Ser Gly Leu Ser Ser 1 5 <210> SEQ ID NO 370 <211>
LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 370 Thr Gly Arg Gly
Pro Ser Trp Val 1 5 <210> SEQ ID NO 371 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 371 Ser Ala Arg Gly Pro Ser Arg
Trp 1 5 <210> SEQ ID NO 372 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 372 Thr Ala Arg Gly Pro Ser Phe Lys 1 5
<210> SEQ ID NO 373 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 373 Gly Gly Trp His Thr Gly Arg Asn 1 5 <210> SEQ
ID NO 374 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 374
His Thr Gly Arg Ser Gly Ala Leu 1 5 <210> SEQ ID NO 375
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 375 Pro
Leu Thr Gly Arg Ser Gly Gly 1 5 <210> SEQ ID NO 376
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 376 Ala
Ala Arg Gly Pro Ala Ile His 1 5 <210> SEQ ID NO 377
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 377 Arg
Gly Pro Ala Phe Asn Pro Met 1 5 <210> SEQ ID NO 378
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 378 Ser
Ser Arg Gly Pro Ala Tyr Leu 1 5 <210> SEQ ID NO 379
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 379 Arg
Gly Pro Ala Thr Pro Ile Met 1 5 <210> SEQ ID NO 380
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 380 Arg
Gly Pro Ala 1 <210> SEQ ID NO 381 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 381 Gly Ser Gly Gly Ser 1 5
<210> SEQ ID NO 382 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 382 Gly Gly Gly Ser 1 <210> SEQ ID NO 383
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 383 Gly
Gly Ser Gly 1 <210> SEQ ID NO 384 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 384 Gly Gly Ser Gly Gly 1 5
<210> SEQ ID NO 385 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 385 Gly Ser Gly Ser Gly 1 5 <210> SEQ ID NO 386
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 386 Gly
Ser Gly Gly Gly 1 5 <210> SEQ ID NO 387 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 387 Gly Gly Gly Ser Gly 1 5
<210> SEQ ID NO 388 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 388 Gly Ser Ser Ser Gly 1 5 <210> SEQ ID NO 389
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 389 Gly
Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 1 5 10 <210>
SEQ ID NO 390 <211> LENGTH: 11 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 390 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 1 5 10
<210> SEQ ID NO 391 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 391 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 1 5
10 <210> SEQ ID NO 392 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 392 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly
Gly Ser Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 393
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 393 Gly
Ser Ser Gly Gly Ser Gly Gly Ser Gly 1 5 10 <210> SEQ ID NO
394 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 394
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Ser 1 5 10 <210> SEQ
ID NO 395 <211> LENGTH: 4 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 395
Gly Gly Gly Ser 1 <210> SEQ ID NO 396 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 396 Gly Ser Ser Gly Thr 1 5
<210> SEQ ID NO 397 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 397 Gly Ser Ser Gly 1 <210> SEQ ID NO 398
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 398 Ser
Tyr Ala Met Ser 1 5 <210> SEQ ID NO 399 <211> LENGTH:
17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 399 Ser Ile Asp Pro Glu Gly Arg
Gln Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 400 <211> LENGTH: 10 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 400
Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr 1 5 10 <210> SEQ ID
NO 401 <211> LENGTH: 9 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 401
Arg Ala Ser Gln Ser Ile Ser Ser Tyr 1 5 <210> SEQ ID NO 402
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 402 Ala
Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO 403 <211>
LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 403 Gln Gln Thr Val
Val Ala Pro Pro Leu 1 5 <210> SEQ ID NO 404 <211>
LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 404 Asn Tyr Gly Val
His 1 5 <210> SEQ ID NO 405 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 405 Val Ile Trp Ser Gly Gly Asn
Thr Asp Tyr Asn Thr Pro Phe Thr Ser 1 5 10 15 <210> SEQ ID NO
406 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 406
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> SEQ
ID NO 407 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 407
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 1 5 10 <210> SEQ
ID NO 408 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 408
Lys Tyr Ala Ser Glu Ser Ile Ser 1 5 <210> SEQ ID NO 409
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 409 Gln
Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> SEQ ID NO 410
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 410 Gln
Gly Gln Ser Gly Gln 1 5 <210> SEQ ID NO 411 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 411 Val His Met Pro
Leu Gly Phe Leu Gly Pro 1 5 10 <210> SEQ ID NO 412
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 412 Leu
Ser Gly Arg Ser Gly Asn His 1 5 <210> SEQ ID NO 413
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 413 Thr
Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly 1 5 10 <210> SEQ
ID NO 414 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 414
Thr Ser Gly Arg Ser Ala Asn Pro 1 5 <210> SEQ ID NO 415
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 415 Val
Ala Gly Arg Ser Met Arg Pro 1 5 <210> SEQ ID NO 416
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 416 Gly
Gln Ser Gly Gln 1 5 <210> SEQ ID NO 417 <211> LENGTH: 4
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 417 Gln Ser Gly Gln 1 <210>
SEQ ID NO 418 <211> LENGTH: 3 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 418 Ser Gly Gln 1 <210> SEQ ID NO 419 <211>
LENGTH: 756 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 419 tgcaatattt
ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc 60
tctatctctt ccggactgct gtccggcaga tccgacaatc acggcggagg ctctgacatc
120 cagatgaccc agtctccatc ctccctgtct gcatctgtag gagacagagt
caccatcact 180 tgccgggcaa gtcagagcat tagcagctat ttaaattggt
atcagcagaa accagggaaa 240 gcccctaagc tcctgatcta tgcggcatcc
agtttgcaaa gtggggtccc atcaaggttc 300 agtggcagtg gatctgggac
agatttcact ctcaccatca gcagtctgca acctgaagat 360 tttgcaactt
actactgtca acagacggtt gtggcgcctc cgttattcgg ccaagggacc 420
aaggtggaaa tcaaacgtac ggtggctgca ccatctgtct tcatcttccc gccatctgat
480 gagcagttga aatctggaac tgcctctgtt gtgtgcctgc tgaataactt
ctatcccaga 540 gaggccaaag tacagtggaa ggtggataac gccctccaat
cgggtaactc ccaggagagt 600 gtcacagagc aggacagcaa ggacagcacc
tacagcctca gcagcaccct gacgctgagc 660 aaagcagact acgagaaaca
caaagtctac gcctgcgaag tcacccatca gggcctgagc 720 tcgcccgtca
caaagagctt caacagggga gagtgt 756 <210> SEQ ID NO 420
<211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 420 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp
20 25 30 Asn His Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val
Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 130 135 140
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145
150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230 235 240 Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 <210> SEQ ID NO
421 <211> LENGTH: 783 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 421
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tctatctctt ctggcctgct gtctagcggc ggctccggcg gatctctgtc
tggcagatct 120 gacaaccacg gcggaggctc cgacatccag atgacccagt
ctccatcctc cctgtctgca 180 tctgtaggag acagagtcac catcacttgc
cgggcaagtc agagcattag cagctattta 240 aattggtatc agcagaaacc
agggaaagcc cctaagctcc tgatctatgc ggcatccagt 300 ttgcaaagtg
gggtcccatc aaggttcagt ggcagtggat ctgggacaga tttcactctc 360
accatcagca gtctgcaacc tgaagatttt gcaacttact actgtcaaca gacggttgtg
420 gcgcctccgt tattcggcca agggaccaag gtggaaatca aacgtacggt
ggctgcacca 480 tctgtcttca tcttcccgcc atctgatgag cagttgaaat
ctggaactgc ctctgttgtg 540 tgcctgctga ataacttcta tcccagagag
gccaaagtac agtggaaggt ggataacgcc 600 ctccaatcgg gtaactccca
ggagagtgtc acagagcagg acagcaagga cagcacctac 660 agcctcagca
gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 720
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag
780 tgt 783 <210> SEQ ID NO 422 <211> LENGTH: 261
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 422 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser 20 25 30 Gly Gly Ser
Leu Ser Gly Arg Ser Asp Asn His Gly Gly Gly Ser Asp 35 40 45 Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 50 55
60 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu
65 70 75 80 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile Tyr 85 90 95 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Gln Pro Glu 115 120 125 Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Thr Val Val Ala Pro Pro Leu 130 135 140 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 423 <211> LENGTH: 780 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 423 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggagga 60 tctgctgtgg gactgctggc tcctcctggc
ggcacatcta cctctggcag atccgccaac 120 cctcggggcg gaggatctga
catccagatg acccagtctc catcctccct gtctgcatct 180 gtaggagaca
gagtcaccat cacttgccgg gcaagtcaga gcattagcag ctatttaaat 240
tggtatcagc agaaaccagg gaaagcccct aagctcctga tctatgcggc atccagtttg
300 caaagtgggg tcccatcaag gttcagtggc agtggatctg ggacagattt
cactctcacc 360 atcagcagtc tgcaacctga agattttgca acttactact
gtcaacagac ggttgtggcg 420 cctccgttat tcggccaagg gaccaaggtg
gaaatcaaac gtacggtggc tgcaccatct 480 gtcttcatct tcccgccatc
tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 540 ctgctgaata
acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 600
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc
660 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt
ctacgcctgc 720 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga
gcttcaacag gggagagtgt 780 <210> SEQ ID NO 424 <211>
LENGTH: 260 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 424 Cys Asn Ile Trp
Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser
Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Thr 20 25 30
Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp Ile 35
40 45 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg 50 55 60 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn 65 70 75 80 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala 85 90 95 Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp 115 120 125 Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe 130 135 140 Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165
170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys
260 <210> SEQ ID NO 425 <211> LENGTH: 780 <212>
TYPE: DNA <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 425 tgcaatattt ggctcgtagg tggtgattgc
aggggctggc aggggggctc gagcggcggc 60 tccacatcta cctctggcag
atccgccaac cccagaggtg gcggagctgt gggactgctg 120 gctccaccag
gcggatctga catccagatg acccagtctc catcctccct gtctgcatct 180
gtaggagaca gagtcaccat cacttgccgg gcaagtcaga gcattagcag ctatttaaat
240 tggtatcagc agaaaccagg gaaagcccct aagctcctga tctatgcggc
atccagtttg 300 caaagtgggg tcccatcaag gttcagtggc agtggatctg
ggacagattt cactctcacc 360 atcagcagtc tgcaacctga agattttgca
acttactact gtcaacagac ggttgtggcg 420 cctccgttat tcggccaagg
gaccaaggtg gaaatcaaac gtacggtggc tgcaccatct 480 gtcttcatct
tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 540
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc
600 caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag
cacctacagc 660 ctcagcagca ccctgacgct gagcaaagca gactacgaga
aacacaaagt ctacgcctgc 720 gaagtcaccc atcagggcct gagctcgccc
gtcacaaaga gcttcaacag gggagagtgt 780 <210> SEQ ID NO 426
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 426 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg
20 25 30 Gly Gly Gly Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Ser
Asp Ile 35 40 45 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
Val Gly Asp Arg 50 55 60 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser
Ile Ser Ser Tyr Leu Asn 65 70 75 80 Trp Tyr Gln Gln Lys Pro Gly Lys
Ala Pro Lys Leu Leu Ile Tyr Ala 85 90 95 Ala Ser Ser Leu Gln Ser
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 115 120 125 Phe Ala
Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe 130 135 140
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 427 <211> LENGTH: 786
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 427 tgcaatattt ggctcgtagg
tggtgattgc aggggctggc aggggggctc gagcggcggc 60 tctgtgcata
tgcccctggg ctttctgggc cctggcggca catctacctc tggcagatcc 120
gccaaccctc ggggcggagg atctgacatc cagatgaccc agtctccatc ctccctgtct
180 gcatctgtag gagacagagt caccatcact tgccgggcaa gtcagagcat
tagcagctat 240 ttaaattggt atcagcagaa accagggaaa gcccctaagc
tcctgatcta tgcggcatcc 300 agtttgcaaa gtggggtccc atcaaggttc
agtggcagtg gatctgggac agatttcact 360 ctcaccatca gcagtctgca
acctgaagat tttgcaactt actactgtca acagacggtt 420 gtggcgcctc
cgttattcgg ccaagggacc aaggtggaaa tcaaacgtac ggtggctgca 480
ccatctgtct tcatcttccc gccatctgat gagcagttga aatctggaac tgcctctgtt
540 gtgtgcctgc tgaataactt ctatcccaga gaggccaaag tacagtggaa
ggtggataac 600 gccctccaat cgggtaactc ccaggagagt gtcacagagc
aggacagcaa ggacagcacc 660 tacagcctca gcagcaccct gacgctgagc
aaagcagact acgagaaaca caaagtctac 720 gcctgcgaag tcacccatca
gggcctgagc tcgcccgtca caaagagctt caacagggga 780 gagtgt 786
<210> SEQ ID NO 428 <211> LENGTH: 262 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 428 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Val His Met Pro Leu Gly
Phe Leu Gly Pro Gly 20 25 30 Gly Thr Ser Thr Ser Gly Arg Ser Ala
Asn Pro Arg Gly Gly Gly Ser 35 40 45 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 50 55 60 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 65 70 75 80 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 85 90 95 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 100 105
110 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
115 120 125 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala
Pro Pro 130 135 140 Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
Thr Val Ala Ala 145 150 155 160 Pro Ser Val Phe Ile Phe Pro Pro Ser
Asp Glu Gln Leu Lys Ser Gly 165 170 175 Thr Ala Ser Val Val Cys Leu
Leu Asn Asn Phe Tyr Pro Arg Glu Ala 180 185 190 Lys Val Gln Trp Lys
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 195 200 205 Glu Ser Val
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 210 215 220 Ser
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 225 230
235 240 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
Ser 245 250 255 Phe Asn Arg Gly Glu Cys 260 <210> SEQ ID NO
429 <211> LENGTH: 786 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 429
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tccacatcta cctctggcag atccgccaac cccagaggcg gcggagtgca
tatgcctctg 120 ggctttctgg gacctggcgg ctctgacatc cagatgaccc
agtctccatc ctccctgtct 180 gcatctgtag gagacagagt caccatcact
tgccgggcaa gtcagagcat tagcagctat 240 ttaaattggt atcagcagaa
accagggaaa gcccctaagc tcctgatcta tgcggcatcc 300 agtttgcaaa
gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 360
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagacggtt
420 gtggcgcctc cgttattcgg ccaagggacc aaggtggaaa tcaaacgtac
ggtggctgca 480 ccatctgtct tcatcttccc gccatctgat gagcagttga
aatctggaac tgcctctgtt 540 gtgtgcctgc tgaataactt ctatcccaga
gaggccaaag tacagtggaa ggtggataac 600 gccctccaat cgggtaactc
ccaggagagt gtcacagagc aggacagcaa ggacagcacc 660 tacagcctca
gcagcaccct gacgctgagc aaagcagact acgagaaaca caaagtctac 720
gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt caacagggga
780 gagtgt 786 <210> SEQ ID NO 430 <211> LENGTH: 262
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 430 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg 20 25 30 Gly Gly Gly
Val His Met Pro Leu Gly Phe Leu Gly Pro Gly Gly Ser 35 40 45 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 50 55
60 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
65 70 75 80 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 85 90 95 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 115 120 125 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Thr Val Val Ala Pro Pro 130 135 140 Leu Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 145 150 155 160 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 165 170 175 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 180 185
190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
195 200 205 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 225 230 235 240 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 431 <211> LENGTH: 768 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 431 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggagga 60 tctgctgtgg gactgctggc tcctcctggt
ggcctgtctg gcagatctga taaccacggc 120 ggctccgaca tccagatgac
ccagtctcca tcctccctgt ctgcatctgt aggagacaga 180 gtcaccatca
cttgccgggc aagtcagagc attagcagct atttaaattg gtatcagcag 240
aaaccaggga aagcccctaa gctcctgatc tatgcggcat ccagtttgca aagtggggtc
300 ccatcaaggt tcagtggcag tggatctggg acagatttca ctctcaccat
cagcagtctg 360 caacctgaag attttgcaac ttactactgt caacagacgg
ttgtggcgcc tccgttattc 420 ggccaaggga ccaaggtgga aatcaaacgt
acggtggctg caccatctgt cttcatcttc 480 ccgccatctg atgagcagtt
gaaatctgga actgcctctg ttgtgtgcct gctgaataac 540 ttctatccca
gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 600
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc
660 ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga
agtcacccat 720 cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt
768 <210> SEQ ID NO 432 <211> LENGTH: 256 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 432 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys
Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Asn
His Gly Gly Ser Asp Ile Gln Met Thr Gln 35 40 45 Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr 50 55 60 Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln 65 70 75 80
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu 85
90 95 Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp 100 105 110 Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
Ala Thr Tyr 115 120 125 Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu
Phe Gly Gln Gly Thr 130 135 140 Lys Val Glu Ile Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe 145 150 155 160 Pro Pro Ser Asp Glu Gln
Leu Lys Ser Gly Thr Ala Ser Val Val Cys 165 170 175 Leu Leu Asn Asn
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 180 185 190 Asp Asn
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 195 200 205
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser 210
215 220 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His 225 230 235 240 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 245 250 255 <210> SEQ ID NO 433 <211>
LENGTH: 771 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 433 tgcaatattt
ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggaggc 60
tctggcctgt ctggcagatc cgataaccat ggcggcgctg tgggactgct ggctcctcct
120 ggtggatctg acatccagat gacccagtct ccatcctccc tgtctgcatc
tgtaggagac 180 agagtcacca tcacttgccg ggcaagtcag agcattagca
gctatttaaa ttggtatcag 240 cagaaaccag ggaaagcccc taagctcctg
atctatgcgg catccagttt gcaaagtggg 300 gtcccatcaa ggttcagtgg
cagtggatct gggacagatt tcactctcac catcagcagt 360 ctgcaacctg
aagattttgc aacttactac tgtcaacaga cggttgtggc gcctccgtta 420
ttcggccaag ggaccaaggt ggaaatcaaa cgtacggtgg ctgcaccatc tgtcttcatc
480 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg
cctgctgaat 540 aacttctatc ccagagaggc caaagtacag tggaaggtgg
ataacgccct ccaatcgggt 600 aactcccagg agagtgtcac agagcaggac
agcaaggaca gcacctacag cctcagcagc 660 accctgacgc tgagcaaagc
agactacgag aaacacaaag tctacgcctg cgaagtcacc 720 catcagggcc
tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 771 <210> SEQ
ID NO 434 <211> LENGTH: 257 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 434
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly
Gly 20 25 30 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Ser Asp Ile
Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135
140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255
Cys <210> SEQ ID NO 435 <211> LENGTH: 774 <212>
TYPE: DNA <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 435 tgcaatattt ggctcgtagg tggtgattgc
aggggctggc aggggggctc gagcggcggc 60 tctgtgcata tgcccctggg
ctttctggga cctggcggcc tgtctggcag atccgataat 120 cacggcggct
ccgacatcca gatgacccag tctccatcct ccctgtctgc atctgtagga 180
gacagagtca ccatcacttg ccgggcaagt cagagcatta gcagctattt aaattggtat
240 cagcagaaac cagggaaagc ccctaagctc ctgatctatg cggcatccag
tttgcaaagt 300 ggggtcccat caaggttcag tggcagtgga tctgggacag
atttcactct caccatcagc 360 agtctgcaac ctgaagattt tgcaacttac
tactgtcaac agacggttgt ggcgcctccg 420 ttattcggcc aagggaccaa
ggtggaaatc aaacgtacgg tggctgcacc atctgtcttc 480 atcttcccgc
catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 540
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg
600 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta
cagcctcagc 660 agcaccctga cgctgagcaa agcagactac gagaaacaca
aagtctacgc ctgcgaagtc 720 acccatcagg gcctgagctc gcccgtcaca
aagagcttca acaggggaga gtgt 774 <210> SEQ ID NO 436
<211> LENGTH: 258 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 436 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Val His Met Pro Leu Gly Phe Leu Gly Pro Gly
20 25 30 Gly Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ser Asp Ile
Gln Met 35 40 45 Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr 50 55 60 Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu Asn Trp Tyr 65 70 75 80 Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr Ala Ala Ser 85 90 95 Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 100 105 110 Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala 115 120 125 Thr Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln 130 135 140
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe 145
150 155 160 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
Ser Val 165 170 175 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys Val Gln Trp 180 185 190 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu Ser Val Thr 195 200 205 Glu Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser Thr Leu Thr 210 215 220 Leu Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala Cys Glu Val 225 230 235 240 Thr His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 245 250 255 Glu
Cys <210> SEQ ID NO 437 <211> LENGTH: 265 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 437 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp
Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly Gly Ser Ser
Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser Asp Asn His Gly Gly
Val His Met Pro Leu Gly Phe Leu Gly Pro 35 40 45 Gly Gly Ser Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala 50 55 60 Ser Val
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile 65 70 75 80
Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 85
90 95 Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser 115 120 125 Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Thr Val Val 130 135 140 Ala Pro Pro Leu Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr 145 150 155 160 Val Ala Ala Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185 190 Arg Glu
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 195 200 205
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210
215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly Glu Cys 260
265 <210> SEQ ID NO 438 <211> LENGTH: 777 <212>
TYPE: DNA <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 438 tgcaatattt ggctcgtagg tggtgattgc
aggggctggc aggggggctc gagcggaggc 60 tctggcctgt ctggcagatc
tgataaccac ggcggcgtgc acatgcccct gggctttctg 120 ggacctggcg
gatctgacat ccagatgacc cagtctccat cctccctgtc tgcatctgta 180
ggagacagag tcaccatcac ttgccgggca agtcagagca ttagcagcta tttaaattgg
240 tatcagcaga aaccagggaa agcccctaag ctcctgatct atgcggcatc
cagtttgcaa 300 agtggggtcc catcaaggtt cagtggcagt ggatctggga
cagatttcac tctcaccatc 360 agcagtctgc aacctgaaga ttttgcaact
tactactgtc aacagacggt tgtggcgcct 420 ccgttattcg gccaagggac
caaggtggaa atcaaacgta cggtggctgc accatctgtc 480 ttcatcttcc
cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 540
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa
600 tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac
ctacagcctc 660 agcagcaccc tgacgctgag caaagcagac tacgagaaac
acaaagtcta cgcctgcgaa 720 gtcacccatc agggcctgag ctcgcccgtc
acaaagagct tcaacagggg agagtgt 777 <210> SEQ ID NO 439
<211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 439 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg Ser Asp Asn His Gly Gly
20 25 30 Val His Met Pro Leu Gly Phe Leu Gly Pro Gly Gly Ser Asp
Ile Gln 35 40 45 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp Arg Val 50 55 60 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Ser Tyr Leu Asn Trp 65 70 75 80 Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu Ile Tyr Ala Ala 85 90 95 Ser Ser Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 100 105 110 Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 115 120 125 Ala Thr
Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly 130 135 140
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 145
150 155 160 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
Ala Ser 165 170 175 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala Lys Val Gln 180 185 190 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln Glu Ser Val 195 200 205 Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu Ser Ser Thr Leu 210 215 220 Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 225 230 235 240 Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 245 250 255 Gly
Glu Cys <210> SEQ ID NO 440 <211> LENGTH: 765
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 440 tgcatctccc cccgcggttg
tcccgacggg ccgtacgtga tgtacggcag ctccggcggc 60 agtgggggta
gcggtgggtc cgggctgagt ggccggtccg acaatcacgg gagctcggga 120
acacagattc tgctgacgca atctcccgtg atcctctcgg tctcacccgg cgaacgggtc
180 tcgttcagct gcagagcgtc ccaatcaatc gggaccaata ttcactggta
ccagcaaagg 240 actaatgggt ctccccggct gctgataaaa tacgcctccg
agtctatctc gggcatccca 300 tcccgattta gtggtagcgg aagcggcact
gatttcacct tgtctattaa cagcgtagaa 360 tctgaggaca ttgcagacta
ttactgtcag cagaataaca attggcctac aactttcggc 420 gccgggacca
aactagagtt aaagcgtact gtggctgccc ccagcgtttt tatttttccg 480
cccagcgacg aacagctgaa gtcaggcaca gcctctgtgg tgtgtctcct gaataacttc
540 taccccagag aggccaaagt tcagtggaaa gtggacaatg ccttgcagtc
cggaaacagt 600 caagagtccg tgaccgagca ggacagtaag gatagcacgt
atagcctctc tagtacttta 660 acactgtcca aggccgacta cgagaagcac
aaggtgtacg catgcgaagt gacccatcag 720 gggctttcct cccccgtcac
caagtctttc aatcgcgggg agtgt 765 <210> SEQ ID NO 441
<211> LENGTH: 255 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 441 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg
20 25 30 Ser Asp Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser 35 40 45 Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys 50 55 60 Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg 65 70 75 80 Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile 85 90 95 Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 100 105 110 Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr 115 120 125 Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys 130 135 140
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 145
150 155 160 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu 165 170 175 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp 180 185 190 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp 195 200 205 Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys 210 215 220 Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala Cys Glu Val Thr His Gln 225 230 235 240 Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255
<210> SEQ ID NO 442 <211> LENGTH: 765 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 442 tgtatttccc ctagaggttg ccctgacggg ccgtatgtca
tgtacggtag ttctggcggt 60 agtggcggat ctggcggcag tgggctgagc
ggacgtagcg ggaatcacgg ctcatccggg 120 acgcagatac tgctgaccca
gtcccccgtg atcctgtccg tgtcaccggg cgaaagggtc 180 agtttctctt
gccgagcatc acagtccata ggtacgaata tccattggta ccagcagcgg 240
accaatggga gcccaagact gctcattaag tacgcatctg agagtatctc aggcattcca
300 agcaggtttt ccggcagtgg gagcggcact gacttcaccc tcagcattaa
cagcgtggaa 360 agcgaagaca ttgcagatta ctactgccaa cagaacaata
actggcctac tacattcggg 420 gcaggaacta agttggagct caaacgtacc
gtcgctgctc ctagcgtatt tattttccct 480 cctagcgatg aacagttgaa
atctggtacc gctagtgttg tgtgcttact gaacaacttt 540 tatccccggg
aggccaaggt acaatggaag gtggacaatg ccctccaatc agggaacagc 600
caggagtctg ttaccgagca ggactccaag gacagcacct acagcctgag ctctaccctt
660 acattgagca aggctgatta tgagaagcat aaggtctacg cttgtgaggt
gacccatcag 720 gggctcagca gcccggtgac aaaaagcttt aaccgggggg aatgc
765 <210> SEQ ID NO 443 <211> LENGTH: 255 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 443 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser Gly Asn His Gly Ser
Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser 35 40 45 Pro Val Ile Leu
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys 50 55 60 Arg Ala
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg 65 70 75 80
Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile 85
90 95 Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe 100 105 110 Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr 115 120 125 Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys 130 135 140 Leu Glu Leu Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165 170 175 Leu Asn Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 180 185 190 Asn Ala
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 195 200 205
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 210
215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln 225 230 235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 255 <210> SEQ ID NO 444 <211>
LENGTH: 765 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 444 tgtattagcc
ccagggggtg ccccgacggg ccttacgtga tgtatggcag ctccggtggc 60
agcggaggct ctggcgggag tgggatcagt tccggcctgc tgagctccgg gtcaagcggg
120 acccagatct tgctcaccca atcaccagtg atcctaagcg tgagccctgg
cgaacgggtc 180 agcttctctt gccgggcatc tcagagtatt ggcactaaca
tacactggta ccagcagcga 240 accaatgggt ccccccgcct tctaatcaaa
tatgctagcg aatccatttc aggaattcct 300 agccgattta gcggcagcgg
atcaggcact gacttcactc tgtcaatcaa ctcagttgaa 360 agcgaggaca
ttgcagacta ctattgccag cagaataata attggcccac tacatttgga 420
gctggaacaa aattggagct taagaggaca gtggctgcgc ctagtgtatt tatctttccc
480 ccctctgacg aacagttgaa atcgggaacc gcatccgtcg tctgtttact
gaacaacttc 540 tatcccagag aggccaaagt gcagtggaaa gtggataatg
ctttgcagtc tggcaacagc 600 caggaaagcg tgacggagca ggactcaaag
gatagtacat actccctgtc ctccaccctg 660 actctgagta aggccgacta
cgagaagcac aaggtctacg cctgcgaagt gacgcaccaa 720 gggctatcga
gcccggtcac caagtctttc aatcgtggag aatgc 765 <210> SEQ ID NO
445 <211> LENGTH: 255 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 445
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu
Thr Gln Ser 35 40 45 Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg
Val Ser Phe Ser Cys 50 55 60 Arg Ala Ser Gln Ser Ile Gly Thr Asn
Ile His Trp Tyr Gln Gln Arg 65 70 75 80 Thr Asn Gly Ser Pro Arg Leu
Leu Ile Lys Tyr Ala Ser Glu Ser Ile 85 90 95 Ser Gly Ile Pro Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 100 105 110 Thr Leu Ser
Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr 115 120 125 Cys
Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys 130 135
140 Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
145 150 155 160 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
Val Cys Leu 165 170 175 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
Gln Trp Lys Val Asp 180 185 190 Asn Ala Leu Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp 195 200 205 Ser Lys Asp Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys 210 215 220 Ala Asp Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln 225 230 235 240 Gly Leu
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255
<210> SEQ ID NO 446 <211> LENGTH: 765 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 446 tgcatcagcc ctaggggctg cccagacggc ccatatgtga
tgtacggtag ctctgggggc 60 tcaggaggca gcgggggaag cggacaaaac
caggccttac gaatggctgg cagctctggc 120 acccagatat tgctgacgca
gagtccagtt atccttagtg tcagccctgg tgaacgggtt 180 tcatttagtt
gccgtgcctc ccagtctatt ggaacgaaca ttcattggta ccagcaaagg 240
accaacggtt cacccaggtt gcttatcaag tatgcttcag agtcaatctc cgggattccc
300 tcaaggtttt caggctctgg ctcaggtacc gattttacgc tgagcatcaa
ctccgtggag 360 agtgaggaca ttgctgatta ttactgtcag cagaataaca
attggccgac aactttcggc 420 gccggcacaa agctggaact taagcgtact
gtggctgcgc catctgtctt catttttccg 480 ccctcggacg agcagttgaa
gtcagggacc gcctctgtcg tgtgccttct caataacttc 540 tatcccagag
aggctaaagt ccagtggaaa gttgataatg cacttcagag cgggaatagc 600
caggagagcg tgacggaaca ggactctaag gactccacct attctctctc atccaccctt
660 actctctcta aagccgacta cgaaaagcat aaggtttatg cttgcgaagt
cactcatcaa 720 gggctatcta gtccggtcac taaaagcttc aacagaggtg aatgt
765 <210> SEQ ID NO 447 <211> LENGTH: 255 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 447 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Gln Asn Gln Ala 20 25 30 Leu Arg Met Ala Gly Ser
Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser 35 40 45 Pro Val Ile Leu
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys 50 55 60 Arg Ala
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg 65 70 75 80
Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile 85
90 95 Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe 100 105 110 Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr 115 120 125 Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys 130 135 140 Leu Glu Leu Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165 170 175 Leu Asn Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 180 185 190 Asn Ala
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 195 200 205
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 210
215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln 225 230 235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 255 <210> SEQ ID NO 448 <211>
LENGTH: 780 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 448 tgtatcagcc
cccgtggctg tccagacggt ccttacgtta tgtatggatc tagcgggggc 60
tctggagggt ctggcggctc tggaatctct agtggacttc tctccggaag aagcgataat
120 catggatcca gcgggacaca aatcctgttg acacagtccc cagtgatcct
gtcagtctcg 180 cccggagaaa gggtgtcttt ctcttgtagg gctagtcagt
ctatcggaac taacatccat 240 tggtaccagc agcggacaaa tgggagcccg
aggcttctga tcaagtatgc ttcagagagt 300 ataagcggca tcccctcaag
atttagtggc agcgggtccg ggacagattt caccttgtca 360 atcaattctg
tcgaatccga agacattgca gactactatt gccagcaaaa caacaactgg 420
cccaccactt tcggtgctgg aaccaaactc gagctgaaac gcactgtggc agctccttca
480 gtgttcatct tcccacctag cgacgagcag ttgaaatcgg ggacagcctc
agtggtgtgt 540 ctactgaaca acttttaccc ccgggaagcc aaagtgcagt
ggaaggtcga caatgcgctg 600 caatcaggga acagtcagga gtcagttaca
gagcaggact ctaaggacag tacatattct 660 ttgagttcca ccttgacatt
aagcaaggca gactacgaga aacacaaggt gtacgcatgt 720 gaagttacac
accagggcct ttcctcccca gttacgaaaa gcttcaacag aggcgaatgc 780
<210> SEQ ID NO 449 <211> LENGTH: 260 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 449 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asn His
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 450
<211> LENGTH: 780 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 450
tgcatatcgc ccagaggatg tcctgacgga ccctacgtga tgtacgggag ttctgggggg
60 agtggaggct ctggcgggtc agggattagt tccggcctct tgtctggacg
ctccggaaat 120 cacggatcat ctgggaccca gatcctcctg acccagtctc
ccgtcattct gtctgtttct 180 ccaggcgagc gggtttcatt tagctgtagg
gccagtcaga gcattggcac caacatccat 240 tggtaccagc agagaactaa
tggcagtccc agactgctca ttaaatatgc aagcgaatca 300 atttccggga
ttccttctcg cttctcggga tctggatctg gcaccgactt cacgctgtcc 360
atcaacagcg tggagagtga ggacatcgcc gattactact gccagcagaa caacaactgg
420 ccaacaactt ttggcgccgg gaccaagctt gagttaaaga gaaccgtagc
tgcaccctct 480 gttttcattt tcccaccctc agacgagcag cttaagtcag
gaactgccag tgtggtgtgc 540 ctgctgaaca acttctaccc gagagaggct
aaagtccagt ggaaggtaga caatgccctt 600 cagtctggca actctcagga
gagtgtcaca gagcaggatt ctaaggactc cacgtacagt 660 ctgagttcca
ccctcaccct cagtaaggca gactacgaga agcacaaagt ctacgcatgt 720
gaggttactc accaggggct cagctctccc gtgacgaagt catttaacag aggtgagtgc
780 <210> SEQ ID NO 451 <211> LENGTH: 260 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 451 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser
Gly Asn His Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln
Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser
Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80
Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85
90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser
Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu
Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn
Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys
Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210
215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID
NO 452 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 452
tgcatttctc cgagaggctg ccctgacggc ccatacgtaa tgtacggatc atccggtggc
60 agtggagggt ccgggggatc cggtctaagc ggcagaagtg ataatcatgg
aggctctggc 120 gggagcatca gctccggatt gctttccagc ggaagttctg
gcactcaaat tctgctgaca 180 caaagccctg tgatcttgtc agtctcacct
ggcgagcggg tgagcttttc atgccgggct 240 tcccagagca tcggtacaaa
tattcactgg tatcagcaga gaaccaatgg cagtccgcgg 300 ttgctgatta
agtatgcgag cgagagcata tcaggcatac caagcagatt tagcgggagt 360
ggctctggga ccgattttac actcagtata aattcagtgg agagcgagga tatagccgac
420 tactactgcc agcaaaacaa taactggccc accaccttcg gcgcagggac
caagcttgaa 480 ctgaagcgta cagttgccgc cccaagcgta tttattttcc
ctccaagcga cgaacagctg 540 aaaagcggta ccgcaagcgt tgtgtgcctg
ctgaataact tttacccaag ggaagctaag 600 gtgcagtgga aggttgacaa
tgcgctgcag tcaggcaact cccaggaatc ggtaacagag 660 caggactcca
aggattcaac ttatagtctt agtagtaccc ttactctttc caaagctgat 720
tatgaaaaac acaaagtgta tgcatgcgag gtgacccacc aaggactgtc atctcctgtc
780 accaagtcct tcaaccgggg agagtgt 807 <210> SEQ ID NO 453
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 453 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg
20 25 30 Ser Asp Asn His Gly Gly Ser Gly Gly Ser Ile Ser Ser Gly
Leu Leu 35 40 45 Ser Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145
150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210>
SEQ ID NO 454 <211> LENGTH: 807 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 454 tgcattagtc ctcgcggttg ccctgatgga ccatacgtaa
tgtatggaag ctctggtgga 60 tccgggggct ctggcggatc aggaatctcc
agcgggctgc tctcatcagg tggcagcggg 120 ggctcattaa gcggccgaag
tgacaatcac ggctcgtccg gtacacagat tctgctcact 180 cagtcacccg
ttatactgtc tgtgtcgcct ggagagcgtg tcagcttttc atgtagagcc 240
tcgcagtcaa taggcacgaa tatacactgg taccagcaga gaactaatgg aagcccaagg
300 ttgctcatca aatacgcatc tgagtcgatt agcggcattc cgtccaggtt
tagtggcagt 360 ggaagcggca ccgatttcac tttgtctatt aactctgtgg
aaagcgagga catcgccgat 420 tattattgtc agcagaataa caattggccc
accaccttcg gtgccggtac taagctggag 480 ctgaaacgta cagttgccgc
tccctctgtg tttattttcc ctccctcgga tgagcaactc 540 aaatcaggga
cagcgagtgt cgtatgtctc ctgaacaatt tttacccacg tgaagctaaa 600
gttcagtgga aggtggacaa cgctctgcag tccggcaaca gtcaggaaag cgtaactgaa
660 caggactcaa aggatagcac ttactccttg agcagcactc tcactctttc
caaggctgat 720 tatgagaagc acaaggtgta cgcgtgtgaa gtcacccatc
agggactgtc aagtccggtg 780 actaaatcat ttaacagggg cgaatgc 807
<210> SEQ ID NO 455 <211> LENGTH: 269 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 455 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Ser Gly Gly Ser Gly Gly
Ser Leu Ser Gly Arg Ser Asp 35 40 45 Asn His Gly Ser Ser Gly Thr
Gln Ile Leu Leu Thr Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser
Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser
Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly
Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105
110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly
Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230
235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
260 265 <210> SEQ ID NO 456 <211> LENGTH: 807
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 456 tgtatttccc ctcgcggatg
tcccgacggt ccatacgtaa tgtatgggtc aagcggggga 60 tcaggaggaa
gtggaggctc cggactcagc ggtcgctccg gcaatcacgg ggggtctggc 120
ggatcaataa gttcgggcct cctgagctcc ggttcatctg gcactcagat cctgctcacg
180 cagtcgccgg taatactgag tgtctcacca ggcgagcgtg tcagcttcag
ctgtcgcgcc 240 tcacagtcaa tcggcacaaa tatccattgg taccagcaaa
ggaccaatgg cagccctagg 300 ctgctgataa aatacgcatc cgagtcaatt
tcagggattc catcgagatt ctcgggcagc 360 ggaagtggga ccgactttac
tctctccatc aacagcgtcg agtcggagga catcgcggac 420 tactactgcc
agcagaataa caattggcca acaacattcg gcgcaggaac aaagctagag 480
ctcaagagga cagtggctgc acccagtgta ttcatcttcc cacctagcga cgagcaactg
540 aagagcggga cggcttccgt cgtttgtcta ttaaataatt tctatccccg
tgaggctaaa 600 gttcagtgga aggttgataa tgcgttgcag tccggcaact
cccaggaatc cgtcacagag 660 caggattcta aggattcaac ctatagctta
agctctacac ttacgctttc taaagccgat 720 tatgaaaaac acaaggtgta
cgcttgtgag gttacccacc agggcctgag cagccccgtg 780 accaagtcgt
tcaaccgggg cgagtgt 807 <210> SEQ ID NO 457 <211>
LENGTH: 269 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 457 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30
Ser Gly Asn His Gly Gly Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu 35
40 45 Ser Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145 150 155 160
Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165
170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
458 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 458
tgtatctcac ctcgcggctg ccccgacggc ccttacgtca tgtacggctc ctcgggtggg
60 tccgggggaa gtggcgggtc tggcattagt tcagggctct tatcttccgg
cggaagcggg 120 ggatctcttt ccgggcggag tggcaatcac ggcagtagcg
gaactcagat cctactcact 180 cagtcaccag tgatcctgtc tgtcagtcca
ggggagagag tgtctttcag ttgtagagct 240 tcccagtcta ttgggacaaa
cattcactgg tatcaacagc gaactaatgg atcgccaaga 300 ctcctgatta
aatatgcttc tgagagcatc tctggaattc catcaagatt ctcagggagt 360
ggtagcggca ccgattttac gttatcgatc aattccgttg agagcgaaga tatcgcggac
420 tattactgtc agcagaacaa taactggcct acaacgttcg gggcagggac
gaaattggag 480 ctgaagcgga ccgtcgccgc gccaagcgtg ttcatcttcc
cccctagcga cgagcaattg 540 aaaagcggca ccgcaagtgt ggtttgcctg
ctgaacaact tttatcctcg cgaggcgaaa 600 gtgcagtgga aagtcgacaa
tgcactccag tcagggaaca gccaagagtc cgttactgaa 660 caagactcta
aagatagtac ttatagctta tccagcacac tgacgctcag taaggccgat 720
tatgaaaaac ataaggtgta tgcgtgtgag gttacccatc aaggattgtc atcacccgtc
780 accaaatcct ttaacagagg agaatgt 807 <210> SEQ ID NO 459
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 459 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg
Ser Gly 35 40 45 Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145
150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210>
SEQ ID NO 460 <211> LENGTH: 807 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 460 tgtatctcgc cccgcggctg cccagacggc ccatatgtga
tgtatggttc ttccggtgga 60 tccggcggat caggtgggtc tggcctctca
ggtcgttccg acaaccacgg cggctcaggt 120 gggtctcaga atcaggcact
gcggatggcc ggatcttctg gcacccagat attgctcaca 180 cagtcaccag
ttattctgtc cgtatctcca ggagaacggg tatctttctc ttgtagggca 240
agccagtcca tcggaacaaa catccattgg taccagcagc ggaccaatgg cagtccacgg
300 cttctgatca agtatgctag tgaaagcatt agcgggattc caagccgatt
ttctgggtcg 360 ggtagtggaa ccgacttcac cctgagcatt aactctgtcg
aatccgaaga tattgctgac 420 tattactgtc agcagaacaa caattggccg
actacgtttg gcgccggaac caaattagaa 480 cttaagagaa ccgtggccgc
tccctctgtc ttcattttcc cgccttccga cgaacagctg 540 aagagcggaa
ctgcctccgt ggtgtgcctg ttgaataact tttatccaag ggaagcaaag 600
gtgcagtgga aagtggacaa tgctctgcag tctggcaata gccaggagtc cgtgactgaa
660 caggacagta aagactcaac ctactcactg agcagtactc tcacattatc
caaagccgat 720 tatgaaaagc ataaggttta tgcatgcgag gttacccacc
agggactgag ctcccccgtg 780 accaaaagct tcaatagggg tgagtgc 807
<210> SEQ ID NO 461 <211> LENGTH: 269 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 461 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Leu Ser Gly Arg 20 25 30 Ser Asp Asn His Gly Gly Ser Gly Gly
Ser Gln Asn Gln Ala Leu Arg 35 40 45 Met Ala Gly Ser Ser Gly Thr
Gln Ile Leu Leu Thr Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser
Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser
Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly
Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105
110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly
Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230
235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
260 265 <210> SEQ ID NO 462 <211> LENGTH: 807
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 462 tgcatcagcc cccgaggctg
ccctgatggc ccctacgtga tgtacgggtc cagcggtggc 60 agcgggggct
caggggggag cgggcagaat caggccctga gaatggcggg tggatccggg 120
gggtcccttt ctggcaggtc cgataaccac ggttctagtg gaacacagat tttgctgaca
180 caaagtcccg tcatcctctc tgtgtctccc ggtgagcggg tcagtttttc
ctgccgagcg 240 tcccagagca tcgggacaaa tatccattgg taccagcaga
gaacgaacgg ctctcctaga 300 ctgctcatca agtacgcctc ggaaagtatt
tccggcattc cctcccgttt cagcggctcc 360 ggaagtggta cagattttac
cctgagtatt aattccgtcg aatctgagga catagccgac 420 tactattgcc
aacagaataa caattggcca acaacttttg gcgccgggac taagctggag 480
ctgaaacgga ccgtcgcagc accaagtgtt ttcatcttcc caccaagtga cgagcagctg
540 aaatccggaa cagcgagcgt ggtgtgccta ctcaataact tctatccacg
cgaagccaag 600 gtgcagtgga aagtggacaa cgctctgcag tccggcaata
gccaggaaag cgtgacagag 660 caagattcta aggacagtac gtattcactg
tccagtacgc tcaccttaag caaggctgac 720 tacgaaaaac acaaggtcta
cgcctgtgag gtcacacatc agggcctctc cagtccggtt 780 acaaaaagtt
tcaatcgcgg ggaatgt 807 <210> SEQ ID NO 463 <211>
LENGTH: 269 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 463 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gln Asn Gln Ala 20 25 30
Leu Arg Met Ala Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg Ser Asp 35
40 45 Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145 150 155 160
Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165
170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
464 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 464
tgcatcagtc ccagaggctg ccctgacggg ccctacgtga tgtatggtag ctcagggggc
60 tccggcggct ccggcggaag cggacttagc ggccgtagcg gcaaccatgg
gggttctgga 120 ggatcccaga atcaggctct gcgcatggct ggaagcagcg
gtacccagat cctgctcacc 180 caatcacccg tcatcttgtc tgtgagtcct
ggcgaaaggg tgtcgttctc ttgtcgcgcg 240 tcccagtcca ttgggaccaa
cattcattgg taccagcaga ggactaacgg gagcccccgc 300 ctgctgatca
aatacgccag tgaatctatc tctggaatcc catcacgatt ttcagggtcc 360
ggtagtggga ccgacttcac tttgagtatt aacagtgtgg aatccgagga catagccgac
420 tattactgtc agcagaacaa taactggcca acaacctttg gcgccgggac
aaagttagag 480 cttaagcgga ctgttgcagc cccctccgtt tttatcttcc
cgcccagtga tgaacagctg 540 aaaagcggta ccgcctccgt agtgtgcctt
ctcaataatt tttaccccag agaagctaaa 600 gtacagtgga aagtcgacaa
cgccctccag agcggcaaca gtcaggagtc cgtcaccgag 660 caggattcta
aagactcaac atatagcctt tcgtccaccc taacactttc aaaagcagac 720
tatgaaaaac ataaggtgta tgcctgcgag gtcacacacc aggggctcag ctctccagtt
780 actaagtcat tcaaccgcgg agagtgt 807 <210> SEQ ID NO 465
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 465 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg
20 25 30 Ser Gly Asn His Gly Gly Ser Gly Gly Ser Gln Asn Gln Ala
Leu Arg 35 40 45 Met Ala Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145
150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210>
SEQ ID NO 466 <211> LENGTH: 807 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 466 tgcattagcc cccgagggtg tcccgatggg ccctacgtaa
tgtacggatc atcgggcgga 60 tctgggggct ccggtggctc tggtcagaat
caagctctgc gcatggccgg aggtagcggt 120 ggaagcctga gcggccgaag
tggaaaccac ggctcctctg gcactcagat tcttctcacg 180 cagtcgcccg
tgatcttgtc cgtgagccca ggcgagcggg tgagcttctc ttgccgggcc 240
agccaaagta taggtacaaa tattcactgg taccaacagc gaaccaacgg gtcgcctagg
300 ttgctcataa agtacgcatc cgagagtata agcggcatac catctaggtt
ctcaggtagc 360 ggcagcggga ccgattttac cctcagcatt aattcggttg
aatctgaaga tatcgccgat 420 tattattgtc agcagaataa caattggcct
actactttcg gcgccggaac aaagctggaa 480 cttaagcgca cagtggccgc
tccttctgtc tttatcttcc ctccatctga cgagcaatta 540 aagagtggga
cagcctcggt ggtgtgtttg ctcaataact tctatccaag ggaggcaaag 600
gtgcagtgga aggtcgataa cgctctccag agtgggaatt cccaggagtc cgtgaccgag
660 caggattcta aagatagcac atactcactg tcttccaccc tgaccctgtc
caaggcagac 720 tacgagaagc acaaagttta cgcctgtgaa gtgacacacc
agggcctcag ctctcctgtc 780 acaaagagtt ttaatcgggg cgagtgt 807
<210> SEQ ID NO 467 <211> LENGTH: 269 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 467 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Gln Asn Gln Ala 20 25 30 Leu Arg Met Ala Gly Gly Ser Gly Gly
Ser Leu Ser Gly Arg Ser Gly 35 40 45 Asn His Gly Ser Ser Gly Thr
Gln Ile Leu Leu Thr Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser
Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser
Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly
Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105
110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly
Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230
235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
260 265 <210> SEQ ID NO 468 <211> LENGTH: 9 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 468 Ser Gly Arg Ser Ala Asn Pro Arg Gly 1 5
<210> SEQ ID NO 469 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 469 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala Asn Pro
Arg Gly 1 5 10 15 <210> SEQ ID NO 470 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 470 Ala Val Gly Leu Leu Ala Pro
Pro Thr Ser Gly Arg Ser Ala Asn Pro 1 5 10 15 Arg Gly <210>
SEQ ID NO 471 <211> LENGTH: 17 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 471 Ala Val Gly Leu Leu Ala Pro Pro Ser Gly Arg Ser Ala
Asn Pro Arg 1 5 10 15 Gly <210> SEQ ID NO 472 <211>
LENGTH: 262 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 472 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30
Leu Leu Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser Ser Gly Thr 35
40 45 Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro
Gly 50 55 60 Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
Gly Thr Asn 65 70 75 80 Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg Leu Leu Ile 85 90 95 Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser Val Glu Ser 115 120 125 Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 130 135 140 Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala 145 150 155 160
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 165
170 175 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala 180 185 190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln 195 200 205 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val Tyr 225 230 235 240 Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe Asn Arg Gly
Glu Cys 260 <210> SEQ ID NO 473 <211> LENGTH: 268
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 473 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala Asn Pro Arg 35 40 45 Gly
Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile 50 55
60 Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
65 70 75 80 Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
Asn Gly 85 90 95 Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser
Ile Ser Gly Ile 100 105 110 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Ser 115 120 125 Ile Asn Ser Val Glu Ser Glu Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln 130 135 140 Asn Asn Asn Trp Pro Thr
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 145 150 155 160 Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 165 170 175 Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 180 185
190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr 225 230 235 240 Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser 245 250 255 Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 474 <211>
LENGTH: 264 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 474 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30
Leu Ala Pro Pro Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser Ser 35
40 45 Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser 50 55 60 Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly 65 70 75 80 Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu 85 90 95 Leu Ile Lys Tyr Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe 100 105 110 Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val 115 120 125 Glu Ser Glu Asp Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp 130 135 140 Pro Thr Thr
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val 145 150 155 160
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 165
170 175 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg 180 185 190 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn 195 200 205 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser 210 215 220 Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys 225 230 235 240 Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr 245 250 255 Lys Ser Phe Asn
Arg Gly Glu Cys 260 <210> SEQ ID NO 475 <211> LENGTH:
270 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 475 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ala
Val Gly Leu Leu Ala Pro Pro Ser Gly Arg Ser Ala Asn 35 40 45 Pro
Arg Gly Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro 50 55
60 Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg
65 70 75 80 Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln
Arg Thr 85 90 95 Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser
Glu Ser Ile Ser 100 105 110 Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr 115 120 125 Leu Ser Ile Asn Ser Val Glu Ser
Glu Asp Ile Ala Asp Tyr Tyr Cys 130 135 140 Gln Gln Asn Asn Asn Trp
Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 145 150 155 160 Glu Leu Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro 165 170 175 Ser
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu 180 185
190 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
195 200 205 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser 210 215 220 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala 225 230 235 240 Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly 245 250 255 Leu Ser Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 260 265 270 <210> SEQ ID NO 476
<211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 476 Gln
Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10
15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu
20 25 30 Leu Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp
Ile Gln 35 40 45 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp Arg Val 50 55 60 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Ser Tyr Leu Asn Trp 65 70 75 80 Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu Ile Tyr Ala Ala 85 90 95 Ser Ser Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 100 105 110 Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 115 120 125 Ala Thr
Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly 130 135 140
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 145
150 155 160 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
Ala Ser 165 170 175 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala Lys Val Gln 180 185 190 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln Glu Ser Val 195 200 205 Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu Ser Ser Thr Leu 210 215 220 Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 225 230 235 240 Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 245 250 255 Gly
Glu Cys <210> SEQ ID NO 477 <211> LENGTH: 253
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 477 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala 20 25 30 Asn Pro Arg
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser 35 40 45 Ser
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala 50 55
60 Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
65 70 75 80 Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
Ser Gly 85 90 95 Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu 100 105 110 Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln 115 120 125 Gln Thr Val Val Ala Pro Pro Leu
Phe Gly Gln Gly Thr Lys Val Glu 130 135 140 Ile Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 145 150 155 160 Asp Glu Gln
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 165 170 175 Asn
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 180 185
190 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
195 200 205 Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp 210 215 220 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu 225 230 235 240 Ser Ser Pro Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 245 250 <210> SEQ ID NO 478 <211>
LENGTH: 261 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 478 Gln Gly Gln Ser
Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly
Trp Gln Gly Gly Ser Ser Gly Gly Ser Ala Val Gly Leu Leu 20 25 30
Ala Pro Pro Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp 35
40 45 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp 50 55 60 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu 65 70 75 80 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr 85 90 95 Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu 115 120 125 Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu 130 135 140 Phe Gly Gln
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro 145 150 155 160
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165
170 175 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys 180 185 190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu 195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu
Cys 260 <210> SEQ ID NO 479 <211> LENGTH: 255
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 479 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ala Val Gly Leu Leu Ala Pro Pro Ser Gly Arg 20 25 30 Ser Ala Asn
Pro Arg Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 35 40 45 Pro
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys 50 55
60 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
65 70 75 80 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
Leu Gln 85 90 95 Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe 100 105 110 Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr 115 120 125 Cys Gln Gln Thr Val Val Ala Pro
Pro Leu Phe Gly Gln Gly Thr Lys 130 135 140 Val Glu Ile Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165 170 175 Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 180 185
190 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
195 200 205 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
Ser Lys 210 215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln 225 230 235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 245 250 255 <210> SEQ ID NO 480
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 480 Ile
Ser Ser Gly Leu 1 5 <210> SEQ ID NO 481 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 481 Ile Ser Ser Gly Leu Leu Ser 1
5 <210> SEQ ID NO 482 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 482 Ile Ser Ser Gly Leu Leu 1 5 <210> SEQ ID NO 483
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 483 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asp His 1 5 10 <210>
SEQ ID NO 484 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 484 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Ile His 1
5 10 <210> SEQ ID NO 485 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 485 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser
Asp Gln His 1 5 10 <210> SEQ ID NO 486 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 486 Ile Ser Ser Gly Leu Leu Ser
Gly Arg Ser Asp Thr His 1 5 10 <210> SEQ ID NO 487
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 487 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Tyr His 1 5 10 <210>
SEQ ID NO 488 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 488 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn Pro 1
5 10 <210> SEQ ID NO 489 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 489 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser
Ala Asn Pro 1 5 10 <210> SEQ ID NO 490 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 490 Ile Ser Ser Gly Leu Leu Ser
Gly Arg Ser Ala Asn Ile 1 5 10 <210> SEQ ID NO 491
<211> LENGTH: 39 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 491
atatcgagtg gattgctgtc tggcagatct gacgatcac 39 <210> SEQ ID NO
492 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 492
atatcgagtg gattgctgtc tggcagatct gacatacac 39 <210> SEQ ID NO
493 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 493
atatcgagtg gattgctgtc tggcagatct gaccaacac 39 <210> SEQ ID NO
494 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 494
atatcgagtg gattgctgtc tggcagatct gacactcac 39 <210> SEQ ID NO
495 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 495
atatcgagtg gattgctgtc tggcagatct gactatcac 39 <210> SEQ ID NO
496 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 496
attagctcag gccttcttag cggccgcagc gacaatccc 39 <210> SEQ ID NO
497 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 497
atatcgagtg gattgctgtc tggcagatct gctaatccc 39 <210> SEQ ID NO
498 <211> LENGTH: 39 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 498
atatcgagtg gattgctgtc tggcagatct gctaatata 39 <210> SEQ ID NO
499 <211> LENGTH: 260 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 499
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asp His Gly Ser Ser Gly
Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135
140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser
145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255
Arg Gly Glu Cys 260 <210> SEQ ID NO 500 <211> LENGTH:
260 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 500 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Gly Arg Ser Asp Ile His Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55
60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe
Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn
Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln
Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu
Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185
190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
195 200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260
<210> SEQ ID NO 501 <211> LENGTH: 260 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 501 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Gln His
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 502
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 502 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Asp Thr His Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 503 <211> LENGTH: 260
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 503 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Gly Arg Ser Asp Tyr His Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55
60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe
Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn
Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln
Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu
Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185
190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
195 200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260
<210> SEQ ID NO 504 <211> LENGTH: 260 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 504 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asn Pro
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 505
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 505 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Ala Asn Pro Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 506 <211> LENGTH: 260
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 506 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Gly Arg Ser Ala Asn Ile Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55
60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe
Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn
Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln
Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu
Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185
190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
195 200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260
<210> SEQ ID NO 507 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 507 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Asp His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 508 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 508 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Ile His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 509 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 509 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Gln His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 510 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 510 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Thr His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 511 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 511 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Tyr His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 512 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 512 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Asn Pro Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 513 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 513 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Ala 20 25 30 Asn Pro Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 514 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 514 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Ala 20 25 30 Asn Ile Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 515 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 515 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Asp His <210> SEQ ID NO 516 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 516 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Ile His
<210> SEQ ID NO 517 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 517 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Gln His <210> SEQ ID NO 518 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 518 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Thr His
<210> SEQ ID NO 519 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 519 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Tyr His <210> SEQ ID NO 520 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 520 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Asn Pro
<210> SEQ ID NO 521 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 521 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Ala 1 5 10 15 Asn Pro <210> SEQ ID NO 522 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 522 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Ala 1 5 10 15 Asn Ile
<210> SEQ ID NO 523 <211> LENGTH: 54 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 523 gctgtgggac tgctggctcc tcctggtggc ctgtctggca
gatctgacga tcac 54 <210> SEQ ID NO 524 <211> LENGTH: 54
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 524 gctgtgggac tgctggctcc
tcctggtggc ctgtctggca gatctgacat acac 54 <210> SEQ ID NO 525
<211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 525
gctgtgggac tgctggctcc tcctggtggc ctgtctggca gatctgacca acac 54
<210> SEQ ID NO 526 <211> LENGTH: 54 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 526 gctgtgggac tgctggctcc tcctggtggc ctgtctggca
gatctgacac tcac 54 <210> SEQ ID NO 527 <211> LENGTH: 54
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 527 gctgtgggac tgctggctcc
tcctggtggc ctgtctggca gatctgacta tcac 54 <210> SEQ ID NO 528
<211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 528
gctgtgggac tgctggctcc tcctggtggc ctgtctggca gatctgacaa tccc 54
<210> SEQ ID NO 529 <211> LENGTH: 54 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 529 gctgtgggac tgctggctcc tcctggtggc ctgtctggca
gatctgctaa tccc 54 <210> SEQ ID NO 530 <211> LENGTH: 54
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 530 gctgtgggac tgctggctcc
tcctggtggc ctgtctggca gatctgctaa tata 54 <210> SEQ ID NO 531
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 531 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Asp His
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 532
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 532 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Ile His
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 533
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 533 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Gln His
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 534
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 534 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Thr His
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 535
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 535 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Tyr His
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 536
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 536 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp Asn Pro
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 537
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 537 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Ala Asn Pro
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 538
<211> LENGTH: 265 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 538 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu
20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Ala Asn Ile
Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu
Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140
Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145
150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr
Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 539
<211> LENGTH: 257 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 539 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu
20 25 30 Ser Gly Arg Ser Asp Asp His Gly Gly Gly Ser Asp Ile Gln
Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145
150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
<210> SEQ ID NO 540 <211> LENGTH: 257 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 540 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala
Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Ile His Gly Gly
Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105
110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly
Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230
235 240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu 245 250 255 Cys <210> SEQ ID NO 541 <211> LENGTH:
257 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 541 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg
Ser Asp Gln His Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55
60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185
190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys <210> SEQ ID NO
542 <211> LENGTH: 257 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 542
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly
Leu 20 25 30 Ser Gly Arg Ser Asp Thr His Gly Gly Gly Ser Asp Ile
Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135
140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255
Cys <210> SEQ ID NO 543 <211> LENGTH: 257 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 543 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys
Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Tyr
His Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85
90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro
Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val
Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210
215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu 245 250 255 Cys <210> SEQ ID NO 544
<211> LENGTH: 257 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 544 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu
20 25 30 Ser Gly Arg Ser Asp Asn Pro Gly Gly Gly Ser Asp Ile Gln
Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145
150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
<210> SEQ ID NO 545 <211> LENGTH: 257 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 545 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala
Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Ala Asn Pro Gly Gly
Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105
110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly
Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230
235 240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu 245 250 255 Cys <210> SEQ ID NO 546 <211> LENGTH:
257 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 546 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg
Ser Ala Asn Ile Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55
60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185
190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys <210> SEQ ID NO
547 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 547
Leu Ser Gly Arg Ser Asp Asp His 1 5 <210> SEQ ID NO 548
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 548 Leu
Ser Gly Arg Ser Asp Ile His 1 5 <210> SEQ ID NO 549
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 549 Leu
Ser Gly Arg Ser Asp Gln His 1 5 <210> SEQ ID NO 550
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 550 Leu
Ser Gly Arg Ser Asp Thr His 1 5 <210> SEQ ID NO 551
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 551 Leu
Ser Gly Arg Ser Asp Tyr His 1 5 <210> SEQ ID NO 552
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 552 Leu
Ser Gly Arg Ser Asp Asn Pro 1 5 <210> SEQ ID NO 553
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 553 Leu
Ser Gly Arg Ser Ala Asn Pro 1 5 <210> SEQ ID NO 554
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 554 Leu
Ser Gly Arg Ser Ala Asn Ile 1 5 <210> SEQ ID NO 555
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 555 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn Ile 1 5 10 <210>
SEQ ID NO 556 <211> LENGTH: 39 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 556 atatcgagtg gattgctgtc tggcagatct gacaatata 39
<210> SEQ ID NO 557 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 557 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Asn Ile <210> SEQ ID NO 558 <211>
LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 558 gctgtgggac
tgctggctcc tcctggtggc ctgtctggca gatctgacaa tata 54 <210> SEQ
ID NO 559 <211> LENGTH: 260 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 559
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asn Ile Gly Ser Ser Gly
Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135
140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser
145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255
Arg Gly Glu Cys 260 <210> SEQ ID NO 560 <211> LENGTH:
265 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 560 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp Asn Ile Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 561 <211> LENGTH: 252
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 561 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp 20 25 30 Asn Ile Gly
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55
60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val Val Ala Pro Pro Leu Phe
Gly Gln Gly Thr Lys Val Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 165 170 175 Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 180 185
190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 225 230 235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 <210> SEQ ID NO 562 <211> LENGTH:
257 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 562 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg
Ser Asp Asn Ile Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55
60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185
190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 562
<210> SEQ ID NO 1 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 1 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn His 1 5
10 <210> SEQ ID NO 2 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 2 Ile Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser
Leu Ser 1 5 10 15 Gly Arg Ser Asp Asn His 20 <210> SEQ ID NO
3 <211> LENGTH: 22 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 3
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Thr Ser Thr Ser Gly Arg 1 5
10 15 Ser Ala Asn Pro Arg Gly 20 <210> SEQ ID NO 4
<211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 4 Thr Ser
Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ala Val 1 5 10 15
Gly Leu Leu Ala Pro Pro 20 <210> SEQ ID NO 5 <211>
LENGTH: 24 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 5 Val His Met Pro Leu
Gly Phe Leu Gly Pro Gly Gly Thr Ser Thr Ser 1 5 10 15 Gly Arg Ser
Ala Asn Pro Arg Gly 20 <210> SEQ ID NO 6 <211> LENGTH:
24 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 6 Thr Ser Thr Ser Gly Arg Ser Ala
Asn Pro Arg Gly Gly Gly Val His 1 5 10 15 Met Pro Leu Gly Phe Leu
Gly Pro 20 <210> SEQ ID NO 7 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 7 Ala Val Gly Leu Leu Ala Pro Pro
Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Asn His <210> SEQ
ID NO 8 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 8
Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ala Val Gly Leu Leu Ala 1 5
10 15 Pro Pro <210> SEQ ID NO 9 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 9 Val His Met Pro Leu Gly Phe Leu
Gly Pro Gly Gly Leu Ser Gly Arg 1 5 10 15 Ser Asp Asn His 20
<210> SEQ ID NO 10 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 10 Leu Ser Gly Arg Ser Asp Asn His Gly Gly Val His Met
Pro Leu Gly 1 5 10 15 Phe Leu Gly Pro 20 <210> SEQ ID NO 11
<211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 11 Leu
Ser Gly Arg Ser Asp Asn His Gly Gly Ser Gly Gly Ser Ile Ser 1 5 10
15 Ser Gly Leu Leu Ser Ser 20 <210> SEQ ID NO 12 <211>
LENGTH: 22 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 12 Leu Ser Gly Arg Ser
Gly Asn His Gly Gly Ser Gly Gly Ser Ile Ser 1 5 10 15 Ser Gly Leu
Leu Ser Ser 20 <210> SEQ ID NO 13 <211> LENGTH: 22
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 13 Ile Ser Ser Gly Leu Leu Ser
Ser Gly Gly Ser Gly Gly Ser Leu Ser 1 5 10 15 Gly Arg Ser Gly Asn
His 20 <210> SEQ ID NO 14 <211> LENGTH: 22 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 14 Leu Ser Gly Arg Ser Asp Asn His Gly Gly
Ser Gly Gly Ser Gln Asn 1 5 10 15 Gln Ala Leu Arg Met Ala 20
<210> SEQ ID NO 15 <211> LENGTH: 22 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 15 Gln Asn Gln Ala Leu Arg Met Ala Gly Gly Ser Gly Gly
Ser Leu Ser 1 5 10 15 Gly Arg Ser Asp Asn His 20 <210> SEQ ID
NO 16 <211> LENGTH: 22 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE:
16
Leu Ser Gly Arg Ser Gly Asn His Gly Gly Ser Gly Gly Ser Gln Asn 1 5
10 15 Gln Ala Leu Arg Met Ala 20 <210> SEQ ID NO 17
<211> LENGTH: 22 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 17 Gln
Asn Gln Ala Leu Arg Met Ala Gly Gly Ser Gly Gly Ser Leu Ser 1 5 10
15 Gly Arg Ser Gly Asn His 20 <210> SEQ ID NO 18 <211>
LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 18 Leu Ser Gly Arg Ser
Asp Asn His 1 5 <210> SEQ ID NO 19 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 19 Leu Ser Gly Arg Ser Gly Asn
His 1 5 <210> SEQ ID NO 20 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 20 Ile Ser Ser Gly Leu Leu Ser Ser 1 5
<210> SEQ ID NO 21 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 21 Gln Asn Gln Ala Leu Arg Met Ala 1 5 <210> SEQ ID
NO 22 <211> LENGTH: 13 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 22
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Gly Asn His 1 5 10
<210> SEQ ID NO 23 <211> LENGTH: 24 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 23 ttaagcgggc ggtcggacaa ccac 24 <210> SEQ ID NO 24
<211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 24
cttagcgggc ggagcggcaa ccac 24 <210> SEQ ID NO 25 <211>
LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 25 atctcctccg
ggctactgag ttct 24 <210> SEQ ID NO 26 <211> LENGTH: 24
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 26 cagaaccagg cgctcagaat ggca 24
<210> SEQ ID NO 27 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 27 atatcatccg gcctccttag cggccgttcc gacaatcac 39
<210> SEQ ID NO 28 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 28 ataagttctg ggctcctgtc gggccggagt ggaaatcac 39
<210> SEQ ID NO 29 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 29 ctgagcgggc ggtccgataa tcatggtggt tcaggaggga gtatttcttc
cggcttactg 60 agtagc 66 <210> SEQ ID NO 30 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 30 atctcctctg
ggttgctttc ttcaggaggt tcagggggga gcctgagcgg acgctccgac 60 aaccat 66
<210> SEQ ID NO 31 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 31 ctctcaggaa gatccggaaa tcatgggggg tctgggggga gtatctcatc
aggtctgctg 60 agcagc 66 <210> SEQ ID NO 32 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 32 atctcaagtg
ggctgttaag ttccggcggc agtggagggt ccctaagcgg ccgcagcggg 60 aatcac 66
<210> SEQ ID NO 33 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 33 ctctctggcc gctccgataa tcatggtgga tccggtggct ctcagaacca
ggcactacgg 60 atggca 66 <210> SEQ ID NO 34 <211>
LENGTH: 66 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 34 cagaaccagg
cgctcaggat ggcagggggg agtggcggaa gcctttctgg tcgatccgat 60 aatcac 66
<210> SEQ ID NO 35 <211> LENGTH: 66 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 35 cttagcggac gctctggcaa ccacggagga
tctggaggaa gtcagaacca ggccttgcgc 60 atggcc 66 <210> SEQ ID NO
36 <211> LENGTH: 66 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 36
caaaaccagg ctctgcgcat ggctgggggg tctggtggga gcctgagcgg gcggtcagga
60 aaccac 66 <210> SEQ ID NO 37 <211> LENGTH: 37
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 37 gtgcagccac cgtacgtttg
atttccacct tggtccc 37 <210> SEQ ID NO 38 <211> LENGTH:
97 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 38 caggggggct cgagcggcgg
ctctatctct tccggactgc tgtccggcag atccgacaat 60 cacggcggag
gctctgacat ccagatgacc cagtctc 97 <210> SEQ ID NO 39
<211> LENGTH: 124 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 39
caggggggct cgagcggcgg ctctatctct tctggcctgc tgtctagcgg cggctccggc
60 ggatctctgt ctggcagatc tgacaaccac ggcggaggct ccgacatcca
gatgacccag 120 tctc 124 <210> SEQ ID NO 40 <211>
LENGTH: 121 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 40 caggggggct
cgagcggagg atctgctgtg ggactgctgg ctcctcctgg cggcacatct 60
acctctggca gatccgccaa ccctcggggc ggaggatctg acatccagat gacccagtct
120 c 121 <210> SEQ ID NO 41 <211> LENGTH: 121
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 41 caggggggct cgagcggcgg
ctccacatct acctctggca gatccgccaa ccccagaggt 60 ggcggagctg
tgggactgct ggctccacca ggcggatctg acatccagat gacccagtct 120 c 121
<210> SEQ ID NO 42 <211> LENGTH: 127 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 42 caggggggct cgagcggcgg ctctgtgcat atgcccctgg gctttctggg
ccctggcggc 60 acatctacct ctggcagatc cgccaaccct cggggcggag
gatctgacat ccagatgacc 120 cagtctc 127 <210> SEQ ID NO 43
<211> LENGTH: 127 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 43
caggggggct cgagcggcgg ctccacatct acctctggca gatccgccaa ccccagaggc
60 ggcggagtgc atatgcctct gggctttctg ggacctggcg gctctgacat
ccagatgacc 120 cagtctc 127 <210> SEQ ID NO 44 <211>
LENGTH: 109 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 44 caggggggct
cgagcggagg atctgctgtg ggactgctgg ctcctcctgg tggcctgtct 60
ggcagatctg ataaccacgg cggctccgac atccagatga cccagtctc 109
<210> SEQ ID NO 45 <211> LENGTH: 112 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 45 caggggggct cgagcggagg ctctggcctg tctggcagat ccgataacca
tggcggcgct 60 gtgggactgc tggctcctcc tggtggatct gacatccaga
tgacccagtc tc 112 <210> SEQ ID NO 46 <211> LENGTH: 115
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 46 caggggggct cgagcggcgg
ctctgtgcat atgcccctgg gctttctggg acctggcggc 60 ctgtctggca
gatccgataa tcacggcggc tccgacatcc agatgaccca gtctc 115 <210>
SEQ ID NO 47 <211> LENGTH: 118 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 47 caggggggct cgagcggagg ctctggcctg tctggcagat ctgataacca
cggcggcgtg 60 cacatgcccc tgggctttct gggacctggc ggatctgaca
tccagatgac ccagtctc 118 <210> SEQ ID NO 48 <211>
LENGTH: 774 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 48 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc tatctcttcc ggactgctgt ccggcagatc cgacaatcac
120 ggcggaggct ctgacatcca gatgacccag tctccatcct ccctgtctgc
atctgtagga 180 gacagagtca ccatcacttg ccgggcaagt cagagcatta
gcagctattt aaattggtat 240 cagcagaaac cagggaaagc ccctaagctc
ctgatctatg cggcatccag tttgcaaagt 300 ggggtcccat caaggttcag
tggcagtgga tctgggacag atttcactct caccatcagc 360 agtctgcaac
ctgaagattt tgcaacttac tactgtcaac agacggttgt ggcgcctccg 420
ttattcggcc aagggaccaa ggtggaaatc aaacgtacgg tggctgcacc atctgtcttc
480 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt
gtgcctgctg 540 aataacttct atcccagaga ggccaaagta cagtggaagg
tggataacgc cctccaatcg 600 ggtaactccc aggagagtgt cacagagcag
gacagcaagg acagcaccta cagcctcagc 660 agcaccctga cgctgagcaa
agcagactac gagaaacaca aagtctacgc ctgcgaagtc 720 acccatcagg
gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 774 <210>
SEQ ID NO 49 <211> LENGTH: 258 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 49 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu 20 25 30 Leu Ser Gly Arg Ser Asp Asn His Gly
Gly Gly Ser Asp Ile Gln Met 35 40 45 Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly Asp Arg Val Thr 50 55 60 Ile Thr Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr 65 70 75 80 Gln Gln Lys
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser 85 90 95 Ser
Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly 100 105
110 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
115 120 125
Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln 130
135 140 Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
Phe 145 150 155 160 Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val 165 170 175 Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln Trp 180 185 190 Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val Thr 195 200 205 Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr 210 215 220 Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val 225 230 235 240 Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly 245 250
255 Glu Cys <210> SEQ ID NO 50 <211> LENGTH: 801
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 50 caaggccagt ctggccagtg
caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60 gggggctcga
gcggcggctc tatctcttct ggcctgctgt ctagcggcgg ctccggcgga 120
tctctgtctg gcagatctga caaccacggc ggaggctccg acatccagat gacccagtct
180 ccatcctccc tgtctgcatc tgtaggagac agagtcacca tcacttgccg
ggcaagtcag 240 agcattagca gctatttaaa ttggtatcag cagaaaccag
ggaaagcccc taagctcctg 300 atctatgcgg catccagttt gcaaagtggg
gtcccatcaa ggttcagtgg cagtggatct 360 gggacagatt tcactctcac
catcagcagt ctgcaacctg aagattttgc aacttactac 420 tgtcaacaga
cggttgtggc gcctccgtta ttcggccaag ggaccaaggt ggaaatcaaa 480
cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct
540 ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc
caaagtacag 600 tggaaggtgg ataacgccct ccaatcgggt aactcccagg
agagtgtcac agagcaggac 660 agcaaggaca gcacctacag cctcagcagc
accctgacgc tgagcaaagc agactacgag 720 aaacacaaag tctacgcctg
cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 780 agcttcaaca
ggggagagtg t 801 <210> SEQ ID NO 51 <211> LENGTH: 267
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 51 Gln Gly Gln Ser Gly Gln Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly
Gly Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu 20 25 30 Leu Ser Ser
Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg Ser Asp Asn 35 40 45 His
Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu 50 55
60 Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
65 70 75 80 Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala 85 90 95 Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro 100 105 110 Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile 115 120 125 Ser Ser Leu Gln Pro Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Thr 130 135 140 Val Val Ala Pro Pro Leu
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 145 150 155 160 Arg Thr Val
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 165 170 175 Gln
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 180 185
190 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
195 200 205 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp Ser 210 215 220 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr Glu 225 230 235 240 Lys His Lys Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser 245 250 255 Pro Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 260 265 <210> SEQ ID NO 52 <211>
LENGTH: 798 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 52 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggaggatc tgctgtggga ctgctggctc ctcctggcgg cacatctacc
120 tctggcagat ccgccaaccc tcggggcgga ggatctgaca tccagatgac
ccagtctcca 180 tcctccctgt ctgcatctgt aggagacaga gtcaccatca
cttgccgggc aagtcagagc 240 attagcagct atttaaattg gtatcagcag
aaaccaggga aagcccctaa gctcctgatc 300 tatgcggcat ccagtttgca
aagtggggtc ccatcaaggt tcagtggcag tggatctggg 360 acagatttca
ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 420
caacagacgg ttgtggcgcc tccgttattc ggccaaggga ccaaggtgga aatcaaacgt
480 acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt
gaaatctgga 540 actgcctctg ttgtgtgcct gctgaataac ttctatccca
gagaggccaa agtacagtgg 600 aaggtggata acgccctcca atcgggtaac
tcccaggaga gtgtcacaga gcaggacagc 660 aaggacagca cctacagcct
cagcagcacc ctgacgctga gcaaagcaga ctacgagaaa 720 cacaaagtct
acgcctgcga agtcacccat cagggcctga gctcgcccgt cacaaagagc 780
ttcaacaggg gagagtgt 798 <210> SEQ ID NO 53 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 53 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Ala Val Gly Leu Leu 20 25 30 Ala
Pro Pro Gly Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg 35 40
45 Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
50 55 60 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro 85 90 95 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser 115 120 125 Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val 130 135 140 Val Ala Pro Pro
Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 54 <211>
LENGTH: 798 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 54 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc cacatctacc tctggcagat ccgccaaccc cagaggtggc
120 ggagctgtgg gactgctggc tccaccaggc ggatctgaca tccagatgac
ccagtctcca 180 tcctccctgt ctgcatctgt aggagacaga gtcaccatca
cttgccgggc aagtcagagc 240 attagcagct atttaaattg gtatcagcag
aaaccaggga aagcccctaa gctcctgatc 300 tatgcggcat ccagtttgca
aagtggggtc ccatcaaggt tcagtggcag tggatctggg 360 acagatttca
ctctcaccat cagcagtctg caacctgaag attttgcaac ttactactgt 420
caacagacgg ttgtggcgcc tccgttattc ggccaaggga ccaaggtgga aatcaaacgt
480
acggtggctg caccatctgt cttcatcttc ccgccatctg atgagcagtt gaaatctgga
540 actgcctctg ttgtgtgcct gctgaataac ttctatccca gagaggccaa
agtacagtgg 600 aaggtggata acgccctcca atcgggtaac tcccaggaga
gtgtcacaga gcaggacagc 660 aaggacagca cctacagcct cagcagcacc
ctgacgctga gcaaagcaga ctacgagaaa 720 cacaaagtct acgcctgcga
agtcacccat cagggcctga gctcgcccgt cacaaagagc 780 ttcaacaggg gagagtgt
798 <210> SEQ ID NO 55 <211> LENGTH: 266 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 55 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp
Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly Gly Ser Ser
Gly Gly Ser Thr Ser Thr Ser Gly 20 25 30 Arg Ser Ala Asn Pro Arg
Gly Gly Gly Ala Val Gly Leu Leu Ala Pro 35 40 45 Pro Gly Gly Ser
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 50 55 60 Ala Ser
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser 65 70 75 80
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 85
90 95 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser 115 120 125 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Val 130 135 140 Val Ala Pro Pro Leu Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 145 150 155 160 Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170 175 Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 180 185 190 Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 195 200 205
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 210
215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
260 265 <210> SEQ ID NO 56 <211> LENGTH: 804
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 56 caaggccagt ctggccagtg
caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60 gggggctcga
gcggcggctc tgtgcatatg cccctgggct ttctgggccc tggcggcaca 120
tctacctctg gcagatccgc caaccctcgg ggcggaggat ctgacatcca gatgacccag
180 tctccatcct ccctgtctgc atctgtagga gacagagtca ccatcacttg
ccgggcaagt 240 cagagcatta gcagctattt aaattggtat cagcagaaac
cagggaaagc ccctaagctc 300 ctgatctatg cggcatccag tttgcaaagt
ggggtcccat caaggttcag tggcagtgga 360 tctgggacag atttcactct
caccatcagc agtctgcaac ctgaagattt tgcaacttac 420 tactgtcaac
agacggttgt ggcgcctccg ttattcggcc aagggaccaa ggtggaaatc 480
aaacgtacgg tggctgcacc atctgtcttc atcttcccgc catctgatga gcagttgaaa
540 tctggaactg cctctgttgt gtgcctgctg aataacttct atcccagaga
ggccaaagta 600 cagtggaagg tggataacgc cctccaatcg ggtaactccc
aggagagtgt cacagagcag 660 gacagcaagg acagcaccta cagcctcagc
agcaccctga cgctgagcaa agcagactac 720 gagaaacaca aagtctacgc
ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca 780 aagagcttca
acaggggaga gtgt 804 <210> SEQ ID NO 57 <211> LENGTH:
268 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 57 Gln Gly Gln Ser Gly Gln Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly
Gly Ser Ser Gly Gly Ser Val His Met Pro Leu 20 25 30 Gly Phe Leu
Gly Pro Gly Gly Thr Ser Thr Ser Gly Arg Ser Ala Asn 35 40 45 Pro
Arg Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 50 55
60 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
65 70 75 80 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys 85 90 95 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val 100 105 110 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr 115 120 125 Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln 130 135 140 Thr Val Val Ala Pro Pro
Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 145 150 155 160 Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 165 170 175 Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 180 185
190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr 225 230 235 240 Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser 245 250 255 Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 58 <211>
LENGTH: 804 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 58 caaggccagt
ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60
gggggctcga gcggcggctc cacatctacc tctggcagat ccgccaaccc cagaggcggc
120 ggagtgcata tgcctctggg ctttctggga cctggcggct ctgacatcca
gatgacccag 180 tctccatcct ccctgtctgc atctgtagga gacagagtca
ccatcacttg ccgggcaagt 240 cagagcatta gcagctattt aaattggtat
cagcagaaac cagggaaagc ccctaagctc 300 ctgatctatg cggcatccag
tttgcaaagt ggggtcccat caaggttcag tggcagtgga 360 tctgggacag
atttcactct caccatcagc agtctgcaac ctgaagattt tgcaacttac 420
tactgtcaac agacggttgt ggcgcctccg ttattcggcc aagggaccaa ggtggaaatc
480 aaacgtacgg tggctgcacc atctgtcttc atcttcccgc catctgatga
gcagttgaaa 540 tctggaactg cctctgttgt gtgcctgctg aataacttct
atcccagaga ggccaaagta 600 cagtggaagg tggataacgc cctccaatcg
ggtaactccc aggagagtgt cacagagcag 660 gacagcaagg acagcaccta
cagcctcagc agcaccctga cgctgagcaa agcagactac 720 gagaaacaca
aagtctacgc ctgcgaagtc acccatcagg gcctgagctc gcccgtcaca 780
aagagcttca acaggggaga gtgt 804 <210> SEQ ID NO 59 <211>
LENGTH: 268 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 59 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Thr Ser Thr Ser Gly 20 25 30 Arg
Ser Ala Asn Pro Arg Gly Gly Gly Val His Met Pro Leu Gly Phe 35 40
45 Leu Gly Pro Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
50 55 60 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser 65 70 75 80 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys 85 90 95 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val 100 105 110 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 115 120 125 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 130 135 140 Thr Val Val Ala
Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 145 150 155 160 Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
165 170 175 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn 180 185 190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 225 230 235 240 Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 245 250 255 Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
60 <211> LENGTH: 786 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 60
caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag gggctggcag
60 gggggctcga gcggaggatc tgctgtggga ctgctggctc ctcctggtgg
cctgtctggc 120 agatctgata accacggcgg ctccgacatc cagatgaccc
agtctccatc ctccctgtct 180 gcatctgtag gagacagagt caccatcact
tgccgggcaa gtcagagcat tagcagctat 240 ttaaattggt atcagcagaa
accagggaaa gcccctaagc tcctgatcta tgcggcatcc 300 agtttgcaaa
gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 360
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagacggtt
420 gtggcgcctc cgttattcgg ccaagggacc aaggtggaaa tcaaacgtac
ggtggctgca 480 ccatctgtct tcatcttccc gccatctgat gagcagttga
aatctggaac tgcctctgtt 540 gtgtgcctgc tgaataactt ctatcccaga
gaggccaaag tacagtggaa ggtggataac 600 gccctccaat cgggtaactc
ccaggagagt gtcacagagc aggacagcaa ggacagcacc 660 tacagcctca
gcagcaccct gacgctgagc aaagcagact acgagaaaca caaagtctac 720
gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt caacagggga
780 gagtgt 786 <210> SEQ ID NO 61 <211> LENGTH: 262
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 61 Gln Gly Gln Ser Gly Gln Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly
Gly Ser Ser Gly Gly Ser Ala Val Gly Leu Leu 20 25 30 Ala Pro Pro
Gly Gly Leu Ser Gly Arg Ser Asp Asn His Gly Gly Ser 35 40 45 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 50 55
60 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
65 70 75 80 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 85 90 95 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 115 120 125 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Thr Val Val Ala Pro Pro 130 135 140 Leu Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 145 150 155 160 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 165 170 175 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 180 185
190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
195 200 205 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 225 230 235 240 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 62 <211> LENGTH: 789 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 62 caaggccagt ctggccagtg caatatttgg ctcgtaggtg gtgattgcag
gggctggcag 60 gggggctcga gcggaggctc tggcctgtct ggcagatccg
ataaccatgg cggcgctgtg 120 ggactgctgg ctcctcctgg tggatctgac
atccagatga cccagtctcc atcctccctg 180 tctgcatctg taggagacag
agtcaccatc acttgccggg caagtcagag cattagcagc 240 tatttaaatt
ggtatcagca gaaaccaggg aaagccccta agctcctgat ctatgcggca 300
tccagtttgc aaagtggggt cccatcaagg ttcagtggca gtggatctgg gacagatttc
360 actctcacca tcagcagtct gcaacctgaa gattttgcaa cttactactg
tcaacagacg 420 gttgtggcgc ctccgttatt cggccaaggg accaaggtgg
aaatcaaacg tacggtggct 480 gcaccatctg tcttcatctt cccgccatct
gatgagcagt tgaaatctgg aactgcctct 540 gttgtgtgcc tgctgaataa
cttctatccc agagaggcca aagtacagtg gaaggtggat 600 aacgccctcc
aatcgggtaa ctcccaggag agtgtcacag agcaggacag caaggacagc 660
acctacagcc tcagcagcac cctgacgctg agcaaagcag actacgagaa acacaaagtc
720 tacgcctgcg aagtcaccca tcagggcctg agctcgcccg tcacaaagag
cttcaacagg 780 ggagagtgt 789 <210> SEQ ID NO 63 <211>
LENGTH: 263 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 63 Gln Gly Gln Ser Gly
Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp
Gln Gly Gly Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser
Asp Asn His Gly Gly Ala Val Gly Leu Leu Ala Pro Pro Gly Gly 35 40
45 Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
50 55 60 Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Ser 65 70 75 80 Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu 85 90 95 Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser 100 105 110 Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln 115 120 125 Pro Glu Asp Phe Ala Thr
Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro 130 135 140 Pro Leu Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 145 150 155 160 Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 165 170
175 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
180 185 190 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser 195 200 205 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu 210 215 220 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val 225 230 235 240 Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys 245 250 255 Ser Phe Asn Arg Gly
Glu Cys 260 <210> SEQ ID NO 64 <211> LENGTH: 792
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 64 caaggccagt ctggccagtg
caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60 gggggctcga
gcggcggctc tgtgcatatg cccctgggct ttctgggacc tggcggcctg 120
tctggcagat ccgataatca cggcggctcc gacatccaga tgacccagtc tccatcctcc
180 ctgtctgcat ctgtaggaga cagagtcacc atcacttgcc gggcaagtca
gagcattagc 240 agctatttaa attggtatca gcagaaacca gggaaagccc
ctaagctcct gatctatgcg 300 gcatccagtt tgcaaagtgg ggtcccatca
aggttcagtg gcagtggatc tgggacagat 360 ttcactctca ccatcagcag
tctgcaacct gaagattttg caacttacta ctgtcaacag 420 acggttgtgg
cgcctccgtt attcggccaa gggaccaagg tggaaatcaa acgtacggtg 480
gctgcaccat ctgtcttcat cttcccgcca tctgatgagc agttgaaatc tggaactgcc
540 tctgttgtgt gcctgctgaa taacttctat cccagagagg ccaaagtaca
gtggaaggtg 600 gataacgccc tccaatcggg taactcccag gagagtgtca
cagagcagga cagcaaggac 660 agcacctaca gcctcagcag caccctgacg
ctgagcaaag cagactacga gaaacacaaa 720
gtctacgcct gcgaagtcac ccatcagggc ctgagctcgc ccgtcacaaa gagcttcaac
780 aggggagagt gt 792 <210> SEQ ID NO 65 <211> LENGTH:
264 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 65 Gln Gly Gln Ser Gly Gln Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly
Gly Ser Ser Gly Gly Ser Val His Met Pro Leu 20 25 30 Gly Phe Leu
Gly Pro Gly Gly Leu Ser Gly Arg Ser Asp Asn His Gly 35 40 45 Gly
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 50 55
60 Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser
65 70 75 80 Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu 85 90 95 Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe 100 105 110 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu 115 120 125 Gln Pro Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln Thr Val Val Ala 130 135 140 Pro Pro Leu Phe Gly Gln
Gly Thr Lys Val Glu Ile Lys Arg Thr Val 145 150 155 160 Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 165 170 175 Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 180 185
190 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn
195 200 205 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
Tyr Ser 210 215 220 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
Glu Lys His Lys 225 230 235 240 Val Tyr Ala Cys Glu Val Thr His Gln
Gly Leu Ser Ser Pro Val Thr 245 250 255 Lys Ser Phe Asn Arg Gly Glu
Cys 260 <210> SEQ ID NO 66 <211> LENGTH: 795
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 66 caaggccagt ctggccagtg
caatatttgg ctcgtaggtg gtgattgcag gggctggcag 60 gggggctcga
gcggaggctc tggcctgtct ggcagatctg ataaccacgg cggcgtgcac 120
atgcccctgg gctttctggg acctggcgga tctgacatcc agatgaccca gtctccatcc
180 tccctgtctg catctgtagg agacagagtc accatcactt gccgggcaag
tcagagcatt 240 agcagctatt taaattggta tcagcagaaa ccagggaaag
cccctaagct cctgatctat 300 gcggcatcca gtttgcaaag tggggtccca
tcaaggttca gtggcagtgg atctgggaca 360 gatttcactc tcaccatcag
cagtctgcaa cctgaagatt ttgcaactta ctactgtcaa 420 cagacggttg
tggcgcctcc gttattcggc caagggacca aggtggaaat caaacgtacg 480
gtggctgcac catctgtctt catcttcccg ccatctgatg agcagttgaa atctggaact
540 gcctctgttg tgtgcctgct gaataacttc tatcccagag aggccaaagt
acagtggaag 600 gtggataacg ccctccaatc gggtaactcc caggagagtg
tcacagagca ggacagcaag 660 gacagcacct acagcctcag cagcaccctg
acgctgagca aagcagacta cgagaaacac 720 aaagtctacg cctgcgaagt
cacccatcag ggcctgagct cgcccgtcac aaagagcttc 780 aacaggggag agtgt
795 <210> SEQ ID NO 67 <211> LENGTH: 449 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 67 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Asp
Pro Glu Gly Arg Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr Trp Gly Gln
Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr
Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210
215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val
Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr
Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330
335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe
Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln
Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys
<210> SEQ ID NO 68 <211> LENGTH: 1347 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 68 Cys Ala Gly Gly Thr Ala Cys Ala Gly Cys Thr Gly Ala
Ala Ala Cys 1 5 10 15 Ala Gly Thr Cys Thr Gly Gly Ala Cys Cys Cys
Gly Gly Gly Cys Thr 20 25 30 Thr Gly Thr Ala Cys Ala Gly Cys Cys
Thr Ala Gly Thr Cys Ala Gly 35 40 45 Thr Cys Ala Cys Thr Gly Thr
Cys Thr Ala Thr Cys Ala Cys Cys Thr 50 55 60 Gly Thr Ala Cys Cys
Gly Thr Cys Thr Cys Ala Gly Gly Thr Thr Thr 65 70 75 80 Thr Ala Gly
Cys Cys Thr Gly Ala Cys Ala Ala Ala Thr Thr Ala Cys 85 90 95 Gly
Gly Thr Gly Thr Gly Cys Ala Thr Thr Gly Gly Gly Thr Ala Cys 100 105
110 Gly Cys Cys Ala Gly Thr Cys Thr Cys Cys Cys Gly Gly Thr Ala Ala
115 120 125 Gly Gly Gly Gly Cys Thr Gly Gly Ala Gly Thr Gly Gly Cys
Thr Cys 130 135 140 Gly Gly Cys Gly Thr Gly Ala Thr Cys Thr Gly Gly
Thr Cys Cys Gly 145 150 155 160 Gly Gly Gly Gly Gly Ala Ala Cys Ala
Cys Ala Gly Ala Thr Thr Ala 165 170 175 Thr Ala Ala Thr Ala Cys Thr
Cys Cys Thr Thr Thr Cys Ala Cys Ala 180 185 190 Thr Cys Thr Ala Gly
Ala Cys Thr Gly Thr Cys Cys Ala Thr Cys Ala 195 200 205 Ala Cys Ala
Ala Ala Gly Ala Cys Ala Ala Cys Thr Cys Cys Ala Ala 210 215 220
Ala Thr Cys Gly Cys Ala Gly Gly Thr Thr Thr Thr Thr Thr Thr Cys 225
230 235 240 Ala Ala Gly Ala Thr Gly Ala Ala Thr Thr Cys Cys Cys Thr
Gly Cys 245 250 255 Ala Ala Thr Cys Ala Cys Ala Gly Gly Ala Cys Ala
Cys Thr Gly Cys 260 265 270 Cys Ala Thr Cys Thr Ala Thr Thr Ala Thr
Thr Gly Cys Gly Cys Gly 275 280 285 Ala Gly Gly Gly Cys Cys Cys Thr
Gly Ala Cys Thr Thr Ala Thr Thr 290 295 300 Ala Thr Gly Ala Cys Thr
Ala Thr Gly Ala Gly Thr Thr Cys Gly Cys 305 310 315 320 Thr Thr Ala
Thr Thr Gly Gly Gly Gly Cys Cys Ala Gly Gly Gly Gly 325 330 335 Ala
Cys Gly Cys Thr Thr Gly Thr Gly Ala Cys Cys Gly Thr Ala Ala 340 345
350 Gly Cys Gly Cys Thr Gly Cys Thr Ala Gly Thr Ala Cys Cys Ala Ala
355 360 365 Gly Gly Gly Cys Cys Cys Cys Ala Gly Thr Gly Thr Gly Thr
Thr Cys 370 375 380 Cys Cys Cys Cys Thr Thr Gly Cys Cys Cys Cys Cys
Ala Gly Cys Ala 385 390 395 400 Gly Thr Ala Ala Gly Thr Cys Cys Ala
Cys Cys Thr Cys Ala Gly Gly 405 410 415 Thr Gly Gly Cys Ala Cys Ala
Gly Cys Thr Gly Cys Cys Cys Thr Thr 420 425 430 Gly Gly Gly Thr Gly
Cys Cys Thr Thr Gly Thr Gly Ala Ala Gly Gly 435 440 445 Ala Thr Thr
Ala Cys Thr Thr Cys Cys Cys Ala Gly Ala Ala Cys Cys 450 455 460 Ala
Gly Thr Gly Ala Cys Cys Gly Thr Gly Ala Gly Cys Thr Gly Gly 465 470
475 480 Ala Ala Thr Thr Cys Cys Gly Gly Ala Gly Cys Cys Cys Thr Thr
Ala 485 490 495 Cys Cys Ala Gly Cys Gly Gly Thr Gly Thr Gly Cys Ala
Thr Ala Cys 500 505 510 Cys Thr Thr Thr Cys Cys Gly Gly Cys Cys Gly
Thr Cys Cys Thr Gly 515 520 525 Cys Ala Ala Ala Gly Cys Ala Gly Cys
Gly Gly Ala Cys Thr Thr Thr 530 535 540 Ala Cys Ala Gly Thr Cys Thr
Gly Thr Cys Thr Ala Gly Cys Gly Thr 545 550 555 560 Gly Gly Thr Cys
Ala Cys Cys Gly Thr Gly Cys Cys Cys Ala Gly Cys 565 570 575 Ala Gly
Cys Ala Gly Cys Cys Thr Gly Gly Gly Thr Ala Cys Ala Cys 580 585 590
Ala Gly Ala Cys Gly Thr Ala Thr Ala Thr Thr Thr Gly Cys Ala Ala 595
600 605 Cys Gly Thr Thr Ala Ala Thr Cys Ala Cys Ala Ala Ala Cys Cys
Cys 610 615 620 Thr Cys Ala Ala Ala Cys Ala Cys Ala Ala Ala Gly Gly
Thr Gly Gly 625 630 635 640 Ala Cys Ala Ala Gly Ala Ala Ala Gly Thr
Gly Gly Ala Gly Cys Cys 645 650 655 Thr Ala Ala Ala Thr Cys Ala Thr
Gly Thr Gly Ala Thr Ala Ala Gly 660 665 670 Ala Cys Ala Cys Ala Thr
Ala Cys Ala Thr Gly Cys Cys Cys Thr Cys 675 680 685 Cys Cys Thr Gly
Cys Cys Cys Thr Gly Cys Ala Cys Cys Gly Gly Ala 690 695 700 Gly Cys
Thr Cys Thr Thr Ala Gly Gly Thr Gly Gly Ala Cys Cys Thr 705 710 715
720 Thr Cys Ala Gly Thr Cys Thr Thr Thr Thr Thr Ala Thr Thr Thr Cys
725 730 735 Cys Ala Cys Cys Thr Ala Ala Ala Cys Cys Cys Ala Ala Ala
Gly Ala 740 745 750 Thr Ala Cys Ala Cys Thr Thr Ala Thr Gly Ala Thr
Cys Thr Cys Ala 755 760 765 Cys Gly Gly Ala Cys Ala Cys Cys Cys Gly
Ala Gly Gly Thr Gly Ala 770 775 780 Cys Cys Thr Gly Cys Gly Thr Thr
Gly Thr Cys Gly Thr Gly Gly Ala 785 790 795 800 Thr Gly Thr Cys Thr
Cys Ala Cys Ala Cys Gly Ala Ala Gly Ala Cys 805 810 815 Cys Cys Thr
Gly Ala Ala Gly Thr Gly Ala Ala Ala Thr Thr Cys Ala 820 825 830 Ala
Thr Thr Gly Gly Thr Ala Thr Gly Thr Thr Gly Ala Cys Gly Gly 835 840
845 Thr Gly Thr Thr Gly Ala Gly Gly Thr Gly Cys Ala Thr Ala Ala Cys
850 855 860 Gly Cys Ala Ala Ala Gly Ala Cys Cys Ala Ala Gly Cys Cys
Ala Cys 865 870 875 880 Gly Cys Gly Ala Gly Gly Ala Gly Cys Ala Gly
Thr Ala Thr Ala Ala 885 890 895 Thr Ala Gly Cys Ala Cys Cys Thr Ala
Thr Ala Gly Gly Gly Thr Ala 900 905 910 Gly Thr Cys Ala Gly Cys Gly
Thr Ala Cys Thr Gly Ala Cys Thr Gly 915 920 925 Thr Thr Cys Thr Gly
Cys Ala Thr Cys Ala Gly Gly Ala Thr Thr Gly 930 935 940 Gly Cys Thr
Gly Ala Ala Cys Gly Gly Thr Ala Ala Ala Gly Ala Gly 945 950 955 960
Thr Ala Cys Ala Ala Ala Thr Gly Cys Ala Ala Gly Gly Thr Cys Thr 965
970 975 Cys Ala Ala Ala Cys Ala Ala Gly Gly Cys Thr Cys Thr Cys Cys
Cys 980 985 990 Thr Gly Cys Cys Cys Cys Gly Ala Thr Cys Gly Ala Gly
Ala Ala Gly 995 1000 1005 Ala Cys Ala Ala Thr Thr Thr Cys Thr Ala
Ala Gly Gly Cys Cys 1010 1015 1020 Ala Ala Ala Gly Gly Gly Cys Ala
Gly Cys Cys Cys Cys Gly Gly 1025 1030 1035 Gly Ala Ala Cys Cys Ala
Cys Ala Ala Gly Thr Cys Thr Ala Thr 1040 1045 1050 Ala Cys Cys Cys
Thr Gly Cys Cys Ala Cys Cys Cys Ala Gly Thr 1055 1060 1065 Cys Gly
Gly Gly Ala Thr Gly Ala Ala Cys Thr Ala Ala Cys Ala 1070 1075 1080
Ala Ala Ala Ala Ala Thr Cys Ala Gly Gly Thr Gly Thr Cys Thr 1085
1090 1095 Cys Thr Ala Ala Cys Cys Thr Gly Cys Cys Thr Gly Gly Thr
Gly 1100 1105 1110 Ala Ala Gly Gly Gly Ala Thr Thr Thr Thr Ala Cys
Cys Cys Thr 1115 1120 1125 Thr Cys Cys Gly Ala Thr Ala Thr Ala Gly
Cys Thr Gly Thr Gly 1130 1135 1140 Gly Ala Gly Thr Gly Gly Gly Ala
Gly Thr Cys Thr Ala Ala Thr 1145 1150 1155 Gly Gly Cys Cys Ala Ala
Cys Cys Ala Gly Ala Gly Ala Ala Thr 1160 1165 1170 Ala Ala Thr Thr
Ala Cys Ala Ala Gly Ala Cys Thr Ala Cys Cys 1175 1180 1185 Cys Cys
Cys Cys Cys Cys Gly Thr Thr Cys Thr Thr Gly Ala Cys 1190 1195 1200
Ala Gly Thr Gly Ala Thr Gly Gly Cys Thr Cys Gly Thr Thr Cys 1205
1210 1215 Thr Thr Cys Thr Thr Ala Thr Ala Cys Thr Cys Ala Ala Ala
Ala 1220 1225 1230 Thr Thr Ala Ala Cys Ala Gly Thr Cys Gly Ala Cys
Ala Ala Ala 1235 1240 1245 Thr Cys Cys Cys Gly Ala Thr Gly Gly Cys
Ala Ala Cys Ala Gly 1250 1255 1260 Gly Gly Cys Ala Ala Thr Gly Thr
Gly Thr Thr Thr Ala Gly Cys 1265 1270 1275 Thr Gly Thr Ala Gly Cys
Gly Thr Gly Ala Thr Gly Cys Ala Thr 1280 1285 1290 Gly Ala Ala Gly
Cys Cys Cys Thr Gly Cys Ala Cys Ala Ala Cys 1295 1300 1305 Cys Ala
Thr Thr Ala Cys Ala Cys Ala Cys Ala Gly Ala Ala Gly 1310 1315 1320
Thr Cys Thr Cys Thr Gly Thr Cys Cys Thr Thr Gly Thr Cys Ala 1325
1330 1335 Cys Cys Thr Gly Gly Cys Ala Ala Gly 1340 1345 <210>
SEQ ID NO 69 <211> LENGTH: 447 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 69 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Ser Leu
Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala Arg Ala 85 90 95 Leu
Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly Thr Leu 100 105
110 Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
Gly Cys
130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val
Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile
Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245
250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370
375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> SEQ ID NO 70
<211> LENGTH: 645 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 70
acccaaatcc tcctgaccca gtcccctgtt atcctttctg tgtcgcccgg ggagcgcgtt
60 agctttagct gccgcgccag tcagtcaatc ggaacaaaca tccattggta
ccagcagcgt 120 acgaacggca gtccaaggct gctgatcaaa tacgcaagtg
aatctatatc ggggattccg 180 tctcggttca gcggatccgg aagcgggact
gactttacgc tctccataaa tagcgtcgaa 240 agtgaggaca ttgcagacta
ttactgtcag cagaataaca actggccgac cacatttggg 300 gccggaacca
agttggaact gaagcgcact gtggcagctc ctagtgtttt tattttcccc 360
ccttctgacg agcaactgaa aagtggtaca gcttcagtag tttgtttgct caataatttc
420 tacccacggg aagcaaaggt gcagtggaaa gtcgacaacg cattacagag
cggcaactct 480 caagaaagcg tgacggagca ggatagcaag gactcaacat
attccttgtc ttccactctc 540 actctgtcaa aggctgatta tgagaagcat
aaggtgtatg cgtgcgaagt gacacaccag 600 ggattatcaa gcccagtgac
caagtccttt aaccgtggcg aatgc 645 <210> SEQ ID NO 71
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 71 Leu
Ser Gly Arg Ser Asp Asn Ile 1 5 <210> SEQ ID NO 72
<211> LENGTH: 783 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 72
cagggccaga gcggccaatg catctccccc cgcggttgtc ccgacgggcc gtacgtgatg
60 tacggcagct ccggcggcag tgggggtagc ggtgggtccg ggctgagtgg
ccggtccgac 120 aatcacggga gctcgggaac acagattctg ctgacgcaat
ctcccgtgat cctctcggtc 180 tcacccggcg aacgggtctc gttcagctgc
agagcgtccc aatcaatcgg gaccaatatt 240 cactggtacc agcaaaggac
taatgggtct ccccggctgc tgataaaata cgcctccgag 300 tctatctcgg
gcatcccatc ccgatttagt ggtagcggaa gcggcactga tttcaccttg 360
tctattaaca gcgtagaatc tgaggacatt gcagactatt actgtcagca gaataacaat
420 tggcctacaa ctttcggcgc cgggaccaaa ctagagttaa agcgtactgt
ggctgccccc 480 agcgttttta tttttccgcc cagcgacgaa cagctgaagt
caggcacagc ctctgtggtg 540 tgtctcctga ataacttcta ccccagagag
gccaaagttc agtggaaagt ggacaatgcc 600 ttgcagtccg gaaacagtca
agagtccgtg accgagcagg acagtaagga tagcacgtat 660 agcctctcta
gtactttaac actgtccaag gccgactacg agaagcacaa ggtgtacgca 720
tgcgaagtga cccatcaggg gctttcctcc cccgtcacca agtctttcaa tcgcggggag
780 tgt 783 <210> SEQ ID NO 73 <211> LENGTH: 261
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 73 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu
Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 74 <211> LENGTH: 783 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 74 caaggtcagt ccggacagtg tatttcccct agaggttgcc ctgacgggcc
gtatgtcatg 60 tacggtagtt ctggcggtag tggcggatct ggcggcagtg
ggctgagcgg acgtagcggg 120 aatcacggct catccgggac gcagatactg
ctgacccagt cccccgtgat cctgtccgtg 180 tcaccgggcg aaagggtcag
tttctcttgc cgagcatcac agtccatagg tacgaatatc 240 cattggtacc
agcagcggac caatgggagc ccaagactgc tcattaagta cgcatctgag 300
agtatctcag gcattccaag caggttttcc ggcagtggga gcggcactga cttcaccctc
360 agcattaaca gcgtggaaag cgaagacatt gcagattact actgccaaca
gaacaataac 420 tggcctacta cattcggggc aggaactaag ttggagctca
aacgtaccgt cgctgctcct 480 agcgtattta ttttccctcc tagcgatgaa
cagttgaaat ctggtaccgc tagtgttgtg 540 tgcttactga acaactttta
tccccgggag gccaaggtac aatggaaggt ggacaatgcc 600 ctccaatcag
ggaacagcca ggagtctgtt accgagcagg actccaagga cagcacctac 660
agcctgagct ctacccttac attgagcaag gctgattatg agaagcataa ggtctacgct
720 tgtgaggtga cccatcaggg gctcagcagc ccggtgacaa aaagctttaa
ccggggggaa 780 tgc 783 <210> SEQ ID NO 75 <211> LENGTH:
261 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 75
Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5
10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly
Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Gly Asn His Gly Ser Ser
Gly Thr Gln 35 40 45 Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser
Val Ser Pro Gly Glu 50 55 60 Arg Val Ser Phe Ser Cys Arg Ala Ser
Gln Ser Ile Gly Thr Asn Ile 65 70 75 80 His Trp Tyr Gln Gln Arg Thr
Asn Gly Ser Pro Arg Leu Leu Ile Lys 85 90 95 Tyr Ala Ser Glu Ser
Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser 100 105 110 Gly Ser Gly
Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu 115 120 125 Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr 130 135
140 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
145 150 155 160 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr 165 170 175 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys 180 185 190 Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu 195 200 205 Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser 210 215 220 Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 225 230 235 240 Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 245 250 255
Asn Arg Gly Glu Cys 260 <210> SEQ ID NO 76 <211>
LENGTH: 783 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 76 caggggcagt
ctgggcagtg tattagcccc agggggtgcc ccgacgggcc ttacgtgatg 60
tatggcagct ccggtggcag cggaggctct ggcgggagtg ggatcagttc cggcctgctg
120 agctccgggt caagcgggac ccagatcttg ctcacccaat caccagtgat
cctaagcgtg 180 agccctggcg aacgggtcag cttctcttgc cgggcatctc
agagtattgg cactaacata 240 cactggtacc agcagcgaac caatgggtcc
ccccgccttc taatcaaata tgctagcgaa 300 tccatttcag gaattcctag
ccgatttagc ggcagcggat caggcactga cttcactctg 360 tcaatcaact
cagttgaaag cgaggacatt gcagactact attgccagca gaataataat 420
tggcccacta catttggagc tggaacaaaa ttggagctta agaggacagt ggctgcgcct
480 agtgtattta tctttccccc ctctgacgaa cagttgaaat cgggaaccgc
atccgtcgtc 540 tgtttactga acaacttcta tcccagagag gccaaagtgc
agtggaaagt ggataatgct 600 ttgcagtctg gcaacagcca ggaaagcgtg
acggagcagg actcaaagga tagtacatac 660 tccctgtcct ccaccctgac
tctgagtaag gccgactacg agaagcacaa ggtctacgcc 720 tgcgaagtga
cgcaccaagg gctatcgagc ccggtcacca agtctttcaa tcgtggagaa 780 tgc 783
<210> SEQ ID NO 77 <211> LENGTH: 261 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 77 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile Ser Ser Gly Leu Leu Ser
Ser Gly Ser Ser Gly Thr Gln 35 40 45 Ile Leu Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu 50 55 60 Arg Val Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile 65 70 75 80 His Trp Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys 85 90 95 Tyr
Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser 100 105
110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr
Val Ala Ala Pro 145 150 155 160 Ser Val Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala Ser Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185 190 Val Gln Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu 195 200 205 Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser 210 215 220 Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 225 230
235 240 Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe 245 250 255 Asn Arg Gly Glu Cys 260 <210> SEQ ID NO 78
<211> LENGTH: 783 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 78
caggggcaat caggacaatg catcagccct aggggctgcc cagacggccc atatgtgatg
60 tacggtagct ctgggggctc aggaggcagc gggggaagcg gacaaaacca
ggccttacga 120 atggctggca gctctggcac ccagatattg ctgacgcaga
gtccagttat ccttagtgtc 180 agccctggtg aacgggtttc atttagttgc
cgtgcctccc agtctattgg aacgaacatt 240 cattggtacc agcaaaggac
caacggttca cccaggttgc ttatcaagta tgcttcagag 300 tcaatctccg
ggattccctc aaggttttca ggctctggct caggtaccga ttttacgctg 360
agcatcaact ccgtggagag tgaggacatt gctgattatt actgtcagca gaataacaat
420 tggccgacaa ctttcggcgc cggcacaaag ctggaactta agcgtactgt
ggctgcgcca 480 tctgtcttca tttttccgcc ctcggacgag cagttgaagt
cagggaccgc ctctgtcgtg 540 tgccttctca ataacttcta tcccagagag
gctaaagtcc agtggaaagt tgataatgca 600 cttcagagcg ggaatagcca
ggagagcgtg acggaacagg actctaagga ctccacctat 660 tctctctcat
ccacccttac tctctctaaa gccgactacg aaaagcataa ggtttatgct 720
tgcgaagtca ctcatcaagg gctatctagt ccggtcacta aaagcttcaa cagaggtgaa
780 tgt 783 <210> SEQ ID NO 79 <211> LENGTH: 261
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 79 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Gln
Asn Gln Ala Leu Arg Met Ala Gly Ser Ser Gly Thr Gln 35 40 45 Ile
Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu 50 55
60 Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
65 70 75 80 His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys 85 90 95 Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu 115 120 125 Asp Ile Ala Asp Tyr Tyr Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr 130 135 140 Phe Gly Ala Gly Thr Lys
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 80
<211> LENGTH: 798 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 80
caaggccagt ctggacaatg tatcagcccc cgtggctgtc cagacggtcc ttacgttatg
60 tatggatcta gcgggggctc tggagggtct ggcggctctg gaatctctag
tggacttctc 120 tccggaagaa gcgataatca tggatccagc gggacacaaa
tcctgttgac acagtcccca 180 gtgatcctgt cagtctcgcc cggagaaagg
gtgtctttct cttgtagggc tagtcagtct 240 atcggaacta acatccattg
gtaccagcag cggacaaatg ggagcccgag gcttctgatc 300 aagtatgctt
cagagagtat aagcggcatc ccctcaagat ttagtggcag cgggtccggg 360
acagatttca ccttgtcaat caattctgtc gaatccgaag acattgcaga ctactattgc
420 cagcaaaaca acaactggcc caccactttc ggtgctggaa ccaaactcga
gctgaaacgc 480 actgtggcag ctccttcagt gttcatcttc ccacctagcg
acgagcagtt gaaatcgggg 540 acagcctcag tggtgtgtct actgaacaac
ttttaccccc gggaagccaa agtgcagtgg 600 aaggtcgaca atgcgctgca
atcagggaac agtcaggagt cagttacaga gcaggactct 660 aaggacagta
catattcttt gagttccacc ttgacattaa gcaaggcaga ctacgagaaa 720
cacaaggtgt acgcatgtga agttacacac cagggccttt cctccccagt tacgaaaagc
780 ttcaacagag gcgaatgc 798 <210> SEQ ID NO 81 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 81 Gln Gly Gln Ser Gly
Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val
Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser
Gly Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn His Gly 35 40
45 Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser
50 55 60 Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
Asn Gly Ser Pro 85 90 95 Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser
Ile Ser Gly Ile Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Ser Ile Asn 115 120 125 Ser Val Glu Ser Glu Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn 130 135 140 Asn Trp Pro Thr
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 82 <211>
LENGTH: 798 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 82 caaggtcaga
gtggccaatg catatcgccc agaggatgtc ctgacggacc ctacgtgatg 60
tacgggagtt ctggggggag tggaggctct ggcgggtcag ggattagttc cggcctcttg
120 tctggacgct ccggaaatca cggatcatct gggacccaga tcctcctgac
ccagtctccc 180 gtcattctgt ctgtttctcc aggcgagcgg gtttcattta
gctgtagggc cagtcagagc 240 attggcacca acatccattg gtaccagcag
agaactaatg gcagtcccag actgctcatt 300 aaatatgcaa gcgaatcaat
ttccgggatt ccttctcgct tctcgggatc tggatctggc 360 accgacttca
cgctgtccat caacagcgtg gagagtgagg acatcgccga ttactactgc 420
cagcagaaca acaactggcc aacaactttt ggcgccggga ccaagcttga gttaaagaga
480 accgtagctg caccctctgt tttcattttc ccaccctcag acgagcagct
taagtcagga 540 actgccagtg tggtgtgcct gctgaacaac ttctacccga
gagaggctaa agtccagtgg 600 aaggtagaca atgcccttca gtctggcaac
tctcaggaga gtgtcacaga gcaggattct 660 aaggactcca cgtacagtct
gagttccacc ctcaccctca gtaaggcaga ctacgagaag 720 cacaaagtct
acgcatgtga ggttactcac caggggctca gctctcccgt gacgaagtca 780
tttaacagag gtgagtgc 798 <210> SEQ ID NO 83 <211>
LENGTH: 266 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 83 Gln Gly Gln Ser Gly
Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val
Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser
Gly Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Gly Asn His Gly 35 40
45 Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser
50 55 60 Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
Gln Ser 65 70 75 80 Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
Asn Gly Ser Pro 85 90 95 Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser
Ile Ser Gly Ile Pro Ser 100 105 110 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Ser Ile Asn 115 120 125 Ser Val Glu Ser Glu Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn 130 135 140 Asn Trp Pro Thr
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg 145 150 155 160 Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 165 170
175 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
180 185 190 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 195 200 205 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 210 215 220 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 225 230 235 240 His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro 245 250 255 Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 84 <211>
LENGTH: 825 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 84 cagggacagt
cgggacagtg catttctccg agaggctgcc ctgacggccc atacgtaatg 60
tacggatcat ccggtggcag tggagggtcc gggggatccg gtctaagcgg cagaagtgat
120 aatcatggag gctctggcgg gagcatcagc tccggattgc tttccagcgg
aagttctggc 180 actcaaattc tgctgacaca aagccctgtg atcttgtcag
tctcacctgg cgagcgggtg 240 agcttttcat gccgggcttc ccagagcatc
ggtacaaata ttcactggta tcagcagaga 300 accaatggca gtccgcggtt
gctgattaag tatgcgagcg agagcatatc aggcatacca 360 agcagattta
gcgggagtgg ctctgggacc gattttacac tcagtataaa ttcagtggag 420
agcgaggata tagccgacta ctactgccag caaaacaata actggcccac caccttcggc
480 gcagggacca agcttgaact gaagcgtaca gttgccgccc caagcgtatt
tattttccct 540 ccaagcgacg aacagctgaa aagcggtacc gcaagcgttg
tgtgcctgct gaataacttt 600 tacccaaggg aagctaaggt gcagtggaag
gttgacaatg cgctgcagtc aggcaactcc 660 caggaatcgg taacagagca
ggactccaag gattcaactt atagtcttag tagtaccctt 720 actctttcca
aagctgatta tgaaaaacac aaagtgtatg catgcgaggt gacccaccaa 780
ggactgtcat ctcctgtcac caagtccttc aaccggggag agtgt 825 <210>
SEQ ID NO 85 <211> LENGTH: 275 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 85 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Asp Asn
His Gly Gly Ser Gly Gly Ser
35 40 45 Ile Ser Ser Gly Leu Leu Ser Ser Gly Ser Ser Gly Thr Gln
Ile Leu 50 55 60 Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro
Gly Glu Arg Val 65 70 75 80 Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
Gly Thr Asn Ile His Trp 85 90 95 Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg Leu Leu Ile Lys Tyr Ala 100 105 110 Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 115 120 125 Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 130 135 140 Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly 145 150 155
160 Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val
165 170 175 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
Ala Ser 180 185 190 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala Lys Val Gln 195 200 205 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln Glu Ser Val 210 215 220 Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu Ser Ser Thr Leu 225 230 235 240 Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 245 250 255 Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 260 265 270 Gly
Glu Cys 275 <210> SEQ ID NO 86 <211> LENGTH: 825
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 86 caaggtcaga gcggccagtg
cattagtcct cgcggttgcc ctgatggacc atacgtaatg 60 tatggaagct
ctggtggatc cgggggctct ggcggatcag gaatctccag cgggctgctc 120
tcatcaggtg gcagcggggg ctcattaagc ggccgaagtg acaatcacgg ctcgtccggt
180 acacagattc tgctcactca gtcacccgtt atactgtctg tgtcgcctgg
agagcgtgtc 240 agcttttcat gtagagcctc gcagtcaata ggcacgaata
tacactggta ccagcagaga 300 actaatggaa gcccaaggtt gctcatcaaa
tacgcatctg agtcgattag cggcattccg 360 tccaggttta gtggcagtgg
aagcggcacc gatttcactt tgtctattaa ctctgtggaa 420 agcgaggaca
tcgccgatta ttattgtcag cagaataaca attggcccac caccttcggt 480
gccggtacta agctggagct gaaacgtaca gttgccgctc cctctgtgtt tattttccct
540 ccctcggatg agcaactcaa atcagggaca gcgagtgtcg tatgtctcct
gaacaatttt 600 tacccacgtg aagctaaagt tcagtggaag gtggacaacg
ctctgcagtc cggcaacagt 660 caggaaagcg taactgaaca ggactcaaag
gatagcactt actccttgag cagcactctc 720 actctttcca aggctgatta
tgagaagcac aaggtgtacg cgtgtgaagt cacccatcag 780 ggactgtcaa
gtccggtgac taaatcattt aacaggggcg aatgc 825 <210> SEQ ID NO 87
<211> LENGTH: 275 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 87 Gln
Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10
15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly
20 25 30 Ser Gly Ile Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser Gly
Gly Ser 35 40 45 Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly
Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105 110 Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 115 120 125 Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 130 135 140
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly 145
150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230 235 240 Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 245 250 255 Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 260 265
270 Gly Glu Cys 275 <210> SEQ ID NO 88 <211> LENGTH:
825 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 88 cagggccaga gtgggcagtg
tatttcccct cgcggatgtc ccgacggtcc atacgtaatg 60 tatgggtcaa
gcgggggatc aggaggaagt ggaggctccg gactcagcgg tcgctccggc 120
aatcacgggg ggtctggcgg atcaataagt tcgggcctcc tgagctccgg ttcatctggc
180 actcagatcc tgctcacgca gtcgccggta atactgagtg tctcaccagg
cgagcgtgtc 240 agcttcagct gtcgcgcctc acagtcaatc ggcacaaata
tccattggta ccagcaaagg 300 accaatggca gccctaggct gctgataaaa
tacgcatccg agtcaatttc agggattcca 360 tcgagattct cgggcagcgg
aagtgggacc gactttactc tctccatcaa cagcgtcgag 420 tcggaggaca
tcgcggacta ctactgccag cagaataaca attggccaac aacattcggc 480
gcaggaacaa agctagagct caagaggaca gtggctgcac ccagtgtatt catcttccca
540 cctagcgacg agcaactgaa gagcgggacg gcttccgtcg tttgtctatt
aaataatttc 600 tatccccgtg aggctaaagt tcagtggaag gttgataatg
cgttgcagtc cggcaactcc 660 caggaatccg tcacagagca ggattctaag
gattcaacct atagcttaag ctctacactt 720 acgctttcta aagccgatta
tgaaaaacac aaggtgtacg cttgtgaggt tacccaccag 780 ggcctgagca
gccccgtgac caagtcgttc aaccggggcg agtgt 825 <210> SEQ ID NO 89
<211> LENGTH: 275 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 89 Gln
Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10
15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly
20 25 30 Ser Gly Leu Ser Gly Arg Ser Gly Asn His Gly Gly Ser Gly
Gly Ser 35 40 45 Ile Ser Ser Gly Leu Leu Ser Ser Gly Ser Ser Gly
Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105 110 Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 115 120 125 Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 130 135 140
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly 145
150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230 235 240 Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 245 250 255 Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 260 265
270 Gly Glu Cys 275
<210> SEQ ID NO 90 <211> LENGTH: 825 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 90 caaggacaga gcggacagtg tatctcacct cgcggctgcc ccgacggccc
ttacgtcatg 60 tacggctcct cgggtgggtc cgggggaagt ggcgggtctg
gcattagttc agggctctta 120 tcttccggcg gaagcggggg atctctttcc
gggcggagtg gcaatcacgg cagtagcgga 180 actcagatcc tactcactca
gtcaccagtg atcctgtctg tcagtccagg ggagagagtg 240 tctttcagtt
gtagagcttc ccagtctatt gggacaaaca ttcactggta tcaacagcga 300
actaatggat cgccaagact cctgattaaa tatgcttctg agagcatctc tggaattcca
360 tcaagattct cagggagtgg tagcggcacc gattttacgt tatcgatcaa
ttccgttgag 420 agcgaagata tcgcggacta ttactgtcag cagaacaata
actggcctac aacgttcggg 480 gcagggacga aattggagct gaagcggacc
gtcgccgcgc caagcgtgtt catcttcccc 540 cctagcgacg agcaattgaa
aagcggcacc gcaagtgtgg tttgcctgct gaacaacttt 600 tatcctcgcg
aggcgaaagt gcagtggaaa gtcgacaatg cactccagtc agggaacagc 660
caagagtccg ttactgaaca agactctaaa gatagtactt atagcttatc cagcacactg
720 acgctcagta aggccgatta tgaaaaacat aaggtgtatg cgtgtgaggt
tacccatcaa 780 ggattgtcat cacccgtcac caaatccttt aacagaggag aatgt
825 <210> SEQ ID NO 91 <211> LENGTH: 275 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 91 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile Ser Ser Gly
Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg
Ser Gly Asn His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr
Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80
Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85
90 95 Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala 100 105 110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser 115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu
Leu Lys Arg Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210
215 220 Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu 225 230 235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ
ID NO 92 <211> LENGTH: 825 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 92
cagggtcaaa gtggacagtg tatctcgccc cgcggctgcc cagacggccc atatgtgatg
60 tatggttctt ccggtggatc cggcggatca ggtgggtctg gcctctcagg
tcgttccgac 120 aaccacggcg gctcaggtgg gtctcagaat caggcactgc
ggatggccgg atcttctggc 180 acccagatat tgctcacaca gtcaccagtt
attctgtccg tatctccagg agaacgggta 240 tctttctctt gtagggcaag
ccagtccatc ggaacaaaca tccattggta ccagcagcgg 300 accaatggca
gtccacggct tctgatcaag tatgctagtg aaagcattag cgggattcca 360
agccgatttt ctgggtcggg tagtggaacc gacttcaccc tgagcattaa ctctgtcgaa
420 tccgaagata ttgctgacta ttactgtcag cagaacaaca attggccgac
tacgtttggc 480 gccggaacca aattagaact taagagaacc gtggccgctc
cctctgtctt cattttcccg 540 ccttccgacg aacagctgaa gagcggaact
gcctccgtgg tgtgcctgtt gaataacttt 600 tatccaaggg aagcaaaggt
gcagtggaaa gtggacaatg ctctgcagtc tggcaatagc 660 caggagtccg
tgactgaaca ggacagtaaa gactcaacct actcactgag cagtactctc 720
acattatcca aagccgatta tgaaaagcat aaggtttatg catgcgaggt tacccaccag
780 ggactgagct cccccgtgac caaaagcttc aataggggtg agtgc 825
<210> SEQ ID NO 93 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 93 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Asp Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Gln Asn Gln Ala Leu Arg Met
Ala Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 94
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 94
caggggcagt ccggacaatg catcagcccc cgaggctgcc ctgatggccc ctacgtgatg
60 tacgggtcca gcggtggcag cgggggctca ggggggagcg ggcagaatca
ggccctgaga 120 atggcgggtg gatccggggg gtccctttct ggcaggtccg
ataaccacgg ttctagtgga 180 acacagattt tgctgacaca aagtcccgtc
atcctctctg tgtctcccgg tgagcgggtc 240 agtttttcct gccgagcgtc
ccagagcatc gggacaaata tccattggta ccagcagaga 300 acgaacggct
ctcctagact gctcatcaag tacgcctcgg aaagtatttc cggcattccc 360
tcccgtttca gcggctccgg aagtggtaca gattttaccc tgagtattaa ttccgtcgaa
420 tctgaggaca tagccgacta ctattgccaa cagaataaca attggccaac
aacttttggc 480 gccgggacta agctggagct gaaacggacc gtcgcagcac
caagtgtttt catcttccca 540 ccaagtgacg agcagctgaa atccggaaca
gcgagcgtgg tgtgcctact caataacttc 600 tatccacgcg aagccaaggt
gcagtggaaa gtggacaacg ctctgcagtc cggcaatagc 660 caggaaagcg
tgacagagca agattctaag gacagtacgt attcactgtc cagtacgctc 720
accttaagca aggctgacta cgaaaaacac aaggtctacg cctgtgaggt cacacatcag
780 ggcctctcca gtccggttac aaaaagtttc aatcgcgggg aatgt 825
<210> SEQ ID NO 95 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 95
Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5
10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly
Gly 20 25 30 Ser Gly Gln Asn Gln Ala Leu Arg Met Ala Gly Gly Ser
Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser
Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro Val Ile Leu Ser
Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser Cys Arg Ala Ser
Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr Gln Gln Arg Thr
Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105 110 Ser Glu Ser
Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser 115 120 125 Gly
Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile 130 135
140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly
145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr Glu Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230 235 240 Thr Leu
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 245 250 255
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 260
265 270 Gly Glu Cys 275 <210> SEQ ID NO 96 <211>
LENGTH: 825 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 96 caaggccaat
ccggtcagtg catcagtccc agaggctgcc ctgacgggcc ctacgtgatg 60
tatggtagct cagggggctc cggcggctcc ggcggaagcg gacttagcgg ccgtagcggc
120 aaccatgggg gttctggagg atcccagaat caggctctgc gcatggctgg
aagcagcggt 180 acccagatcc tgctcaccca atcacccgtc atcttgtctg
tgagtcctgg cgaaagggtg 240 tcgttctctt gtcgcgcgtc ccagtccatt
gggaccaaca ttcattggta ccagcagagg 300 actaacggga gcccccgcct
gctgatcaaa tacgccagtg aatctatctc tggaatccca 360 tcacgatttt
cagggtccgg tagtgggacc gacttcactt tgagtattaa cagtgtggaa 420
tccgaggaca tagccgacta ttactgtcag cagaacaata actggccaac aacctttggc
480 gccgggacaa agttagagct taagcggact gttgcagccc cctccgtttt
tatcttcccg 540 cccagtgatg aacagctgaa aagcggtacc gcctccgtag
tgtgccttct caataatttt 600 taccccagag aagctaaagt acagtggaaa
gtcgacaacg ccctccagag cggcaacagt 660 caggagtccg tcaccgagca
ggattctaaa gactcaacat atagcctttc gtccacccta 720 acactttcaa
aagcagacta tgaaaaacat aaggtgtatg cctgcgaggt cacacaccag 780
gggctcagct ctccagttac taagtcattc aaccgcggag agtgt 825 <210>
SEQ ID NO 97 <211> LENGTH: 275 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 97 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Leu Ser Gly Arg Ser Gly Asn
His Gly Gly Ser Gly Gly Ser 35 40 45 Gln Asn Gln Ala Leu Arg Met
Ala Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu 245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 98
<211> LENGTH: 825 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 98
cagggccaat caggtcagtg cattagcccc cgagggtgtc ccgatgggcc ctacgtaatg
60 tacggatcat cgggcggatc tgggggctcc ggtggctctg gtcagaatca
agctctgcgc 120 atggccggag gtagcggtgg aagcctgagc ggccgaagtg
gaaaccacgg ctcctctggc 180 actcagattc ttctcacgca gtcgcccgtg
atcttgtccg tgagcccagg cgagcgggtg 240 agcttctctt gccgggccag
ccaaagtata ggtacaaata ttcactggta ccaacagcga 300 accaacgggt
cgcctaggtt gctcataaag tacgcatccg agagtataag cggcatacca 360
tctaggttct caggtagcgg cagcgggacc gattttaccc tcagcattaa ttcggttgaa
420 tctgaagata tcgccgatta ttattgtcag cagaataaca attggcctac
tactttcggc 480 gccggaacaa agctggaact taagcgcaca gtggccgctc
cttctgtctt tatcttccct 540 ccatctgacg agcaattaaa gagtgggaca
gcctcggtgg tgtgtttgct caataacttc 600 tatccaaggg aggcaaaggt
gcagtggaag gtcgataacg ctctccagag tgggaattcc 660 caggagtccg
tgaccgagca ggattctaaa gatagcacat actcactgtc ttccaccctg 720
accctgtcca aggcagacta cgagaagcac aaagtttacg cctgtgaagt gacacaccag
780 ggcctcagct ctcctgtcac aaagagtttt aatcggggcg agtgt 825
<210> SEQ ID NO 99 <211> LENGTH: 275 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 99 Gln Gly Gln Ser Gly Gln Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr Gly Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly 20 25 30 Ser Gly Gln Asn Gln Ala Leu Arg Met
Ala Gly Gly Ser Gly Gly Ser 35 40 45 Leu Ser Gly Arg Ser Gly Asn
His Gly Ser Ser Gly Thr Gln Ile Leu 50 55 60 Leu Thr Gln Ser Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val 65 70 75 80 Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp 85 90 95 Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala 100 105
110 Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
115 120 125 Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile 130 135 140 Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly 145 150 155 160 Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala Pro Ser Val 165 170 175 Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser 180 185 190 Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln 195 200 205 Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val 210 215 220 Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu 225 230
235 240 Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
Glu
245 250 255 Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn Arg 260 265 270 Gly Glu Cys 275 <210> SEQ ID NO 100
<211> LENGTH: 449 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 100 Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Arg Pro Ser Gln 1 5 10
15 Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30 His Ala Trp Ser Trp Val Arg Gln Pro Pro Gly Arg Gly Leu
Glu Trp 35 40 45 Ile Gly Tyr Ile Ser Tyr Ser Gly Ile Thr Thr Tyr
Asn Pro Ser Leu 50 55 60 Lys Ser Arg Val Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Leu Ala Arg
Thr Thr Ala Met Asp Tyr Trp Gly Gln Gly 100 105 110 Ser Leu Val Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145
150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265
270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala
Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390
395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser Pro Gly 435 440 445 Lys <210> SEQ ID NO 101
<211> LENGTH: 214 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 101 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys
Gln Gln Gly Asn Thr Leu Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145
150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210
<210> SEQ ID NO 102 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 102 Tyr Gly Ser Cys Ser Trp Asn Tyr Val His Ile Phe Met
Asp Cys 1 5 10 15 <210> SEQ ID NO 103 <211> LENGTH: 16
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 103 Gln Gly Asp Phe Asp Ile Pro
Phe Pro Ala His Trp Val Pro Ile Thr 1 5 10 15 <210> SEQ ID NO
104 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 104
Met Gly Val Pro Ala Gly Cys Val Trp Asn Tyr Ala His Ile Phe Met 1 5
10 15 Asp Cys <210> SEQ ID NO 105 <211> LENGTH: 21
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 105 Gln Gly Gln Ser Gly Gln Tyr
Gly Ser Cys Ser Trp Asn Tyr Val His 1 5 10 15 Ile Phe Met Asp Cys
20 <210> SEQ ID NO 106 <211> LENGTH: 21 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 106 Gln Gly Gln Ser Gly Gln Gly Asp Phe Asp
Ile Pro Phe Pro Ala His 1 5 10 15 Trp Val Pro Ile Thr 20
<210> SEQ ID NO 107 <211> LENGTH: 24 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 107 Gln Gly Gln Ser Gly Gln Met Gly Val Pro Ala Gly Cys
Val Trp Asn 1 5 10 15 Tyr Ala His Ile Phe Met Asp Cys 20
<210> SEQ ID NO 108 <211> LENGTH: 449 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 108 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 109 <211> LENGTH: 449 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 109 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 110 <211> LENGTH: 449 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 110 Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln
Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
Ser Leu Thr Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ser Pro
Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Val Ile Trp Ser Gly Gly
Asn Thr Asp Tyr Asn Thr Pro Phe Thr 50 55 60 Ser Arg Leu Ser Ile
Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe 65 70 75 80 Lys Met Asn
Ser Leu Gln Ser Gln Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95 Arg
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Ala Ser Thr Tyr Arg Val 290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305
310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425
430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445 Lys <210> SEQ ID NO 111 <211> LENGTH: 214
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 111 Gln Ile Leu Leu Thr Gln Ser
Pro Val Ile Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Val Ser Phe
Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn 20 25 30 Ile His Trp
Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile 35 40 45 Lys
Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80 Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp
Pro Thr 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185
190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 112
<211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 112 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 113
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 113 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 114 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 114 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 115 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 115 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Tyr His Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 116 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 116 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 117 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE:
117
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro
Phe Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 118 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 118 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 119 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 119 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys His Ile Gly Arg Thr Asn Pro Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 120 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 120 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 121 <211> LENGTH: 116 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 121
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Glu
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala
Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser
Ser 115 <210> SEQ ID NO 122 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 122 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 123 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 123 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Tyr Tyr Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 124 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 124 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105
<210> SEQ ID NO 125 <211> LENGTH: 119 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 125 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly
Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Lys Ser Pro Pro Phe Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115 <210> SEQ ID NO 126
<211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 126 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 127
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 127 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 128 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 128 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 129 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 129 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Glu Met Gly Trp Gln Thr Leu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 130 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 130
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 131
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 131 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 132 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 132 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 133 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 133 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Pro Pro Phe Tyr Gly Gln Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 134 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 134 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 135 <211> LENGTH: 119 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 135
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Pro Pro
Phe Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser 115 <210> SEQ ID NO 136 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 136 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 137 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 137 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Glu Met Gly Trp Gln Thr Leu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Ala 85 90 95 Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
138 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 138
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 139
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 139 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 140 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 140 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 141
<211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 141 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Asp Pro Glu Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser
115 <210> SEQ ID NO 142 <211> LENGTH: 108 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 142 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85
90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105
<210> SEQ ID NO 143 <211> LENGTH: 119 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 143 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly
Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Lys Ser Pro Pro His Asn Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115 <210> SEQ ID NO 144
<211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 144 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Val Val Ala Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 145
<211> LENGTH: 116 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 145 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Glu Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser
115 <210> SEQ ID NO 146 <211> LENGTH: 108 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 146 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala Pro Leu 85
90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105
<210> SEQ ID NO 147 <211> LENGTH: 119 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 147 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly
Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Lys Ser Pro Pro Phe Phe Gly Gln Phe Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser 115 <210> SEQ ID NO 148
<211> LENGTH: 108 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 148 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Val Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 149 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 149 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Glu Met Gly Trp Gln Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 150 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 150
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Leu Asp Ala Pro Pro 85 90 95 Gln Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ ID NO 151
<211> LENGTH: 119 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 151 Glu
Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Glu Gln Met Gly Trp Gln Thr Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly
Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 <210> SEQ ID NO 152 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 152 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala
Pro Pro 85 90 95 Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 153 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 153 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Pro Glu Gly Arg Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 154 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 154 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ser Leu Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 155 <211> LENGTH: 116 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 155
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Glu Glu Met Gly Trp Gln Thr Lys
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala
Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110
Thr Val Ser Ser 115 <210> SEQ ID NO 156 <211> LENGTH:
108 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 156 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Asp Ala
Pro Leu 85 90 95 Met Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 157 <211> LENGTH: 119
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 157 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Glu Pro Met Gly Gln Leu Thr Glu Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr
Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
<210> SEQ ID NO 158 <211> LENGTH: 108 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 158 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala
Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln
Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly
Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe
Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Val Ala Pro Leu 85 90 95 Thr
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg 100 105 <210> SEQ
ID NO 159 <211> LENGTH: 116 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 159
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ser Ile Asp Glu Met Gly Trp Gln Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Ala Ala
Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser
Ser 115 <210> SEQ ID NO 160 <211> LENGTH: 108
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 160 Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Leu Val Ala
Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 <210> SEQ ID NO 161 <211> LENGTH: 116
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 161 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Asp Glu Met Gly Trp Gln Thr Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Ala Ala Ala Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> SEQ ID
NO 162 <211> LENGTH: 214 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 162
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5
10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro 85 90 95 Leu Phe Gly Gln Gly
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135
140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys
210
<210> SEQ ID NO 163 <211> LENGTH: 449 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 163 Glu Val His Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Asp Pro Glu Gly
Arg Gln Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Lys Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr Trp Gly Gln Gly 100 105
110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230
235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln
Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu
His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355
360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210>
SEQ ID NO 164 <211> LENGTH: 214 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(182)..(182) <223> OTHER INFORMATION: X is any amino acid
<400> SEQUENCE: 164 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro 85
90 95 Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr
Leu Xaa Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205
Phe Asn Arg Gly Glu Cys 210 <210> SEQ ID NO 165 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 165 Cys Ile Ser Pro
Arg Gly 1 5 <210> SEQ ID NO 166 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 166 Cys Ile Ser Pro Arg Gly Cys 1
5 <210> SEQ ID NO 167 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 167 Cys Ile Ser Pro Arg Gly Cys Gly 1 5 <210> SEQ
ID NO 168 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 168
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr 1 5 10
15 <210> SEQ ID NO 169 <211> LENGTH: 14 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 169 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met 1 5 10 <210> SEQ ID NO 170 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 170 Cys Ile Ser Pro
Arg Gly Cys Glu Pro Gly Thr Tyr Val Pro Thr 1 5 10 15 <210>
SEQ ID NO 171 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 171 Cys Ile Ser Pro Arg Gly Cys Pro Gly Gln Ile Trp His
Pro Pro 1 5 10 15 <210> SEQ ID NO 172 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 172
Gly Ser His Cys Leu Ile Pro Ile Asn Met Gly Ala Pro Ser Cys 1 5 10
15 <210> SEQ ID NO 173 <211> LENGTH: 32 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 173 Cys Ile Ser Pro Arg Gly Cys Gly Gly Ser
Ser Ala Ser Gln Ser Gly 1 5 10 15 Gln Gly Ser His Cys Leu Ile Pro
Ile Asn Met Gly Ala Pro Ser Cys 20 25 30 <210> SEQ ID NO 174
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 174 Cys
Asn His His Tyr Phe Tyr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 175 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 175 Ala Asp His Val Phe Trp Gly
Ser Tyr Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 176 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 176 Cys His His Val Tyr Trp Gly His Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 177
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 177 Cys
Pro His Phe Thr Thr Thr Ser Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 178 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 178 Cys Asn His His Tyr His Tyr
Tyr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 179 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 179 Cys Pro His Val Ser Phe Gly Ser Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 180
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 180 Cys
Pro Tyr Tyr Thr Leu Ser Tyr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 181 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 181 Cys Asn His Val Tyr Phe Gly
Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Pro Gly
<210> SEQ ID NO 182 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 182 Cys Asn His Phe Thr Leu Thr Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Pro Gly <210> SEQ ID NO 183
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 183 Cys
His His Phe Thr Leu Thr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10
15 Cys Pro Gly <210> SEQ ID NO 184 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 184 Tyr Asn Pro Cys Ala Thr Pro
Met Cys Cys Ile Ser Pro Arg Gly Cys 1 5 10 15 Pro Gly <210>
SEQ ID NO 185 <211> LENGTH: 18 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 185 Cys Asn His His Tyr Phe Tyr Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 186 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 186 Cys Asn His His
Tyr His Tyr Tyr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 187 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 187 Cys Asn His Val Tyr Phe Gly Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 188 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 188 Cys His His Val
Tyr Trp Gly His Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 189 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 189 Cys Pro His Phe Thr Thr Thr Ser Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 190 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 190 Cys Asn His Phe
Thr Leu Thr Thr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 191 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 191 Cys His His Phe Thr Leu Thr Thr Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 192 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 192 Cys Pro Tyr Tyr
Thr Leu Ser Tyr Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 193 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 193 Cys Pro His Val Ser Phe Gly Ser Cys Gly Cys Ile Ser
Pro Arg Gly 1 5 10 15 Cys Gly <210> SEQ ID NO 194 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 194 Ala Asp His Val
Phe Trp Gly Ser Tyr Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 195 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 195 Tyr Asn Pro Cys Ala Thr Pro Met Cys Cys Ile Ser Pro
Arg Gly Cys 1 5 10 15 Gly <210> SEQ ID NO 196 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 196 Cys His His Val
Tyr Trp Gly His Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly
<210> SEQ ID NO 197 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(2)..(2) <223> OTHER INFORMATION: X is N or P <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(4)..(4) <223> OTHER INFORMATION: X is H, V, or F <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(5)..(5) <223> OTHER INFORMATION: X is Y or T <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(6)..(6) <223> OTHER INFORMATION: X is F, W, T, or L
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: X is Y, G, T, or
S <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: X is
T, S, Y, or H <400> SEQUENCE: 197 Cys Xaa His Xaa Xaa Xaa Xaa
Xaa Cys Gly Cys Ile Ser Pro Arg Gly 1 5 10 15 Cys Gly <210>
SEQ ID NO 198 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 198 Cys Ile Ser Pro Arg Gly Cys Gly Gln Pro Ile Pro Ser
Val Lys 1 5 10 15 <210> SEQ ID NO 199 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 199 Cys Ile Ser Pro Arg Gly Cys
Thr Gln Pro Tyr His Val Ser Arg 1 5 10 15 <210> SEQ ID NO 200
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 200 Cys
Ile Ser Pro Arg Gly Cys Asn Ala Val Ser Gly Leu Gly Ser 1 5 10 15
<210> SEQ ID NO 201 <211> LENGTH: 21 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 201 Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys 1 5 10 15 Arg Gly Trp Gln Gly 20 <210> SEQ ID NO
202 <211> LENGTH: 26 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 202
Gln Gly Gln Ser Gly Gln Gly Gln Gln Gln Trp Cys Asn Ile Trp Ile 1 5
10 15 Asn Gly Gly Asp Cys Arg Gly Trp Asn Gly 20 25 <210> SEQ
ID NO 203 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 203
Pro Trp Cys Met Gln Arg Gln Asp Phe Leu Arg Cys Pro Gln Pro 1 5 10
15 <210> SEQ ID NO 204 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 204 Gln Leu Gly Leu Pro Ala Tyr Met Cys Thr
Phe Glu Cys Leu Arg 1 5 10 15
<210> SEQ ID NO 205 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 205 Cys Asn Leu Trp Val Ser Gly Gly Asp Cys Gly Gly Leu
Gln Gly 1 5 10 15 <210> SEQ ID NO 206 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 206 Ser Cys Ser Leu Trp Thr Ser
Gly Ser Cys Leu Pro His Ser Pro 1 5 10 15 <210> SEQ ID NO 207
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 207 Tyr
Cys Leu Gln Leu Pro His Tyr Met Gln Ala Met Cys Gly Arg 1 5 10 15
<210> SEQ ID NO 208 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 208 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ser Tyr Trp Asn
Asn Thr 1 5 10 15 <210> SEQ ID NO 209 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 209 Pro Trp Cys Met Gln Arg Gln
Asp Tyr Leu Arg Cys Pro Gln Pro 1 5 10 15 <210> SEQ ID NO 210
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 210 Cys
Asn Leu Trp Ile Ser Gly Gly Asp Cys Arg Gly Leu Ala Gly 1 5 10 15
<210> SEQ ID NO 211 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 211 Cys Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Gly Val
Gln Gly 1 5 10 15 <210> SEQ ID NO 212 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 212 Cys Asn Leu Trp Val Ser Gly
Gly Asp Cys Arg Gly Leu Arg Gly 1 5 10 15 <210> SEQ ID NO 213
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 213 Cys
Asn Leu Trp Ile Ser Gly Gly Asp Cys Arg Gly Leu Pro Gly 1 5 10 15
<210> SEQ ID NO 214 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 214 Cys Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Asp Ala
Pro Trp 1 5 10 15 <210> SEQ ID NO 215 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 215 Cys Asn Leu Trp Val Ser Gly
Gly Asp Cys Arg Asp Leu Leu Gly 1 5 10 15 <210> SEQ ID NO 216
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 216 Cys
Asn Leu Trp Val Ser Gly Gly Asp Cys Arg Gly Leu Gln Gly 1 5 10 15
<210> SEQ ID NO 217 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 217 Cys Asn Leu Trp Leu His Gly Gly Asp Cys Arg Gly Trp
Gln Gly 1 5 10 15 <210> SEQ ID NO 218 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 218 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly 1 5 10 15 <210> SEQ ID NO 219
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 219 Cys
Thr Thr Trp Phe Cys Gly Gly Asp Cys Gly Val Met Arg Gly 1 5 10 15
<210> SEQ ID NO 220 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 220 Cys Asn Ile Trp Gly Pro Ser Val Asp Cys Gly Ala Leu
Leu Gly 1 5 10 15 <210> SEQ ID NO 221 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 221 Cys Asn Ile Trp Val Asn Gly
Gly Asp Cys Arg Ser Phe Glu Gly 1 5 10 15 <210> SEQ ID NO 222
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 222 Tyr
Cys Leu Asn Leu Pro Arg Tyr Met Gln Asp Met Cys Trp Ala 1 5 10 15
<210> SEQ ID NO 223 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 223 Tyr Cys Leu Ala Leu Pro His Tyr Met Gln Ala Asp Cys
Ala Arg 1 5 10 15 <210> SEQ ID NO 224 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 224 Cys Phe Leu Tyr Ser Cys Gly
Asp Val Ser Tyr Trp Gly Ser Ala 1 5 10 15 <210> SEQ ID NO 225
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 225 Cys
Tyr Leu Tyr Ser Cys Thr Asp Ser Ala Phe Trp Asn Asn Arg 1 5 10 15
<210> SEQ ID NO 226 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 226 Cys Tyr Leu Tyr Ser Cys Asn Asp Val Ser Tyr Trp Ser
Asn Thr 1 5 10 15 <210> SEQ ID NO 227 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 227 Cys Phe Leu Tyr Ser Cys Thr
Asp Val Ser Tyr Trp 1 5 10 <210> SEQ ID NO 228 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 228 Cys Phe Leu Tyr
Ser Cys Thr Asp Val Ala Tyr Trp Asn Ser Ala 1 5 10 15 <210>
SEQ ID NO 229 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 229 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ser Tyr Trp Gly
Asp Thr 1 5 10 15 <210> SEQ ID NO 230 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 230 Cys Phe Leu Tyr Ser Cys Thr
Asp Val Ser Tyr Trp Gly Asn Ser 1 5 10 15 <210> SEQ ID NO 231
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 231 Cys
Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp Asn Asn Thr 1 5 10 15
<210> SEQ ID NO 232 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 232 Cys Phe Leu Tyr Ser Cys Gly Asp Val Ser Tyr Trp Gly
Asn Pro Gly 1 5 10 15 Leu Ser <210> SEQ ID NO 233 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 233 Cys Phe Leu Tyr
Ser Cys Thr Asp Val Ala Tyr Trp Ser Gly Leu 1 5 10 15 <210>
SEQ ID NO 234 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 234 Cys Tyr Leu Tyr Ser Cys Thr Asp Gly Ser Tyr Trp Asn
Ser Thr 1 5 10 15 <210> SEQ ID NO 235 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 235 Cys Phe Leu Tyr Ser Cys Ser
Asp Val Ser Tyr Trp Gly Asn Ile 1 5 10 15 <210> SEQ ID NO 236
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 236 Cys
Phe Leu Tyr Ser Cys Thr Asp Val Ala Tyr Trp 1 5 10 <210> SEQ
ID NO 237 <211> LENGTH: 15 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 237
Cys Phe Leu Tyr Ser Cys Thr Asp Val Ser Tyr Trp Gly Ser Thr 1 5 10
15 <210> SEQ ID NO 238 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 238 Cys Phe Leu Tyr Ser Cys Thr Asp Val Ala
Tyr Trp Gly Asp Thr 1 5 10 15 <210> SEQ ID NO 239 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 239 Gly Cys Asn Ile
Trp Leu Asn Gly Gly Asp Cys Arg Gly Trp Val Asp 1 5 10 15 Pro Leu
Gln Gly 20 <210> SEQ ID NO 240 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 240 Gly Cys Asn Ile Trp Leu Val
Gly Gly Asp Cys Arg Gly Trp Ile Gly 1 5 10 15 Asp Thr Asn Gly 20
<210> SEQ ID NO 241 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 241 Gly Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly
Trp Ile Glu 1 5 10 15 Asp Ser Asn Gly 20 <210> SEQ ID NO 242
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 242 Gly
Cys Asn Ile Trp Ala Asn Gly Gly Asp Cys Arg Gly Trp Ile Asp
1 5 10 15 Asn Ile Asp Gly 20 <210> SEQ ID NO 243 <211>
LENGTH: 20 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 243 Gly Cys Asn Ile
Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Leu Gly 1 5 10 15 Glu Ala
Val Gly 20 <210> SEQ ID NO 244 <211> LENGTH: 20
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 244 Gly Cys Asn Ile Trp Leu Val
Gly Gly Asp Cys Arg Gly Trp Leu Glu 1 5 10 15 Glu Ala Val Gly 20
<210> SEQ ID NO 245 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 245 Gly Gly Pro Ala Leu Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Gly Trp Ser Gly 20 <210> SEQ ID NO 246
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 246 Gly
Ala Pro Val Phe Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg 1 5 10
15 Gly Trp Met Gly 20 <210> SEQ ID NO 247 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 247 Gly Gln Gln Gln Trp Cys Asn
Ile Trp Ile Asn Gly Gly Asp Cys Arg 1 5 10 15 Gly Trp Asn Gly 20
<210> SEQ ID NO 248 <211> LENGTH: 20 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 248 Gly Lys Ser Glu Phe Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Gly Trp Ile Gly 20 <210> SEQ ID NO 249
<211> LENGTH: 20 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 249 Gly
Thr Pro Gly Gly Cys Asn Ile Trp Ala Asn Gly Gly Asp Cys Arg 1 5 10
15 Gly Trp Glu Gly 20 <210> SEQ ID NO 250 <211> LENGTH:
20 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 250 Gly Ala Ser Gln Tyr Cys Asn
Leu Trp Ile Asn Gly Gly Asp Cys Arg 1 5 10 15 Gly Trp Arg Gly 20
<210> SEQ ID NO 251 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 251 Gly Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Pro
Trp Val Glu 1 5 10 15 Gly Gly <210> SEQ ID NO 252 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 252 Gly Cys Asn Ile
Trp Ala Val Gly Gly Asp Cys Arg Pro Phe Val Asp 1 5 10 15 Gly Gly
<210> SEQ ID NO 253 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 253 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Ala
Trp Val Asp 1 5 10 15 Thr Gly <210> SEQ ID NO 254 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 254 Gly Cys Asn Ile
Trp Ile Val Gly Gly Asp Cys Arg Pro Phe Ile Asn 1 5 10 15 Asp Gly
<210> SEQ ID NO 255 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 255 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Pro
Val Val Phe 1 5 10 15 Gly Gly <210> SEQ ID NO 256 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 256 Gly Cys Asn Ile
Trp Leu Ser Gly Gly Asp Cys Arg Met Phe Met Asn 1 5 10 15 Glu Gly
<210> SEQ ID NO 257 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 257 Gly Cys Asn Ile Trp Val Asn Gly Gly Asp Cys Arg Ser
Phe Val Tyr 1 5 10 15 Ser Gly <210> SEQ ID NO 258 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 258 Gly Cys Asn Ile
Trp Leu Asn Gly Gly Asp Cys Arg Gly Trp Glu Ala 1 5 10 15
Ser Gly <210> SEQ ID NO 259 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 259 Gly Cys Asn Ile Trp Ala His
Gly Gly Asp Cys Arg Gly Phe Ile Glu 1 5 10 15 Pro Gly <210>
SEQ ID NO 260 <211> LENGTH: 18 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 260 Gly Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg Thr
Phe Val Ala 1 5 10 15 Ser Gly <210> SEQ ID NO 261 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 261 Gly Cys Asn Ile
Trp Ala His Gly Gly Asp Cys Arg Gly Phe Ile Glu 1 5 10 15 Pro Gly
<210> SEQ ID NO 262 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 262 Gly Phe Leu Glu Asn Cys Asn Ile Trp Leu Asn Gly Gly
Asp Cys Arg 1 5 10 15 Thr Gly <210> SEQ ID NO 263 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 263 Gly Ile Tyr Glu
Asn Cys Asn Ile Trp Leu Asn Gly Gly Asp Cys Arg 1 5 10 15 Met Gly
<210> SEQ ID NO 264 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 264 Gly Ile Pro Asp Asn Cys Asn Ile Trp Ile Asn Gly Gly
Asp Cys Arg 1 5 10 15 Tyr Gly <210> SEQ ID NO 265 <211>
LENGTH: 21 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 265 Gln Gly Gln Ser
Gly Gln Tyr Gly Ser Cys Ser Trp Asn Tyr Val His 1 5 10 15 Ile Phe
Met Asp Cys 20 <210> SEQ ID NO 266 <211> LENGTH: 21
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 266 Gln Gly Gln Ser Gly Gln Gly
Asp Phe Asp Ile Pro Phe Pro Ala His 1 5 10 15 Trp Val Pro Ile Thr
20 <210> SEQ ID NO 267 <211> LENGTH: 24 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 267 Gln Gly Gln Ser Gly Gln Met Gly Val Pro
Ala Gly Cys Val Trp Asn 1 5 10 15 Tyr Ala His Ile Phe Met Asp Cys
20 <210> SEQ ID NO 268 <211> LENGTH: 15 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 268 Tyr Arg Ser Cys Asn Trp Asn Tyr Val Ser
Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 269 <211>
LENGTH: 16 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 269 Pro Gly Ala Phe
Asp Ile Pro Phe Pro Ala His Trp Val Pro Asn Thr 1 5 10 15
<210> SEQ ID NO 270 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 270 Glu Ser Ser Cys Val Trp Asn Tyr Val His Ile Tyr Met
Asp Cys 1 5 10 15 <210> SEQ ID NO 271 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 271 Tyr Pro Gly Cys Lys Trp Asn
Tyr Asp Arg Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 272
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 272 Tyr
Arg Thr Cys Ser Trp Asn Tyr Val Gly Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 273 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 273 Tyr Gly Ser Cys Ser Trp Asn Tyr Val His Ile Phe Met
Asp Cys 1 5 10 15 <210> SEQ ID NO 274 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 274 Tyr Gly Ser Cys Ser Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 275
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 275 Tyr
Gly Ser Cys Asn Trp Asn Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 276 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 276 Tyr Thr Ser Cys Asn Trp Asn Tyr Val His
Ile Phe Met Asp Cys 1 5 10 15 <210> SEQ ID NO 277 <211>
LENGTH: 15 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 277 Tyr Pro Gly Cys
Lys Trp Asn Tyr Asp Arg Ile Phe Leu Asp Cys 1 5 10 15 <210>
SEQ ID NO 278 <211> LENGTH: 15 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 278 Trp Arg Ser Cys Asn Trp Asn Tyr Ala His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 279 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 279 Trp Ser Asn Cys His Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 280
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 280 Asp
Arg Ser Cys Thr Trp Asn Tyr Val Arg Ile Ser Tyr Asp Cys 1 5 10 15
<210> SEQ ID NO 281 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 281 Ser Gly Ser Cys Lys Trp Asp Tyr Val His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 282 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 282 Ser Arg Ser Cys Ile Trp Asn
Tyr Ala His Ile His Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 283
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 283 Ser
Met Ser Cys Tyr Trp Gln Tyr Glu Arg Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 284 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 284 Tyr Arg Ser Cys Asn Trp Asn Tyr Val Ser Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 285 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 285 Ser Gly Ser Cys Lys Trp Asp
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 286
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 286 Tyr
Lys Ser Cys His Trp Asp Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 287 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 287 Tyr Gly Ser Cys Thr Trp Asn Tyr Val His Ile Phe Met
Glu Cys 1 5 10 15 <210> SEQ ID NO 288 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 288 Phe Ser Ser Cys Asn Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 289
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 289 Trp
Arg Ser Cys Asn Trp Asn Tyr Ala His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 290 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 290 Tyr Gly Ser Cys Gln Trp Asn Tyr Val His Ile Phe Leu
Asp Cys 1 5 10 15 <210> SEQ ID NO 291 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 291 Tyr Arg Ser Cys Asn Trp Asn
Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15 <210> SEQ ID NO 292
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 292 Asn
Met Ser Cys His Trp Asp Tyr Val His Ile Phe Leu Asp Cys 1 5 10 15
<210> SEQ ID NO 293 <211> LENGTH: 15 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 293 Phe Gly Pro Cys Thr Trp Asn Tyr Ala Arg Ile Ser Trp
Asp Cys 1 5 10 15 <210> SEQ ID NO 294 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (1)..(2) <223> OTHER INFORMATION: X is
any amino acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: X is any amino acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: X is any amino acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: X is any amino acid
<400> SEQUENCE: 294 Xaa Xaa Ser Cys Xaa Trp Xaa Tyr Val His
Ile Phe Xaa Asp Cys 1 5 10 15 <210> SEQ ID NO 295 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 295 Met Gly Val Pro
Ala Gly Cys Val Trp Asn Tyr Ala His Ile Phe Met 1 5 10 15 Asp Cys
<210> SEQ ID NO 296 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 296 Arg Asp Thr Gly Gly Gln Cys Arg Trp Asp Tyr Val His
Ile Phe Met 1 5 10 15 Asp Cys <210> SEQ ID NO 297 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 297 Ala Gly Val Pro
Ala Gly Cys Thr Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 298 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 298 Val Gly Val Pro Asn Gly Cys Val Trp Asn Tyr Ala His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 299 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 299 Asp Gly Gly Pro
Ala Gly Cys Ser Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 300 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 300 Ala Val Gly Pro Ala Gly Cys Trp Trp Asn Tyr Val His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 301 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 301 Cys Thr Trp Asn
Tyr Val His Ile Phe Met Asp Cys Gly Glu Gly Glu 1 5 10 15 Gly Pro
<210> SEQ ID NO 302 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 302 Gly Gly Val Pro Glu Gly Cys Thr Trp Asn Tyr Ala His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 303 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 303 Ala Glu Val Pro
Ala Gly Cys Trp Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 304 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 304 Ala Gly Val Pro Ala Gly Cys Thr Trp Asn Tyr Val His
Ile Phe Met 1 5 10 15 Glu Cys <210> SEQ ID NO 305 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 305 Ser Gly Ala Ser
Gly Gly Cys Lys Trp Asn Tyr Val His Ile Phe Met 1 5 10 15 Asp Cys
<210> SEQ ID NO 306 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 306 Thr Pro Gly Cys Arg Trp Asn Tyr Val His Ile Phe Met
Glu Cys Glu 1 5 10 15 Ala Leu <210> SEQ ID NO 307 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 307 Val Gly Val Pro
Asn Gly Cys Val Trp Asn Tyr Ala His Ile Phe Met 1 5 10 15 Glu Cys
<210> SEQ ID NO 308 <211> LENGTH: 16 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 308 Pro Gly Ala Phe Asp Ile Pro Phe Pro Ala His Trp Val
Pro Asn Thr 1 5 10 15 <210> SEQ ID NO 309 <211> LENGTH:
16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 309 Arg Gly Ala Cys Asp Ile Pro
Phe Pro Ala His Trp Ile Pro Asn Thr 1 5 10 15 <210> SEQ ID NO
310 <211> LENGTH: 16 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 310
Gln Gly Asp Phe Asp Ile Pro Phe Pro Ala His Trp Val Pro Ile Thr 1 5
10 15 <210> SEQ ID NO 311 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: X is any amino
acid
<400> SEQUENCE: 311 Xaa Gly Ala Phe Asp Ile Pro Phe Pro Ala
His Trp Val Pro Asn Thr 1 5 10 15 <210> SEQ ID NO 312
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 312 Arg
Gly Asp Gly Asn Asp Ser Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Arg Thr <210> SEQ ID NO 313 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 313 Ser Gly Val Gly Arg Asp Arg
Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10 15 Pro Arg Thr
<210> SEQ ID NO 314 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 314 Trp Ala Gly Gly Asn Asp Cys Asp Ile Pro Phe Pro Ala
His Trp Ile 1 5 10 15 Pro Asn Thr <210> SEQ ID NO 315
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 315 Trp
Gly Asp Gly Met Asp Val Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Val Thr <210> SEQ ID NO 316 <211> LENGTH: 19
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 316 Ala Gly Ser Gly Asn Asp Ser
Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10 15 Pro Arg Thr
<210> SEQ ID NO 317 <211> LENGTH: 19 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 317 Glu Ser Arg Ser Gly Tyr Ala Asp Ile Pro Phe Pro Ala
His Trp Val 1 5 10 15 Pro Arg Thr <210> SEQ ID NO 318
<211> LENGTH: 19 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 318 Arg
Glu Cys Gly Arg Cys Gly Asp Ile Pro Phe Pro Ala His Trp Val 1 5 10
15 Pro Arg Thr <210> SEQ ID NO 319 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 319 Pro Arg Phe Lys Ile Ile Gly
Gly 1 5 <210> SEQ ID NO 320 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 320 Pro Arg Phe Arg Ile Ile Gly Gly 1 5
<210> SEQ ID NO 321 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 321 Ser Ser Arg His Arg Arg Ala Leu Asp 1 5 <210>
SEQ ID NO 322 <211> LENGTH: 14 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 322 Arg Lys Ser Ser Ile Ile Ile Arg Met Arg Asp Val Val
Leu 1 5 10 <210> SEQ ID NO 323 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 323 Ser Ser Ser Phe Asp Lys Gly
Lys Tyr Lys Lys Gly Asp Asp Ala 1 5 10 15 <210> SEQ ID NO 324
<211> LENGTH: 15 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 324 Ser
Ser Ser Phe Asp Lys Gly Lys Tyr Lys Arg Gly Asp Asp Ala 1 5 10 15
<210> SEQ ID NO 325 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 325 Ile Glu Gly Arg 1 <210> SEQ ID NO 326
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 326 Ile
Asp Gly Arg 1 <210> SEQ ID NO 327 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 327 Gly Gly Ser Ile Asp Gly Arg 1
5 <210> SEQ ID NO 328 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 328 Pro Leu Gly Leu Trp Ala 1 5 <210> SEQ ID NO 329
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 329 Gly
Pro Gln Gly Ile Ala Gly Gln
1 5 <210> SEQ ID NO 330 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 330 Gly Pro Gln Gly Leu Leu Gly Ala 1 5
<210> SEQ ID NO 331 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 331 Gly Ile Ala Gly Gln 1 5 <210> SEQ ID NO 332
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 332 Gly
Pro Leu Gly Ile Ala Gly Ile 1 5 <210> SEQ ID NO 333
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 333 Gly
Pro Glu Gly Leu Arg Val Gly 1 5 <210> SEQ ID NO 334
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 334 Tyr
Gly Ala Gly Leu Gly Val Val 1 5 <210> SEQ ID NO 335
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 335 Ala
Gly Leu Gly Val Val Glu Arg 1 5 <210> SEQ ID NO 336
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 336 Ala
Gly Leu Gly Ile Ser Ser Thr 1 5 <210> SEQ ID NO 337
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 337 Glu
Pro Gln Ala Leu Ala Met Ser 1 5 <210> SEQ ID NO 338
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 338 Gln
Ala Leu Ala Met Ser Ala Ile 1 5 <210> SEQ ID NO 339
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 339 Ala
Ala Tyr His Leu Val Ser Gln 1 5 <210> SEQ ID NO 340
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 340 Met
Asp Ala Phe Leu Glu Ser Ser 1 5 <210> SEQ ID NO 341
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 341 Glu
Ser Leu Pro Val Val Ala Val 1 5 <210> SEQ ID NO 342
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 342 Ser
Ala Pro Ala Val Glu Ser Glu 1 5 <210> SEQ ID NO 343
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 343 Asp
Val Ala Gln Phe Val Leu Thr 1 5 <210> SEQ ID NO 344
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 344 Val
Ala Gln Phe Val Leu Thr Glu 1 5 <210> SEQ ID NO 345
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 345 Ala
Gln Phe Val Leu Thr Glu Gly 1 5 <210> SEQ ID NO 346
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 346 Pro
Val Gln Pro Ile Gly Pro Gln 1 5 <210> SEQ ID NO 347
<211> LENGTH: 273 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 347 Gly
Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Ser Gly 1 5 10
15 Gly Gly Gly Ser Gly Gly Gly Glu Ile Val Leu Thr Gln Ser Pro Gly
20 25 30 Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys
Arg Ala 35 40 45 Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
Gln Gln Lys Pro 50 55 60 Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly
Ala Ser Ser Arg Ala Thr 65 70 75 80 Gly Ile Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95
Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys 100
105 110 Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys
Val 115 120 125 Glu Ile Lys Arg Ser Gly Gly Ser Thr Ile Thr Ser Tyr
Asn Val Tyr 130 135 140 Tyr Thr Lys Leu Ser Ser Ser Gly Thr Gln Val
Gln Leu Val Gln Thr 145 150 155 160 Gly Gly Gly Val Val Gln Pro Gly
Arg Ser Leu Arg Leu Ser Cys Ala 165 170 175 Ala Ser Gly Ser Thr Phe
Ser Ser Tyr Ala Met Ser Trp Val Arg Gln 180 185 190 Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly 195 200 205 Gly Ser
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 210 215 220
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg 225
230 235 240 Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Asn Ser Leu
Tyr Trp 245 250 255 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr
Val Ser Ser Ala 260 265 270 Ser <210> SEQ ID NO 348
<400> SEQUENCE: 348 000 <210> SEQ ID NO 349 <211>
LENGTH: 264 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 349 Gly Gly Gly Ser
Gly Gly Gly Gly Ser Gly Ser Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly
Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala 20 25 30
Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser 35
40 45 Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg
Pro 50 55 60 Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser
Arg Gly Tyr 65 70 75 80 Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala
Thr Leu Thr Thr Asp 85 90 95 Lys Ser Ser Ser Thr Ala Tyr Met Gln
Leu Ser Ser Leu Thr Ser Glu 100 105 110 Asp Ser Ala Val Tyr Tyr Cys
Ala Arg Tyr Tyr Asp Asp His Tyr Cys 115 120 125 Leu Asp Tyr Trp Gly
Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly 130 135 140 Gly Gly Ser
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val 145 150 155 160
Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val 165
170 175 Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
Tyr 180 185 190 Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
Asp Thr Ser 195 200 205 Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg
Gly Ser Gly Ser Gly 210 215 220 Thr Ser Tyr Ser Leu Thr Ile Ser Gly
Met Glu Ala Glu Asp Ala Ala 225 230 235 240 Thr Tyr Tyr Cys Gln Gln
Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser 245 250 255 Gly Thr Lys Leu
Glu Ile Asn Arg 260 <210> SEQ ID NO 350 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 350 Gly Gly Ser Gly Gly Ser 1 5
<210> SEQ ID NO 351 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 351 Ala Gln Asn Leu Leu Gly Met Val 1 5 <210> SEQ
ID NO 352 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 352
Ser Thr Phe Pro Phe Gly Met Phe 1 5 <210> SEQ ID NO 353
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 353 Pro
Val Gly Tyr Thr Ser Ser Leu 1 5 <210> SEQ ID NO 354
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 354 Asp
Trp Leu Tyr Trp Pro Gly Ile 1 5 <210> SEQ ID NO 355
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 355 Met
Ile Ala Pro Val Ala Tyr Arg 1 5 <210> SEQ ID NO 356
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 356 Arg
Pro Ser Pro Met Trp Ala Tyr 1 5 <210> SEQ ID NO 357
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 357 Trp
Ala Thr Pro Arg Pro Met Arg 1 5 <210> SEQ ID NO 358
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 358 Phe
Arg Leu Leu Asp Trp Gln Trp 1 5 <210> SEQ ID NO 359
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 359 Leu
Lys Ala Ala Pro Arg Trp Ala 1 5 <210> SEQ ID NO 360
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 360 Gly
Pro Ser His Leu Val Leu Thr 1 5 <210> SEQ ID NO 361
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 361 Leu Pro Gly Gly Leu Ser Pro
Trp 1 5 <210> SEQ ID NO 362 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 362 Met Gly Leu Phe Ser Glu Ala Gly 1 5
<210> SEQ ID NO 363 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 363 Ser Pro Leu Pro Leu Arg Val Pro 1 5 <210> SEQ
ID NO 364 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 364
Arg Met His Leu Arg Ser Leu Gly 1 5 <210> SEQ ID NO 365
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 365 Leu
Ala Ala Pro Leu Gly Leu Leu 1 5 <210> SEQ ID NO 366
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 366 Ala
Val Gly Leu Leu Ala Pro Pro 1 5 <210> SEQ ID NO 367
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 367 Leu
Leu Ala Pro Ser His Arg Ala 1 5 <210> SEQ ID NO 368
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 368 Pro
Ala Gly Leu Trp Leu Asp Pro 1 5 <210> SEQ ID NO 369
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 369 Ile
Ser Ser Gly Leu Ser Ser 1 5 <210> SEQ ID NO 370 <211>
LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 370 Thr Gly Arg Gly
Pro Ser Trp Val 1 5 <210> SEQ ID NO 371 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 371 Ser Ala Arg Gly Pro Ser Arg
Trp 1 5 <210> SEQ ID NO 372 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 372 Thr Ala Arg Gly Pro Ser Phe Lys 1 5
<210> SEQ ID NO 373 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 373 Gly Gly Trp His Thr Gly Arg Asn 1 5 <210> SEQ
ID NO 374 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 374
His Thr Gly Arg Ser Gly Ala Leu 1 5 <210> SEQ ID NO 375
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 375 Pro
Leu Thr Gly Arg Ser Gly Gly 1 5 <210> SEQ ID NO 376
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 376 Ala
Ala Arg Gly Pro Ala Ile His 1 5 <210> SEQ ID NO 377
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 377 Arg
Gly Pro Ala Phe Asn Pro Met 1 5 <210> SEQ ID NO 378
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 378 Ser
Ser Arg Gly Pro Ala Tyr Leu 1 5 <210> SEQ ID NO 379
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 379 Arg
Gly Pro Ala Thr Pro Ile Met 1 5 <210> SEQ ID NO 380
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 380
Arg Gly Pro Ala 1 <210> SEQ ID NO 381 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 381 Gly Ser Gly Gly Ser 1 5
<210> SEQ ID NO 382 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 382 Gly Gly Gly Ser 1 <210> SEQ ID NO 383
<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 383 Gly
Gly Ser Gly 1 <210> SEQ ID NO 384 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 384 Gly Gly Ser Gly Gly 1 5
<210> SEQ ID NO 385 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 385 Gly Ser Gly Ser Gly 1 5 <210> SEQ ID NO 386
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 386 Gly
Ser Gly Gly Gly 1 5 <210> SEQ ID NO 387 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 387 Gly Gly Gly Ser Gly 1 5
<210> SEQ ID NO 388 <211> LENGTH: 5 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 388 Gly Ser Ser Ser Gly 1 5 <210> SEQ ID NO 389
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 389 Gly
Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly 1 5 10 <210>
SEQ ID NO 390 <211> LENGTH: 11 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 390 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 1 5 10
<210> SEQ ID NO 391 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 391 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser 1 5
10 <210> SEQ ID NO 392 <211> LENGTH: 16 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 392 Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly
Gly Ser Gly Gly Gly Ser 1 5 10 15 <210> SEQ ID NO 393
<211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 393 Gly
Ser Ser Gly Gly Ser Gly Gly Ser Gly 1 5 10 <210> SEQ ID NO
394 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 394
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Ser 1 5 10 <210> SEQ
ID NO 395 <211> LENGTH: 4 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 395
Gly Gly Gly Ser 1 <210> SEQ ID NO 396 <211> LENGTH: 5
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 396 Gly Ser Ser Gly Thr 1 5
<210> SEQ ID NO 397 <211> LENGTH: 4 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 397 Gly Ser Ser Gly 1 <210> SEQ ID NO 398
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 398 Ser
Tyr Ala Met Ser 1 5 <210> SEQ ID NO 399 <211> LENGTH:
17 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 399 Ser Ile Asp Pro Glu Gly Arg
Gln Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15
Gly <210> SEQ ID NO 400 <211> LENGTH: 10 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 400 Asp Ile Gly Gly Arg Ser Ala Phe Asp Tyr 1
5 10 <210> SEQ ID NO 401 <211> LENGTH: 9 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 401 Arg Ala Ser Gln Ser Ile Ser Ser Tyr 1 5
<210> SEQ ID NO 402 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 402 Ala Ala Ser Ser Leu Gln Ser 1 5 <210> SEQ ID NO
403 <211> LENGTH: 9 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 403
Gln Gln Thr Val Val Ala Pro Pro Leu 1 5 <210> SEQ ID NO 404
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 404 Asn
Tyr Gly Val His 1 5 <210> SEQ ID NO 405 <211> LENGTH:
16 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 405 Val Ile Trp Ser Gly Gly Asn
Thr Asp Tyr Asn Thr Pro Phe Thr Ser 1 5 10 15 <210> SEQ ID NO
406 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 406
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr 1 5 10 <210> SEQ
ID NO 407 <211> LENGTH: 11 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 407
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 1 5 10 <210> SEQ
ID NO 408 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 408
Lys Tyr Ala Ser Glu Ser Ile Ser 1 5 <210> SEQ ID NO 409
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 409 Gln
Gln Asn Asn Asn Trp Pro Thr Thr 1 5 <210> SEQ ID NO 410
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 410 Gln
Gly Gln Ser Gly Gln 1 5 <210> SEQ ID NO 411 <211>
LENGTH: 10 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 411 Val His Met Pro
Leu Gly Phe Leu Gly Pro 1 5 10 <210> SEQ ID NO 412
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 412 Leu
Ser Gly Arg Ser Gly Asn His 1 5 <210> SEQ ID NO 413
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 413 Thr
Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly 1 5 10 <210> SEQ
ID NO 414 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 414
Thr Ser Gly Arg Ser Ala Asn Pro 1 5 <210> SEQ ID NO 415
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 415 Val
Ala Gly Arg Ser Met Arg Pro 1 5 <210> SEQ ID NO 416
<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 416 Gly
Gln Ser Gly Gln 1 5 <210> SEQ ID NO 417 <211> LENGTH: 4
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 417 Gln Ser Gly Gln 1 <210>
SEQ ID NO 418 <211> LENGTH: 3 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 418 Ser Gly Gln 1 <210> SEQ ID NO 419
<211> LENGTH: 756 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 419
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tctatctctt ccggactgct gtccggcaga tccgacaatc acggcggagg
ctctgacatc 120 cagatgaccc agtctccatc ctccctgtct gcatctgtag
gagacagagt caccatcact 180 tgccgggcaa gtcagagcat tagcagctat
ttaaattggt atcagcagaa accagggaaa 240 gcccctaagc tcctgatcta
tgcggcatcc agtttgcaaa gtggggtccc atcaaggttc 300 agtggcagtg
gatctgggac agatttcact ctcaccatca gcagtctgca acctgaagat 360
tttgcaactt actactgtca acagacggtt gtggcgcctc cgttattcgg ccaagggacc
420 aaggtggaaa tcaaacgtac ggtggctgca ccatctgtct tcatcttccc
gccatctgat 480 gagcagttga aatctggaac tgcctctgtt gtgtgcctgc
tgaataactt ctatcccaga 540 gaggccaaag tacagtggaa ggtggataac
gccctccaat cgggtaactc ccaggagagt 600 gtcacagagc aggacagcaa
ggacagcacc tacagcctca gcagcaccct gacgctgagc 660 aaagcagact
acgagaaaca caaagtctac gcctgcgaag tcacccatca gggcctgagc 720
tcgcccgtca caaagagctt caacagggga gagtgt 756 <210> SEQ ID NO
420 <211> LENGTH: 252 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 420
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser
Asp 20 25 30 Asn His Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro Ser Arg Phe Ser
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105 110 Ile Ser Ser
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr
Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 130 135
140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu
Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser Gln Glu Ser Val
Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr Ser Leu Ser Ser
Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230 235 240 Ser Pro
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 <210> SEQ ID
NO 421 <211> LENGTH: 783 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 421
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tctatctctt ctggcctgct gtctagcggc ggctccggcg gatctctgtc
tggcagatct 120 gacaaccacg gcggaggctc cgacatccag atgacccagt
ctccatcctc cctgtctgca 180 tctgtaggag acagagtcac catcacttgc
cgggcaagtc agagcattag cagctattta 240 aattggtatc agcagaaacc
agggaaagcc cctaagctcc tgatctatgc ggcatccagt 300 ttgcaaagtg
gggtcccatc aaggttcagt ggcagtggat ctgggacaga tttcactctc 360
accatcagca gtctgcaacc tgaagatttt gcaacttact actgtcaaca gacggttgtg
420 gcgcctccgt tattcggcca agggaccaag gtggaaatca aacgtacggt
ggctgcacca 480 tctgtcttca tcttcccgcc atctgatgag cagttgaaat
ctggaactgc ctctgttgtg 540 tgcctgctga ataacttcta tcccagagag
gccaaagtac agtggaaggt ggataacgcc 600 ctccaatcgg gtaactccca
ggagagtgtc acagagcagg acagcaagga cagcacctac 660 agcctcagca
gcaccctgac gctgagcaaa gcagactacg agaaacacaa agtctacgcc 720
tgcgaagtca cccatcaggg cctgagctcg cccgtcacaa agagcttcaa caggggagag
780 tgt 783 <210> SEQ ID NO 422 <211> LENGTH: 261
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 422 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser 20 25 30 Gly Gly Ser
Leu Ser Gly Arg Ser Asp Asn His Gly Gly Gly Ser Asp 35 40 45 Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp 50 55
60 Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu
65 70 75 80 Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile Tyr 85 90 95 Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly Ser 100 105 110 Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Gln Pro Glu 115 120 125 Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Thr Val Val Ala Pro Pro Leu 130 135 140 Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys Arg Thr Val Ala Ala Pro 145 150 155 160 Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr 165 170 175 Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys 180 185
190 Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
195 200 205 Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser 210 215 220 Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala 225 230 235 240 Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe 245 250 255 Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 423 <211> LENGTH: 780 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 423 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggagga 60 tctgctgtgg gactgctggc tcctcctggc
ggcacatcta cctctggcag atccgccaac 120 cctcggggcg gaggatctga
catccagatg acccagtctc catcctccct gtctgcatct 180 gtaggagaca
gagtcaccat cacttgccgg gcaagtcaga gcattagcag ctatttaaat 240
tggtatcagc agaaaccagg gaaagcccct aagctcctga tctatgcggc atccagtttg
300 caaagtgggg tcccatcaag gttcagtggc agtggatctg ggacagattt
cactctcacc 360 atcagcagtc tgcaacctga agattttgca acttactact
gtcaacagac ggttgtggcg 420 cctccgttat tcggccaagg gaccaaggtg
gaaatcaaac gtacggtggc tgcaccatct 480 gtcttcatct tcccgccatc
tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 540 ctgctgaata
acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 600
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc
660 ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt
ctacgcctgc 720 gaagtcaccc atcagggcct gagctcgccc gtcacaaaga
gcttcaacag gggagagtgt 780 <210> SEQ ID NO 424 <211>
LENGTH: 260 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 424 Cys Asn Ile Trp
Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser
Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Thr 20 25 30
Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp Ile 35
40 45 Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg 50 55 60 Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn 65 70 75 80
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 85
90 95 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp 115 120 125 Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe 130 135 140 Gly Gln Gly Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210
215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID
NO 425 <211> LENGTH: 780 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 425
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tccacatcta cctctggcag atccgccaac cccagaggtg gcggagctgt
gggactgctg 120 gctccaccag gcggatctga catccagatg acccagtctc
catcctccct gtctgcatct 180 gtaggagaca gagtcaccat cacttgccgg
gcaagtcaga gcattagcag ctatttaaat 240 tggtatcagc agaaaccagg
gaaagcccct aagctcctga tctatgcggc atccagtttg 300 caaagtgggg
tcccatcaag gttcagtggc agtggatctg ggacagattt cactctcacc 360
atcagcagtc tgcaacctga agattttgca acttactact gtcaacagac ggttgtggcg
420 cctccgttat tcggccaagg gaccaaggtg gaaatcaaac gtacggtggc
tgcaccatct 480 gtcttcatct tcccgccatc tgatgagcag ttgaaatctg
gaactgcctc tgttgtgtgc 540 ctgctgaata acttctatcc cagagaggcc
aaagtacagt ggaaggtgga taacgccctc 600 caatcgggta actcccagga
gagtgtcaca gagcaggaca gcaaggacag cacctacagc 660 ctcagcagca
ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 720
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgt
780 <210> SEQ ID NO 426 <211> LENGTH: 260 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 426 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys
Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Thr Ser Thr
Ser Gly Arg Ser Ala Asn Pro Arg 20 25 30 Gly Gly Gly Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Ser Asp Ile 35 40 45 Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 50 55 60 Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn 65 70 75 80
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala 85
90 95 Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp 115 120 125 Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe 130 135 140 Gly Gln Gly Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210
215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID
NO 427 <211> LENGTH: 786 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 427
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggcggc
60 tctgtgcata tgcccctggg ctttctgggc cctggcggca catctacctc
tggcagatcc 120 gccaaccctc ggggcggagg atctgacatc cagatgaccc
agtctccatc ctccctgtct 180 gcatctgtag gagacagagt caccatcact
tgccgggcaa gtcagagcat tagcagctat 240 ttaaattggt atcagcagaa
accagggaaa gcccctaagc tcctgatcta tgcggcatcc 300 agtttgcaaa
gtggggtccc atcaaggttc agtggcagtg gatctgggac agatttcact 360
ctcaccatca gcagtctgca acctgaagat tttgcaactt actactgtca acagacggtt
420 gtggcgcctc cgttattcgg ccaagggacc aaggtggaaa tcaaacgtac
ggtggctgca 480 ccatctgtct tcatcttccc gccatctgat gagcagttga
aatctggaac tgcctctgtt 540 gtgtgcctgc tgaataactt ctatcccaga
gaggccaaag tacagtggaa ggtggataac 600 gccctccaat cgggtaactc
ccaggagagt gtcacagagc aggacagcaa ggacagcacc 660 tacagcctca
gcagcaccct gacgctgagc aaagcagact acgagaaaca caaagtctac 720
gcctgcgaag tcacccatca gggcctgagc tcgcccgtca caaagagctt caacagggga
780 gagtgt 786 <210> SEQ ID NO 428 <211> LENGTH: 262
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 428 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Val His Met Pro Leu Gly Phe Leu Gly Pro Gly 20 25 30 Gly Thr Ser
Thr Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser 35 40 45 Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 50 55
60 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
65 70 75 80 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 85 90 95 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 115 120 125 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Thr Val Val Ala Pro Pro 130 135 140 Leu Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys Arg Thr Val Ala Ala 145 150 155 160 Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 165 170 175 Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 180 185
190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
195 200 205 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr 225 230 235 240 Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe Asn Arg Gly Glu Cys 260
<210> SEQ ID NO 429 <211> LENGTH: 786 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 429 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggcggc 60 tccacatcta cctctggcag atccgccaac
cccagaggcg gcggagtgca tatgcctctg 120 ggctttctgg gacctggcgg
ctctgacatc cagatgaccc agtctccatc ctccctgtct 180 gcatctgtag
gagacagagt caccatcact tgccgggcaa gtcagagcat tagcagctat 240
ttaaattggt atcagcagaa accagggaaa gcccctaagc tcctgatcta tgcggcatcc
300 agtttgcaaa gtggggtccc atcaaggttc agtggcagtg gatctgggac
agatttcact 360 ctcaccatca gcagtctgca acctgaagat tttgcaactt
actactgtca acagacggtt 420 gtggcgcctc cgttattcgg ccaagggacc
aaggtggaaa tcaaacgtac ggtggctgca 480 ccatctgtct tcatcttccc
gccatctgat gagcagttga aatctggaac tgcctctgtt 540 gtgtgcctgc
tgaataactt ctatcccaga gaggccaaag tacagtggaa ggtggataac 600
gccctccaat cgggtaactc ccaggagagt gtcacagagc aggacagcaa ggacagcacc
660 tacagcctca gcagcaccct gacgctgagc aaagcagact acgagaaaca
caaagtctac 720 gcctgcgaag tcacccatca gggcctgagc tcgcccgtca
caaagagctt caacagggga 780 gagtgt 786 <210> SEQ ID NO 430
<211> LENGTH: 262 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 430 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Thr Ser Thr Ser Gly Arg Ser Ala Asn Pro Arg
20 25 30 Gly Gly Gly Val His Met Pro Leu Gly Phe Leu Gly Pro Gly
Gly Ser 35 40 45 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly 50 55 60 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr 65 70 75 80 Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 85 90 95 Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 100 105 110 Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 115 120 125 Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro 130 135 140
Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 145
150 155 160 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly 165 170 175 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala 180 185 190 Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln 195 200 205 Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser 210 215 220 Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 225 230 235 240 Ala Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 245 250 255 Phe
Asn Arg Gly Glu Cys 260 <210> SEQ ID NO 431 <211>
LENGTH: 768 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 431 tgcaatattt
ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggagga 60
tctgctgtgg gactgctggc tcctcctggt ggcctgtctg gcagatctga taaccacggc
120 ggctccgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt
aggagacaga 180 gtcaccatca cttgccgggc aagtcagagc attagcagct
atttaaattg gtatcagcag 240 aaaccaggga aagcccctaa gctcctgatc
tatgcggcat ccagtttgca aagtggggtc 300 ccatcaaggt tcagtggcag
tggatctggg acagatttca ctctcaccat cagcagtctg 360 caacctgaag
attttgcaac ttactactgt caacagacgg ttgtggcgcc tccgttattc 420
ggccaaggga ccaaggtgga aatcaaacgt acggtggctg caccatctgt cttcatcttc
480 ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct
gctgaataac 540 ttctatccca gagaggccaa agtacagtgg aaggtggata
acgccctcca atcgggtaac 600 tcccaggaga gtgtcacaga gcaggacagc
aaggacagca cctacagcct cagcagcacc 660 ctgacgctga gcaaagcaga
ctacgagaaa cacaaagtct acgcctgcga agtcacccat 720 cagggcctga
gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 768 <210> SEQ ID NO
432 <211> LENGTH: 256 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 432
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly
Leu 20 25 30 Ser Gly Arg Ser Asp Asn His Gly Gly Ser Asp Ile Gln
Met Thr Gln 35 40 45 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr 50 55 60 Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln 65 70 75 80 Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu 85 90 95 Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 100 105 110 Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr 115 120 125 Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr 130 135
140 Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
145 150 155 160 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys 165 170 175 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val 180 185 190 Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln 195 200 205 Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser 210 215 220 Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His 225 230 235 240 Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255
<210> SEQ ID NO 433 <211> LENGTH: 771 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 433 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggaggc 60 tctggcctgt ctggcagatc cgataaccat
ggcggcgctg tgggactgct ggctcctcct 120 ggtggatctg acatccagat
gacccagtct ccatcctccc tgtctgcatc tgtaggagac 180 agagtcacca
tcacttgccg ggcaagtcag agcattagca gctatttaaa ttggtatcag 240
cagaaaccag ggaaagcccc taagctcctg atctatgcgg catccagttt gcaaagtggg
300 gtcccatcaa ggttcagtgg cagtggatct gggacagatt tcactctcac
catcagcagt 360 ctgcaacctg aagattttgc aacttactac tgtcaacaga
cggttgtggc gcctccgtta 420 ttcggccaag ggaccaaggt ggaaatcaaa
cgtacggtgg ctgcaccatc tgtcttcatc 480 ttcccgccat ctgatgagca
gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 540 aacttctatc
ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 600
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc
660 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg
cgaagtcacc 720 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca
ggggagagtg t 771 <210> SEQ ID NO 434 <211> LENGTH: 257
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 434 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Leu Ser Gly Arg Ser Asp Asn His Gly Gly 20 25 30 Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55
60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165
170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys <210>
SEQ ID NO 435 <211> LENGTH: 774 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 435 tgcaatattt ggctcgtagg tggtgattgc aggggctggc
aggggggctc gagcggcggc 60 tctgtgcata tgcccctggg ctttctggga
cctggcggcc tgtctggcag atccgataat 120 cacggcggct ccgacatcca
gatgacccag tctccatcct ccctgtctgc atctgtagga 180 gacagagtca
ccatcacttg ccgggcaagt cagagcatta gcagctattt aaattggtat 240
cagcagaaac cagggaaagc ccctaagctc ctgatctatg cggcatccag tttgcaaagt
300 ggggtcccat caaggttcag tggcagtgga tctgggacag atttcactct
caccatcagc 360 agtctgcaac ctgaagattt tgcaacttac tactgtcaac
agacggttgt ggcgcctccg 420 ttattcggcc aagggaccaa ggtggaaatc
aaacgtacgg tggctgcacc atctgtcttc 480 atcttcccgc catctgatga
gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 540 aataacttct
atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 600
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc
660 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc
ctgcgaagtc 720 acccatcagg gcctgagctc gcccgtcaca aagagcttca
acaggggaga gtgt 774 <210> SEQ ID NO 436 <211> LENGTH:
258 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 436 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Val His Met Pro Leu Gly Phe Leu Gly Pro Gly 20 25 30 Gly Leu Ser
Gly Arg Ser Asp Asn His Gly Gly Ser Asp Ile Gln Met 35 40 45 Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr 50 55
60 Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
65 70 75 80 Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
Ala Ser 85 90 95 Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly 100 105 110 Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala 115 120 125 Thr Tyr Tyr Cys Gln Gln Thr Val
Val Ala Pro Pro Leu Phe Gly Gln 130 135 140 Gly Thr Lys Val Glu Ile
Lys Arg Thr Val Ala Ala Pro Ser Val Phe 145 150 155 160 Ile Phe Pro
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val 165 170 175 Val
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp 180 185
190 Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
195 200 205 Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr 210 215 220 Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
Ala Cys Glu Val 225 230 235 240 Thr His Gln Gly Leu Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly 245 250 255 Glu Cys <210> SEQ ID
NO 437 <211> LENGTH: 265 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 437
Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5
10 15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser Gly Leu Ser Gly
Arg 20 25 30 Ser Asp Asn His Gly Gly Val His Met Pro Leu Gly Phe
Leu Gly Pro 35 40 45 Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser Leu Ser Ala 50 55 60 Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Ser Ile 65 70 75 80 Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys 85 90 95 Leu Leu Ile Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg 100 105 110 Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser 115 120 125 Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val 130 135
140 Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr
145 150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
438 <211> LENGTH: 777 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 438
tgcaatattt ggctcgtagg tggtgattgc aggggctggc aggggggctc gagcggaggc
60 tctggcctgt ctggcagatc tgataaccac ggcggcgtgc acatgcccct
gggctttctg 120 ggacctggcg gatctgacat ccagatgacc cagtctccat
cctccctgtc tgcatctgta 180 ggagacagag tcaccatcac ttgccgggca
agtcagagca ttagcagcta tttaaattgg 240 tatcagcaga aaccagggaa
agcccctaag ctcctgatct atgcggcatc cagtttgcaa 300 agtggggtcc
catcaaggtt cagtggcagt ggatctggga cagatttcac tctcaccatc 360
agcagtctgc aacctgaaga ttttgcaact tactactgtc aacagacggt tgtggcgcct
420 ccgttattcg gccaagggac caaggtggaa atcaaacgta cggtggctgc
accatctgtc 480 ttcatcttcc cgccatctga tgagcagttg aaatctggaa
ctgcctctgt tgtgtgcctg 540 ctgaataact tctatcccag agaggccaaa
gtacagtgga aggtggataa cgccctccaa 600 tcgggtaact cccaggagag
tgtcacagag caggacagca aggacagcac ctacagcctc 660 agcagcaccc
tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 720
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgt 777
<210> SEQ ID NO 439 <211> LENGTH: 259 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 439 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Leu Ser Gly Arg Ser
Asp Asn His Gly Gly 20 25 30 Val His Met Pro Leu Gly Phe Leu Gly
Pro Gly Gly Ser Asp Ile Gln 35 40 45 Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly Asp Arg Val 50 55 60 Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp 65 70 75 80 Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala 85 90 95 Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 100 105
110 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
115 120 125 Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu
Phe Gly 130 135 140 Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
Ala Pro Ser Val
145 150 155 160 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser 165 170 175 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln 180 185 190 Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val 195 200 205 Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu 210 215 220 Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 225 230 235 240 Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 245 250 255
Gly Glu Cys <210> SEQ ID NO 440 <211> LENGTH: 765
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 440 tgcatctccc cccgcggttg
tcccgacggg ccgtacgtga tgtacggcag ctccggcggc 60 agtgggggta
gcggtgggtc cgggctgagt ggccggtccg acaatcacgg gagctcggga 120
acacagattc tgctgacgca atctcccgtg atcctctcgg tctcacccgg cgaacgggtc
180 tcgttcagct gcagagcgtc ccaatcaatc gggaccaata ttcactggta
ccagcaaagg 240 actaatgggt ctccccggct gctgataaaa tacgcctccg
agtctatctc gggcatccca 300 tcccgattta gtggtagcgg aagcggcact
gatttcacct tgtctattaa cagcgtagaa 360 tctgaggaca ttgcagacta
ttactgtcag cagaataaca attggcctac aactttcggc 420 gccgggacca
aactagagtt aaagcgtact gtggctgccc ccagcgtttt tatttttccg 480
cccagcgacg aacagctgaa gtcaggcaca gcctctgtgg tgtgtctcct gaataacttc
540 taccccagag aggccaaagt tcagtggaaa gtggacaatg ccttgcagtc
cggaaacagt 600 caagagtccg tgaccgagca ggacagtaag gatagcacgt
atagcctctc tagtacttta 660 acactgtcca aggccgacta cgagaagcac
aaggtgtacg catgcgaagt gacccatcag 720 gggctttcct cccccgtcac
caagtctttc aatcgcgggg agtgt 765 <210> SEQ ID NO 441
<211> LENGTH: 255 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 441 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg
20 25 30 Ser Asp Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser 35 40 45 Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys 50 55 60 Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg 65 70 75 80 Thr Asn Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile 85 90 95 Ser Gly Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 100 105 110 Thr Leu Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr 115 120 125 Cys Gln
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys 130 135 140
Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 145
150 155 160 Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu 165 170 175 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp 180 185 190 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp 195 200 205 Ser Lys Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys 210 215 220 Ala Asp Tyr Glu Lys His
Lys Val Tyr Ala Cys Glu Val Thr His Gln 225 230 235 240 Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255
<210> SEQ ID NO 442 <211> LENGTH: 765 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 442 tgtatttccc ctagaggttg ccctgacggg ccgtatgtca
tgtacggtag ttctggcggt 60 agtggcggat ctggcggcag tgggctgagc
ggacgtagcg ggaatcacgg ctcatccggg 120 acgcagatac tgctgaccca
gtcccccgtg atcctgtccg tgtcaccggg cgaaagggtc 180 agtttctctt
gccgagcatc acagtccata ggtacgaata tccattggta ccagcagcgg 240
accaatggga gcccaagact gctcattaag tacgcatctg agagtatctc aggcattcca
300 agcaggtttt ccggcagtgg gagcggcact gacttcaccc tcagcattaa
cagcgtggaa 360 agcgaagaca ttgcagatta ctactgccaa cagaacaata
actggcctac tacattcggg 420 gcaggaacta agttggagct caaacgtacc
gtcgctgctc ctagcgtatt tattttccct 480 cctagcgatg aacagttgaa
atctggtacc gctagtgttg tgtgcttact gaacaacttt 540 tatccccggg
aggccaaggt acaatggaag gtggacaatg ccctccaatc agggaacagc 600
caggagtctg ttaccgagca ggactccaag gacagcacct acagcctgag ctctaccctt
660 acattgagca aggctgatta tgagaagcat aaggtctacg cttgtgaggt
gacccatcag 720 gggctcagca gcccggtgac aaaaagcttt aaccgggggg aatgc
765 <210> SEQ ID NO 443 <211> LENGTH: 255 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 443 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser Gly Asn His Gly Ser
Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser 35 40 45 Pro Val Ile Leu
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys 50 55 60 Arg Ala
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg 65 70 75 80
Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile 85
90 95 Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe 100 105 110 Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr 115 120 125 Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys 130 135 140 Leu Glu Leu Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165 170 175 Leu Asn Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 180 185 190 Asn Ala
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 195 200 205
Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 210
215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln 225 230 235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 255 <210> SEQ ID NO 444 <211>
LENGTH: 765 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 444 tgtattagcc
ccagggggtg ccccgacggg ccttacgtga tgtatggcag ctccggtggc 60
agcggaggct ctggcgggag tgggatcagt tccggcctgc tgagctccgg gtcaagcggg
120 acccagatct tgctcaccca atcaccagtg atcctaagcg tgagccctgg
cgaacgggtc 180 agcttctctt gccgggcatc tcagagtatt ggcactaaca
tacactggta ccagcagcga 240 accaatgggt ccccccgcct tctaatcaaa
tatgctagcg aatccatttc aggaattcct 300 agccgattta gcggcagcgg
atcaggcact gacttcactc tgtcaatcaa ctcagttgaa 360 agcgaggaca
ttgcagacta ctattgccag cagaataata attggcccac tacatttgga 420
gctggaacaa aattggagct taagaggaca gtggctgcgc ctagtgtatt tatctttccc
480 ccctctgacg aacagttgaa atcgggaacc gcatccgtcg tctgtttact
gaacaacttc 540 tatcccagag aggccaaagt gcagtggaaa gtggataatg
ctttgcagtc tggcaacagc 600 caggaaagcg tgacggagca ggactcaaag
gatagtacat actccctgtc ctccaccctg 660 actctgagta aggccgacta
cgagaagcac aaggtctacg cctgcgaagt gacgcaccaa 720 gggctatcga
gcccggtcac caagtctttc aatcgtggag aatgc 765 <210> SEQ ID NO
445 <211> LENGTH: 255 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 445 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser 35 40 45 Pro
Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys 50 55
60 Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg
65 70 75 80 Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu
Ser Ile 85 90 95 Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe 100 105 110 Thr Leu Ser Ile Asn Ser Val Glu Ser Glu
Asp Ile Ala Asp Tyr Tyr 115 120 125 Cys Gln Gln Asn Asn Asn Trp Pro
Thr Thr Phe Gly Ala Gly Thr Lys 130 135 140 Leu Glu Leu Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165 170 175 Leu
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp 180 185
190 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
195 200 205 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
Ser Lys 210 215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln 225 230 235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 245 250 255 <210> SEQ ID NO 446
<211> LENGTH: 765 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 446
tgcatcagcc ctaggggctg cccagacggc ccatatgtga tgtacggtag ctctgggggc
60 tcaggaggca gcgggggaag cggacaaaac caggccttac gaatggctgg
cagctctggc 120 acccagatat tgctgacgca gagtccagtt atccttagtg
tcagccctgg tgaacgggtt 180 tcatttagtt gccgtgcctc ccagtctatt
ggaacgaaca ttcattggta ccagcaaagg 240 accaacggtt cacccaggtt
gcttatcaag tatgcttcag agtcaatctc cgggattccc 300 tcaaggtttt
caggctctgg ctcaggtacc gattttacgc tgagcatcaa ctccgtggag 360
agtgaggaca ttgctgatta ttactgtcag cagaataaca attggccgac aactttcggc
420 gccggcacaa agctggaact taagcgtact gtggctgcgc catctgtctt
catttttccg 480 ccctcggacg agcagttgaa gtcagggacc gcctctgtcg
tgtgccttct caataacttc 540 tatcccagag aggctaaagt ccagtggaaa
gttgataatg cacttcagag cgggaatagc 600 caggagagcg tgacggaaca
ggactctaag gactccacct attctctctc atccaccctt 660 actctctcta
aagccgacta cgaaaagcat aaggtttatg cttgcgaagt cactcatcaa 720
gggctatcta gtccggtcac taaaagcttc aacagaggtg aatgt 765 <210>
SEQ ID NO 447 <211> LENGTH: 255 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 447 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Gln Asn Gln Ala 20 25 30 Leu Arg Met Ala Gly Ser Ser Gly Thr
Gln Ile Leu Leu Thr Gln Ser 35 40 45 Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg Val Ser Phe Ser Cys 50 55 60 Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg 65 70 75 80 Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile 85 90 95 Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe 100 105
110 Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr
115 120 125 Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly
Thr Lys 130 135 140 Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser Val
Phe Ile Phe Pro 145 150 155 160 Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu 165 170 175 Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp 180 185 190 Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp 195 200 205 Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys 210 215 220 Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln 225 230
235 240 Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
245 250 255 <210> SEQ ID NO 448 <211> LENGTH: 780
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 448 tgtatcagcc cccgtggctg
tccagacggt ccttacgtta tgtatggatc tagcgggggc 60 tctggagggt
ctggcggctc tggaatctct agtggacttc tctccggaag aagcgataat 120
catggatcca gcgggacaca aatcctgttg acacagtccc cagtgatcct gtcagtctcg
180 cccggagaaa gggtgtcttt ctcttgtagg gctagtcagt ctatcggaac
taacatccat 240 tggtaccagc agcggacaaa tgggagcccg aggcttctga
tcaagtatgc ttcagagagt 300 ataagcggca tcccctcaag atttagtggc
agcgggtccg ggacagattt caccttgtca 360 atcaattctg tcgaatccga
agacattgca gactactatt gccagcaaaa caacaactgg 420 cccaccactt
tcggtgctgg aaccaaactc gagctgaaac gcactgtggc agctccttca 480
gtgttcatct tcccacctag cgacgagcag ttgaaatcgg ggacagcctc agtggtgtgt
540 ctactgaaca acttttaccc ccgggaagcc aaagtgcagt ggaaggtcga
caatgcgctg 600 caatcaggga acagtcagga gtcagttaca gagcaggact
ctaaggacag tacatattct 660 ttgagttcca ccttgacatt aagcaaggca
gactacgaga aacacaaggt gtacgcatgt 720 gaagttacac accagggcct
ttcctcccca gttacgaaaa gcttcaacag aggcgaatgc 780 <210> SEQ ID
NO 449 <211> LENGTH: 260 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 449
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asn His Gly Ser Ser Gly
Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135
140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser
145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255
Arg Gly Glu Cys 260 <210> SEQ ID NO 450 <211> LENGTH:
780 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized
<400> SEQUENCE: 450 tgcatatcgc ccagaggatg tcctgacgga
ccctacgtga tgtacgggag ttctgggggg 60 agtggaggct ctggcgggtc
agggattagt tccggcctct tgtctggacg ctccggaaat 120 cacggatcat
ctgggaccca gatcctcctg acccagtctc ccgtcattct gtctgtttct 180
ccaggcgagc gggtttcatt tagctgtagg gccagtcaga gcattggcac caacatccat
240 tggtaccagc agagaactaa tggcagtccc agactgctca ttaaatatgc
aagcgaatca 300 atttccggga ttccttctcg cttctcggga tctggatctg
gcaccgactt cacgctgtcc 360 atcaacagcg tggagagtga ggacatcgcc
gattactact gccagcagaa caacaactgg 420 ccaacaactt ttggcgccgg
gaccaagctt gagttaaaga gaaccgtagc tgcaccctct 480 gttttcattt
tcccaccctc agacgagcag cttaagtcag gaactgccag tgtggtgtgc 540
ctgctgaaca acttctaccc gagagaggct aaagtccagt ggaaggtaga caatgccctt
600 cagtctggca actctcagga gagtgtcaca gagcaggatt ctaaggactc
cacgtacagt 660 ctgagttcca ccctcaccct cagtaaggca gactacgaga
agcacaaagt ctacgcatgt 720 gaggttactc accaggggct cagctctccc
gtgacgaagt catttaacag aggtgagtgc 780 <210> SEQ ID NO 451
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 451 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Gly Asn His Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 452 <211> LENGTH: 807
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 452 tgcatttctc cgagaggctg
ccctgacggc ccatacgtaa tgtacggatc atccggtggc 60 agtggagggt
ccgggggatc cggtctaagc ggcagaagtg ataatcatgg aggctctggc 120
gggagcatca gctccggatt gctttccagc ggaagttctg gcactcaaat tctgctgaca
180 caaagccctg tgatcttgtc agtctcacct ggcgagcggg tgagcttttc
atgccgggct 240 tcccagagca tcggtacaaa tattcactgg tatcagcaga
gaaccaatgg cagtccgcgg 300 ttgctgatta agtatgcgag cgagagcata
tcaggcatac caagcagatt tagcgggagt 360 ggctctggga ccgattttac
actcagtata aattcagtgg agagcgagga tatagccgac 420 tactactgcc
agcaaaacaa taactggccc accaccttcg gcgcagggac caagcttgaa 480
ctgaagcgta cagttgccgc cccaagcgta tttattttcc ctccaagcga cgaacagctg
540 aaaagcggta ccgcaagcgt tgtgtgcctg ctgaataact tttacccaag
ggaagctaag 600 gtgcagtgga aggttgacaa tgcgctgcag tcaggcaact
cccaggaatc ggtaacagag 660 caggactcca aggattcaac ttatagtctt
agtagtaccc ttactctttc caaagctgat 720 tatgaaaaac acaaagtgta
tgcatgcgag gtgacccacc aaggactgtc atctcctgtc 780 accaagtcct
tcaaccgggg agagtgt 807 <210> SEQ ID NO 453 <211>
LENGTH: 269 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 453 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30
Ser Asp Asn His Gly Gly Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu 35
40 45 Ser Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145 150 155 160
Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165
170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
454 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 454
tgcattagtc ctcgcggttg ccctgatgga ccatacgtaa tgtatggaag ctctggtgga
60 tccgggggct ctggcggatc aggaatctcc agcgggctgc tctcatcagg
tggcagcggg 120 ggctcattaa gcggccgaag tgacaatcac ggctcgtccg
gtacacagat tctgctcact 180 cagtcacccg ttatactgtc tgtgtcgcct
ggagagcgtg tcagcttttc atgtagagcc 240 tcgcagtcaa taggcacgaa
tatacactgg taccagcaga gaactaatgg aagcccaagg 300 ttgctcatca
aatacgcatc tgagtcgatt agcggcattc cgtccaggtt tagtggcagt 360
ggaagcggca ccgatttcac tttgtctatt aactctgtgg aaagcgagga catcgccgat
420 tattattgtc agcagaataa caattggccc accaccttcg gtgccggtac
taagctggag 480 ctgaaacgta cagttgccgc tccctctgtg tttattttcc
ctccctcgga tgagcaactc 540 aaatcaggga cagcgagtgt cgtatgtctc
ctgaacaatt tttacccacg tgaagctaaa 600 gttcagtgga aggtggacaa
cgctctgcag tccggcaaca gtcaggaaag cgtaactgaa 660 caggactcaa
aggatagcac ttactccttg agcagcactc tcactctttc caaggctgat 720
tatgagaagc acaaggtgta cgcgtgtgaa gtcacccatc agggactgtc aagtccggtg
780 actaaatcat ttaacagggg cgaatgc 807 <210> SEQ ID NO 455
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 455 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg
Ser Asp 35 40 45 Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85
90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser
Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210
215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp 225 230 235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 260 265 <210> SEQ ID NO 456 <211> LENGTH:
807 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 456 tgtatttccc ctcgcggatg
tcccgacggt ccatacgtaa tgtatgggtc aagcggggga 60 tcaggaggaa
gtggaggctc cggactcagc ggtcgctccg gcaatcacgg ggggtctggc 120
ggatcaataa gttcgggcct cctgagctcc ggttcatctg gcactcagat cctgctcacg
180 cagtcgccgg taatactgag tgtctcacca ggcgagcgtg tcagcttcag
ctgtcgcgcc 240 tcacagtcaa tcggcacaaa tatccattgg taccagcaaa
ggaccaatgg cagccctagg 300 ctgctgataa aatacgcatc cgagtcaatt
tcagggattc catcgagatt ctcgggcagc 360 ggaagtggga ccgactttac
tctctccatc aacagcgtcg agtcggagga catcgcggac 420 tactactgcc
agcagaataa caattggcca acaacattcg gcgcaggaac aaagctagag 480
ctcaagagga cagtggctgc acccagtgta ttcatcttcc cacctagcga cgagcaactg
540 aagagcggga cggcttccgt cgtttgtcta ttaaataatt tctatccccg
tgaggctaaa 600 gttcagtgga aggttgataa tgcgttgcag tccggcaact
cccaggaatc cgtcacagag 660 caggattcta aggattcaac ctatagctta
agctctacac ttacgctttc taaagccgat 720 tatgaaaaac acaaggtgta
cgcttgtgag gttacccacc agggcctgag cagccccgtg 780 accaagtcgt
tcaaccgggg cgagtgt 807 <210> SEQ ID NO 457 <211>
LENGTH: 269 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 457 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30
Ser Gly Asn His Gly Gly Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu 35
40 45 Ser Ser Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145 150 155 160
Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165
170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
458 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 458
tgtatctcac ctcgcggctg ccccgacggc ccttacgtca tgtacggctc ctcgggtggg
60 tccgggggaa gtggcgggtc tggcattagt tcagggctct tatcttccgg
cggaagcggg 120 ggatctcttt ccgggcggag tggcaatcac ggcagtagcg
gaactcagat cctactcact 180 cagtcaccag tgatcctgtc tgtcagtcca
ggggagagag tgtctttcag ttgtagagct 240 tcccagtcta ttgggacaaa
cattcactgg tatcaacagc gaactaatgg atcgccaaga 300 ctcctgatta
aatatgcttc tgagagcatc tctggaattc catcaagatt ctcagggagt 360
ggtagcggca ccgattttac gttatcgatc aattccgttg agagcgaaga tatcgcggac
420 tattactgtc agcagaacaa taactggcct acaacgttcg gggcagggac
gaaattggag 480 ctgaagcgga ccgtcgccgc gccaagcgtg ttcatcttcc
cccctagcga cgagcaattg 540 aaaagcggca ccgcaagtgt ggtttgcctg
ctgaacaact tttatcctcg cgaggcgaaa 600 gtgcagtgga aagtcgacaa
tgcactccag tcagggaaca gccaagagtc cgttactgaa 660 caagactcta
aagatagtac ttatagctta tccagcacac tgacgctcag taaggccgat 720
tatgaaaaac ataaggtgta tgcgtgtgag gttacccatc aaggattgtc atcacccgtc
780 accaaatcct ttaacagagg agaatgt 807 <210> SEQ ID NO 459
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 459 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg
Ser Gly 35 40 45 Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile
Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140
Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145
150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210>
SEQ ID NO 460 <211> LENGTH: 807 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 460 tgtatctcgc cccgcggctg cccagacggc ccatatgtga
tgtatggttc ttccggtgga 60 tccggcggat caggtgggtc tggcctctca
ggtcgttccg acaaccacgg cggctcaggt 120 gggtctcaga atcaggcact
gcggatggcc ggatcttctg gcacccagat attgctcaca 180
cagtcaccag ttattctgtc cgtatctcca ggagaacggg tatctttctc ttgtagggca
240 agccagtcca tcggaacaaa catccattgg taccagcagc ggaccaatgg
cagtccacgg 300 cttctgatca agtatgctag tgaaagcatt agcgggattc
caagccgatt ttctgggtcg 360 ggtagtggaa ccgacttcac cctgagcatt
aactctgtcg aatccgaaga tattgctgac 420 tattactgtc agcagaacaa
caattggccg actacgtttg gcgccggaac caaattagaa 480 cttaagagaa
ccgtggccgc tccctctgtc ttcattttcc cgccttccga cgaacagctg 540
aagagcggaa ctgcctccgt ggtgtgcctg ttgaataact tttatccaag ggaagcaaag
600 gtgcagtgga aagtggacaa tgctctgcag tctggcaata gccaggagtc
cgtgactgaa 660 caggacagta aagactcaac ctactcactg agcagtactc
tcacattatc caaagccgat 720 tatgaaaagc ataaggttta tgcatgcgag
gttacccacc agggactgag ctcccccgtg 780 accaaaagct tcaatagggg tgagtgc
807 <210> SEQ ID NO 461 <211> LENGTH: 269 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 461 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Leu Ser Gly Arg 20 25 30 Ser Asp Asn His Gly Gly
Ser Gly Gly Ser Gln Asn Gln Ala Leu Arg 35 40 45 Met Ala Gly Ser
Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val 50 55 60 Ile Leu
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 65 70 75 80
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85
90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser
Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210
215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp 225 230 235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 260 265 <210> SEQ ID NO 462 <211> LENGTH:
807 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 462 tgcatcagcc cccgaggctg
ccctgatggc ccctacgtga tgtacgggtc cagcggtggc 60 agcgggggct
caggggggag cgggcagaat caggccctga gaatggcggg tggatccggg 120
gggtcccttt ctggcaggtc cgataaccac ggttctagtg gaacacagat tttgctgaca
180 caaagtcccg tcatcctctc tgtgtctccc ggtgagcggg tcagtttttc
ctgccgagcg 240 tcccagagca tcgggacaaa tatccattgg taccagcaga
gaacgaacgg ctctcctaga 300 ctgctcatca agtacgcctc ggaaagtatt
tccggcattc cctcccgttt cagcggctcc 360 ggaagtggta cagattttac
cctgagtatt aattccgtcg aatctgagga catagccgac 420 tactattgcc
aacagaataa caattggcca acaacttttg gcgccgggac taagctggag 480
ctgaaacgga ccgtcgcagc accaagtgtt ttcatcttcc caccaagtga cgagcagctg
540 aaatccggaa cagcgagcgt ggtgtgccta ctcaataact tctatccacg
cgaagccaag 600 gtgcagtgga aagtggacaa cgctctgcag tccggcaata
gccaggaaag cgtgacagag 660 caagattcta aggacagtac gtattcactg
tccagtacgc tcaccttaag caaggctgac 720 tacgaaaaac acaaggtcta
cgcctgtgag gtcacacatc agggcctctc cagtccggtt 780 acaaaaagtt
tcaatcgcgg ggaatgt 807 <210> SEQ ID NO 463 <211>
LENGTH: 269 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 463 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gln Asn Gln Ala 20 25 30
Leu Arg Met Ala Gly Gly Ser Gly Gly Ser Leu Ser Gly Arg Ser Asp 35
40 45 Asn His Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn
Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu 145 150 155 160
Leu Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165
170 175 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 180 185 190 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 195 200 205 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 210 215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 225 230 235 240 Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu 245 250 255 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
464 <211> LENGTH: 807 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 464
tgcatcagtc ccagaggctg ccctgacggg ccctacgtga tgtatggtag ctcagggggc
60 tccggcggct ccggcggaag cggacttagc ggccgtagcg gcaaccatgg
gggttctgga 120 ggatcccaga atcaggctct gcgcatggct ggaagcagcg
gtacccagat cctgctcacc 180 caatcacccg tcatcttgtc tgtgagtcct
ggcgaaaggg tgtcgttctc ttgtcgcgcg 240 tcccagtcca ttgggaccaa
cattcattgg taccagcaga ggactaacgg gagcccccgc 300 ctgctgatca
aatacgccag tgaatctatc tctggaatcc catcacgatt ttcagggtcc 360
ggtagtggga ccgacttcac tttgagtatt aacagtgtgg aatccgagga catagccgac
420 tattactgtc agcagaacaa taactggcca acaacctttg gcgccgggac
aaagttagag 480 cttaagcgga ctgttgcagc cccctccgtt tttatcttcc
cgcccagtga tgaacagctg 540 aaaagcggta ccgcctccgt agtgtgcctt
ctcaataatt tttaccccag agaagctaaa 600 gtacagtgga aagtcgacaa
cgccctccag agcggcaaca gtcaggagtc cgtcaccgag 660 caggattcta
aagactcaac atatagcctt tcgtccaccc taacactttc aaaagcagac 720
tatgaaaaac ataaggtgta tgcctgcgag gtcacacacc aggggctcag ctctccagtt
780 actaagtcat tcaaccgcgg agagtgt 807 <210> SEQ ID NO 465
<211> LENGTH: 269 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 465 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Leu Ser Gly Arg
20 25 30 Ser Gly Asn His Gly Gly Ser Gly Gly Ser Gln Asn Gln Ala
Leu Arg 35 40 45 Met Ala Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr
Gln Ser Pro Val 50 55 60 Ile Leu Ser Val Ser Pro Gly Glu Arg Val
Ser Phe Ser Cys Arg Ala 65 70 75 80 Ser Gln Ser Ile Gly Thr Asn Ile
His Trp Tyr Gln Gln Arg Thr Asn 85 90 95 Gly Ser Pro Arg Leu Leu
Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly 100 105 110
Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu 115
120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys
Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly Thr
Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala Ala Pro Ser Val
Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe Tyr Pro Arg Glu
Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205 Leu Gln Ser Gly
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210 215 220 Asp Ser
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp 225 230 235
240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 260
265 <210> SEQ ID NO 466 <211> LENGTH: 807 <212>
TYPE: DNA <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 466 tgcattagcc cccgagggtg tcccgatggg
ccctacgtaa tgtacggatc atcgggcgga 60 tctgggggct ccggtggctc
tggtcagaat caagctctgc gcatggccgg aggtagcggt 120 ggaagcctga
gcggccgaag tggaaaccac ggctcctctg gcactcagat tcttctcacg 180
cagtcgcccg tgatcttgtc cgtgagccca ggcgagcggg tgagcttctc ttgccgggcc
240 agccaaagta taggtacaaa tattcactgg taccaacagc gaaccaacgg
gtcgcctagg 300 ttgctcataa agtacgcatc cgagagtata agcggcatac
catctaggtt ctcaggtagc 360 ggcagcggga ccgattttac cctcagcatt
aattcggttg aatctgaaga tatcgccgat 420 tattattgtc agcagaataa
caattggcct actactttcg gcgccggaac aaagctggaa 480 cttaagcgca
cagtggccgc tccttctgtc tttatcttcc ctccatctga cgagcaatta 540
aagagtggga cagcctcggt ggtgtgtttg ctcaataact tctatccaag ggaggcaaag
600 gtgcagtgga aggtcgataa cgctctccag agtgggaatt cccaggagtc
cgtgaccgag 660 caggattcta aagatagcac atactcactg tcttccaccc
tgaccctgtc caaggcagac 720 tacgagaagc acaaagttta cgcctgtgaa
gtgacacacc agggcctcag ctctcctgtc 780 acaaagagtt ttaatcgggg cgagtgt
807 <210> SEQ ID NO 467 <211> LENGTH: 269 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 467 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly
Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser
Gly Gly Ser Gly Gln Asn Gln Ala 20 25 30 Leu Arg Met Ala Gly Gly
Ser Gly Gly Ser Leu Ser Gly Arg Ser Gly 35 40 45 Asn His Gly Ser
Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val 50 55 60 Ile Leu
Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala 65 70 75 80
Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn 85
90 95 Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser
Gly 100 105 110 Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu 115 120 125 Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala
Asp Tyr Tyr Cys Gln 130 135 140 Gln Asn Asn Asn Trp Pro Thr Thr Phe
Gly Ala Gly Thr Lys Leu Glu 145 150 155 160 Leu Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 165 170 175 Asp Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn 180 185 190 Asn Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala 195 200 205
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys 210
215 220 Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp 225 230 235 240 Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu 245 250 255 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 260 265 <210> SEQ ID NO 468 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 468 Ser Gly Arg Ser Ala Asn Pro
Arg Gly 1 5 <210> SEQ ID NO 469 <211> LENGTH: 15
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 469 Ile Ser Ser Gly Leu Leu Ser
Gly Arg Ser Ala Asn Pro Arg Gly 1 5 10 15 <210> SEQ ID NO 470
<211> LENGTH: 18 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 470 Ala
Val Gly Leu Leu Ala Pro Pro Thr Ser Gly Arg Ser Ala Asn Pro 1 5 10
15 Arg Gly <210> SEQ ID NO 471 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 471 Ala Val Gly Leu Leu Ala Pro
Pro Ser Gly Arg Ser Ala Asn Pro Arg 1 5 10 15 Gly <210> SEQ
ID NO 472 <211> LENGTH: 262 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 472
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser
Ser Gly Thr 35 40 45 Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu
Ser Val Ser Pro Gly 50 55 60 Glu Arg Val Ser Phe Ser Cys Arg Ala
Ser Gln Ser Ile Gly Thr Asn 65 70 75 80 Ile His Trp Tyr Gln Gln Arg
Thr Asn Gly Ser Pro Arg Leu Leu Ile 85 90 95 Lys Tyr Ala Ser Glu
Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 100 105 110 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser 115 120 125 Glu
Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr 130 135
140 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
145 150 155 160 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser Gly 165 170 175 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu Ala 180 185 190 Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser Gln 195 200 205 Glu Ser Val Thr Glu Gln Asp
Ser Lys Asp Ser Thr Tyr Ser Leu Ser 210 215 220 Ser Thr Leu Thr Leu
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 225 230 235 240 Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 245 250 255
Phe Asn Arg Gly Glu Cys 260 <210> SEQ ID NO 473 <211>
LENGTH: 268 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 473 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala Asn Pro Arg 35 40 45 Gly
Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile 50 55
60 Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser
65 70 75 80 Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr
Asn Gly 85 90 95 Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu Ser
Ile Ser Gly Ile 100 105 110 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Ser 115 120 125 Ile Asn Ser Val Glu Ser Glu Asp
Ile Ala Asp Tyr Tyr Cys Gln Gln 130 135 140 Asn Asn Asn Trp Pro Thr
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu 145 150 155 160 Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 165 170 175 Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 180 185
190 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
195 200 205 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp 210 215 220 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr 225 230 235 240 Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser 245 250 255 Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO 474 <211>
LENGTH: 264 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 474 Cys Ile Ser Pro
Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30
Leu Ala Pro Pro Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Ser Ser 35
40 45 Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser 50 55 60 Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly 65 70 75 80 Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu 85 90 95 Leu Ile Lys Tyr Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe 100 105 110 Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val 115 120 125 Glu Ser Glu Asp Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp 130 135 140 Pro Thr Thr
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val 145 150 155 160
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 165
170 175 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg 180 185 190 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn 195 200 205 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser 210 215 220 Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys 225 230 235 240 Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr 245 250 255 Lys Ser Phe Asn
Arg Gly Glu Cys 260 <210> SEQ ID NO 475 <211> LENGTH:
270 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 475 Gln Gly Gln Ser Gly Gln Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly 1 5 10 15 Pro Tyr Val Met Tyr
Gly Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly 20 25 30 Ser Gly Ala
Val Gly Leu Leu Ala Pro Pro Ser Gly Arg Ser Ala Asn 35 40 45 Pro
Arg Gly Gly Ser Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro 50 55
60 Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg
65 70 75 80 Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln Gln
Arg Thr 85 90 95 Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser
Glu Ser Ile Ser 100 105 110 Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr 115 120 125 Leu Ser Ile Asn Ser Val Glu Ser
Glu Asp Ile Ala Asp Tyr Tyr Cys 130 135 140 Gln Gln Asn Asn Asn Trp
Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu 145 150 155 160 Glu Leu Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro 165 170 175 Ser
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu 180 185
190 Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
195 200 205 Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser 210 215 220 Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala 225 230 235 240 Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly 245 250 255 Leu Ser Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 260 265 270 <210> SEQ ID NO 476
<211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 476 Gln
Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5 10
15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu
20 25 30 Leu Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp
Ile Gln 35 40 45 Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly Asp Arg Val 50 55 60 Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Ser Tyr Leu Asn Trp 65 70 75 80 Tyr Gln Gln Lys Pro Gly Lys Ala
Pro Lys Leu Leu Ile Tyr Ala Ala 85 90 95 Ser Ser Leu Gln Ser Gly
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 100 105 110 Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 115 120 125 Ala Thr
Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly 130 135 140
Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val 145
150 155 160 Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
Ala Ser 165 170 175 Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
Ala Lys Val Gln 180 185 190 Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
Asn Ser Gln Glu Ser Val 195 200 205 Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr Ser Leu Ser Ser Thr Leu 210 215 220 Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu 225 230 235 240 Val Thr His
Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg 245 250 255 Gly
Glu Cys <210> SEQ ID NO 477 <211> LENGTH: 253
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 477 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15
Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala 20
25 30 Asn Pro Arg Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
Ser 35 40 45 Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Ala 50 55 60 Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly 65 70 75 80 Lys Ala Pro Lys Leu Leu Ile Tyr Ala
Ala Ser Ser Leu Gln Ser Gly 85 90 95 Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu 100 105 110 Thr Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln 115 120 125 Gln Thr Val
Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu 130 135 140 Ile
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser 145 150
155 160 Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn 165 170 175 Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala 180 185 190 Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys 195 200 205 Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp 210 215 220 Tyr Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu 225 230 235 240 Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 <210> SEQ ID NO
478 <211> LENGTH: 261 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 478
Gln Gly Gln Ser Gly Gln Cys Asn Ile Trp Leu Val Gly Gly Asp Cys 1 5
10 15 Arg Gly Trp Gln Gly Gly Ser Ser Gly Gly Ser Ala Val Gly Leu
Leu 20 25 30 Ala Pro Pro Ser Gly Arg Ser Ala Asn Pro Arg Gly Gly
Gly Ser Asp 35 40 45 Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly Asp 50 55 60 Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr Leu 65 70 75 80 Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile Tyr 85 90 95 Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 100 105 110 Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu 115 120 125 Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu 130 135
140 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
145 150 155 160 Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys
Ser Gly Thr 165 170 175 Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
Pro Arg Glu Ala Lys 180 185 190 Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser Gly Asn Ser Gln Glu 195 200 205 Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr Tyr Ser Leu Ser Ser 210 215 220 Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala 225 230 235 240 Cys Glu
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe 245 250 255
Asn Arg Gly Glu Cys 260 <210> SEQ ID NO 479 <211>
LENGTH: 255 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 479 Cys Asn Ile Trp
Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser
Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Ser Gly Arg 20 25 30
Ser Ala Asn Pro Arg Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser 35
40 45 Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys 50 55 60 Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys 65 70 75 80 Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala
Ala Ser Ser Leu Gln 85 90 95 Ser Gly Val Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe 100 105 110 Thr Leu Thr Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr 115 120 125 Cys Gln Gln Thr Val
Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys 130 135 140 Val Glu Ile
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro 145 150 155 160
Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu 165
170 175 Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp 180 185 190 Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp 195 200 205 Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys 210 215 220 Ala Asp Tyr Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln 225 230 235 240 Gly Leu Ser Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 255 <210> SEQ ID
NO 480 <211> LENGTH: 5 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 480
Ile Ser Ser Gly Leu 1 5 <210> SEQ ID NO 481 <211>
LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 481 Ile Ser Ser Gly
Leu Leu Ser 1 5 <210> SEQ ID NO 482 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 482 Ile Ser Ser Gly Leu Leu 1 5
<210> SEQ ID NO 483 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 483 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asp His 1
5 10 <210> SEQ ID NO 484 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 484 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser
Asp Ile His 1 5 10 <210> SEQ ID NO 485 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 485 Ile Ser Ser Gly Leu Leu Ser
Gly Arg Ser Asp Gln His 1 5 10 <210> SEQ ID NO 486
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 486
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Thr His 1 5 10
<210> SEQ ID NO 487 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 487 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Tyr His 1
5 10 <210> SEQ ID NO 488 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 488 Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser
Asp Asn Pro 1 5 10 <210> SEQ ID NO 489 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 489 Ile Ser Ser Gly Leu Leu Ser
Gly Arg Ser Ala Asn Pro 1 5 10 <210> SEQ ID NO 490
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 490 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala Asn Ile 1 5 10 <210>
SEQ ID NO 491 <211> LENGTH: 39 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 491 atatcgagtg gattgctgtc tggcagatct gacgatcac 39
<210> SEQ ID NO 492 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 492 atatcgagtg gattgctgtc tggcagatct gacatacac 39
<210> SEQ ID NO 493 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 493 atatcgagtg gattgctgtc tggcagatct gaccaacac 39
<210> SEQ ID NO 494 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 494 atatcgagtg gattgctgtc tggcagatct gacactcac 39
<210> SEQ ID NO 495 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 495 atatcgagtg gattgctgtc tggcagatct gactatcac 39
<210> SEQ ID NO 496 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 496 attagctcag gccttcttag cggccgcagc gacaatccc 39
<210> SEQ ID NO 497 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 497 atatcgagtg gattgctgtc tggcagatct gctaatccc 39
<210> SEQ ID NO 498 <211> LENGTH: 39 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 498 atatcgagtg gattgctgtc tggcagatct gctaatata 39
<210> SEQ ID NO 499 <211> LENGTH: 260 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 499 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asp His
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 500
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 500 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Asp Ile His Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser
145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255
Arg Gly Glu Cys 260 <210> SEQ ID NO 501 <211> LENGTH:
260 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 501 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Gly Arg Ser Asp Gln His Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55
60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe
Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn
Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln
Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu
Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185
190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
195 200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys
Val Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser
Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260
<210> SEQ ID NO 502 <211> LENGTH: 260 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 502 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Thr His
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 503
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 503 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Asp Tyr His Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 504 <211> LENGTH: 260
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 504 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser
Gly Arg Ser Asp Asn Pro Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55
60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe
Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn
Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln
Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu
Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145 150 155 160 Val Phe Ile
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185
190
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195
200 205 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
Thr 210 215 220 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
Tyr Ala Cys 225 230 235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro
Val Thr Lys Ser Phe Asn 245 250 255 Arg Gly Glu Cys 260 <210>
SEQ ID NO 505 <211> LENGTH: 260 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 505 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ile Ser Ser Gly 20 25 30 Leu Leu Ser Gly Arg Ser Ala Asn Pro
Gly Ser Ser Gly Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val
Ile Leu Ser Val Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105
110 Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp
115 120 125 Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
Thr Phe 130 135 140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val
Ala Ala Pro Ser 145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230
235 240 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn 245 250 255 Arg Gly Glu Cys 260 <210> SEQ ID NO 506
<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 506 Cys
Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10
15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser Gly
20 25 30 Leu Leu Ser Gly Arg Ser Ala Asn Ile Gly Ser Ser Gly Thr
Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser
Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln Ser
Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn Gly
Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile Ser
Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr Asp
Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile Ala
Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135 140
Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser 145
150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg
Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys Asp
Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys Ala
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val Thr
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255 Arg
Gly Glu Cys 260 <210> SEQ ID NO 507 <211> LENGTH: 252
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 507 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp 20 25 30 Asp His Gly
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55
60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val Val Ala Pro Pro Leu Phe
Gly Gln Gly Thr Lys Val Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 165 170 175 Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 180 185
190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 225 230 235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 <210> SEQ ID NO 508 <211> LENGTH:
252 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 508 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp 20 25 30 Ile His Gly
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55
60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val Val Ala Pro Pro Leu Phe
Gly Gln Gly Thr Lys Val Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 165 170 175 Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 180 185
190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 225 230 235 240
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 <210>
SEQ ID NO 509 <211> LENGTH: 252 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 509 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Gln His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 510 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 510 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Thr His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 511 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 511 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Tyr His Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 512 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 512 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Asp 20 25 30 Asn Pro Gly Gly Gly Ser Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105
110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
115 120 125 Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val
Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val Cys Leu Leu Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230
235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250
<210> SEQ ID NO 513 <211> LENGTH: 252 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 513 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu
Ser Gly Arg Ser Ala 20 25 30
Asn Pro Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 35
40 45 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser 50 55 60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys
Pro Gly Lys 65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
Leu Gln Ser Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val Val Ala Pro
Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 130 135 140 Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145 150 155 160
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 165
170 175 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
Leu 180 185 190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
Ser Lys Asp 195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
Ser Lys Ala Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser 225 230 235 240 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 245 250 <210> SEQ ID NO 514
<211> LENGTH: 252 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 514 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Ala
20 25 30 Asn Ile Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser 35 40 45 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser 50 55 60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys 65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val
Val Ala Pro Pro Leu Phe Gly Gln Gly Thr Lys Val Glu Ile 130 135 140
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145
150 155 160 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn 165 170 175 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 180 185 190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser 225 230 235 240 Ser Pro Val
Thr Lys Ser Phe Asn Arg Gly Glu Cys 245 250 <210> SEQ ID NO
515 <211> LENGTH: 18 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 515
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5
10 15 Asp His <210> SEQ ID NO 516 <211> LENGTH: 18
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 516 Ala Val Gly Leu Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Ile His <210>
SEQ ID NO 517 <211> LENGTH: 18 <212> TYPE: PRT
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 517 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Gln His <210> SEQ ID NO 518 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 518 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Thr His
<210> SEQ ID NO 519 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 519 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Tyr His <210> SEQ ID NO 520 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 520 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Asp 1 5 10 15 Asn Pro
<210> SEQ ID NO 521 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 521 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Ala 1 5 10 15 Asn Pro <210> SEQ ID NO 522 <211>
LENGTH: 18 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 522 Ala Val Gly Leu
Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Ala 1 5 10 15 Asn Ile
<210> SEQ ID NO 523 <211> LENGTH: 54 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 523 gctgtgggac tgctggctcc tcctggtggc ctgtctggca
gatctgacga tcac 54 <210> SEQ ID NO 524 <211> LENGTH: 54
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 524 gctgtgggac tgctggctcc
tcctggtggc ctgtctggca gatctgacat acac 54 <210> SEQ ID NO 525
<211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized
<400> SEQUENCE: 525 gctgtgggac tgctggctcc tcctggtggc
ctgtctggca gatctgacca acac 54 <210> SEQ ID NO 526 <211>
LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 526 gctgtgggac
tgctggctcc tcctggtggc ctgtctggca gatctgacac tcac 54 <210> SEQ
ID NO 527 <211> LENGTH: 54 <212> TYPE: DNA <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 527
gctgtgggac tgctggctcc tcctggtggc ctgtctggca gatctgacta tcac 54
<210> SEQ ID NO 528 <211> LENGTH: 54 <212> TYPE:
DNA <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 528 gctgtgggac tgctggctcc tcctggtggc ctgtctggca
gatctgacaa tccc 54 <210> SEQ ID NO 529 <211> LENGTH: 54
<212> TYPE: DNA <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 529 gctgtgggac tgctggctcc
tcctggtggc ctgtctggca gatctgctaa tccc 54 <210> SEQ ID NO 530
<211> LENGTH: 54 <212> TYPE: DNA <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 530
gctgtgggac tgctggctcc tcctggtggc ctgtctggca gatctgctaa tata 54
<210> SEQ ID NO 531 <211> LENGTH: 265 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 531 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp Asp His Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu
Thr Gln Ser Pro Val Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg
Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu
Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105
110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser
115 120 125 Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn
Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu
Leu Lys Arg Thr 145 150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val
Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230
235 240 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265
<210> SEQ ID NO 532 <211> LENGTH: 265 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 532 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp Ile His Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu
Thr Gln Ser Pro Val Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg
Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu
Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105
110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser
115 120 125 Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn
Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu
Leu Lys Arg Thr 145 150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val
Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230
235 240 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265
<210> SEQ ID NO 533 <211> LENGTH: 265 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 533 Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val
Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp Gln His Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu
Thr Gln Ser Pro Val Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg
Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu
Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105
110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser
115 120 125 Val Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn
Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu
Leu Lys Arg Thr 145 150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val
Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230
235 240 Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265
<210> SEQ ID NO 534 <211> LENGTH: 265
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 534 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp Thr His Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 535 <211> LENGTH: 265
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 535 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp Tyr His Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 536 <211> LENGTH: 265
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 536 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp Asn Pro Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 537 <211> LENGTH: 265
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 537 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Ala Asn Pro Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 538 <211> LENGTH: 265
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 538
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ala Val Gly
Leu 20 25 30 Leu Ala Pro Pro Gly Gly Leu Ser Gly Arg Ser Ala Asn
Ile Gly Ser 35 40 45 Ser Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro
Val Ile Leu Ser Val 50 55 60 Ser Pro Gly Glu Arg Val Ser Phe Ser
Cys Arg Ala Ser Gln Ser Ile 65 70 75 80 Gly Thr Asn Ile His Trp Tyr
Gln Gln Arg Thr Asn Gly Ser Pro Arg 85 90 95 Leu Leu Ile Lys Tyr
Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg 100 105 110 Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser 115 120 125 Val
Glu Ser Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135
140 Trp Pro Thr Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr
145 150 155 160 Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
Glu Gln Leu 165 170 175 Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
Asn Asn Phe Tyr Pro 180 185 190 Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu Gln Ser Gly 195 200 205 Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr 210 215 220 Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 225 230 235 240 Lys Val
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val 245 250 255
Thr Lys Ser Phe Asn Arg Gly Glu Cys 260 265 <210> SEQ ID NO
539 <211> LENGTH: 257 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 539
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly
Leu 20 25 30 Ser Gly Arg Ser Asp Asp His Gly Gly Gly Ser Asp Ile
Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135
140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255
Cys <210> SEQ ID NO 540 <211> LENGTH: 257 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 540 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys
Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Ile
His Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85
90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro
Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val
Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210
215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu 245 250 255 Cys <210> SEQ ID NO 541
<211> LENGTH: 257 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 541 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu
20 25 30 Ser Gly Arg Ser Asp Gln His Gly Gly Gly Ser Asp Ile Gln
Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145
150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
<210> SEQ ID NO 542 <211> LENGTH: 257 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 542 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala
Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Thr His Gly Gly
Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly Asp Arg Val Thr Ile
50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp
Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr
Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe
Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170
175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val
Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro
Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys <210> SEQ
ID NO 543 <211> LENGTH: 257 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 543
Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5
10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly
Leu 20 25 30 Ser Gly Arg Ser Asp Tyr His Gly Gly Gly Ser Asp Ile
Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser
Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr
Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135
140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn
Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr
Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln
Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255
Cys <210> SEQ ID NO 544 <211> LENGTH: 257 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 544 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys
Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly
Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Asp Asn
Pro Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85
90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro
Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val
Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210
215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu 245 250 255 Cys <210> SEQ ID NO 545
<211> LENGTH: 257 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 545 Cys
Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10
15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu
20 25 30 Ser Gly Arg Ser Ala Asn Pro Gly Gly Gly Ser Asp Ile Gln
Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser
Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys
Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr
Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145
150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235 240 His Gln Gly
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
<210> SEQ ID NO 546 <211> LENGTH: 257 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 546 Cys Asn Ile Trp Leu Val Gly Gly Asp Cys Arg Gly Trp
Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser Ala Val Gly Leu Leu Ala
Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg Ser Ala Asn Ile Gly Gly
Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln Ser Pro Ser Ser Leu Ser
Ala Ser Val Gly Asp Arg Val Thr Ile 50 55 60 Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln 65 70 75 80 Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser 85 90 95 Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr 100 105
110
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr 115
120 125 Tyr Tyr Cys Gln Gln Thr Val Val Ala Pro Pro Leu Phe Gly Gln
Gly 130 135 140 Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile 145 150 155 160 Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val 165 170 175 Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys 180 185 190 Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu 195 200 205 Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu 210 215 220 Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr 225 230 235
240 His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
245 250 255 Cys <210> SEQ ID NO 547 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 547 Leu Ser Gly Arg Ser Asp Asp
His 1 5 <210> SEQ ID NO 548 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Artificial Sequence <220>
FEATURE: <223> OTHER INFORMATION: chemically synthesized
<400> SEQUENCE: 548 Leu Ser Gly Arg Ser Asp Ile His 1 5
<210> SEQ ID NO 549 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 549 Leu Ser Gly Arg Ser Asp Gln His 1 5 <210> SEQ
ID NO 550 <211> LENGTH: 8 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 550
Leu Ser Gly Arg Ser Asp Thr His 1 5 <210> SEQ ID NO 551
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 551 Leu
Ser Gly Arg Ser Asp Tyr His 1 5 <210> SEQ ID NO 552
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 552 Leu
Ser Gly Arg Ser Asp Asn Pro 1 5 <210> SEQ ID NO 553
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 553 Leu
Ser Gly Arg Ser Ala Asn Pro 1 5 <210> SEQ ID NO 554
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 554 Leu
Ser Gly Arg Ser Ala Asn Ile 1 5 <210> SEQ ID NO 555
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Artificial Sequence <220> FEATURE: <223> OTHER
INFORMATION: chemically synthesized <400> SEQUENCE: 555 Ile
Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp Asn Ile 1 5 10 <210>
SEQ ID NO 556 <211> LENGTH: 39 <212> TYPE: DNA
<213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 556 atatcgagtg gattgctgtc tggcagatct gacaatata 39
<210> SEQ ID NO 557 <211> LENGTH: 18 <212> TYPE:
PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:
<223> OTHER INFORMATION: chemically synthesized <400>
SEQUENCE: 557 Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu Ser Gly
Arg Ser Asp 1 5 10 15 Asn Ile <210> SEQ ID NO 558 <211>
LENGTH: 54 <212> TYPE: DNA <213> ORGANISM: Artificial
Sequence <220> FEATURE: <223> OTHER INFORMATION:
chemically synthesized <400> SEQUENCE: 558 gctgtgggac
tgctggctcc tcctggtggc ctgtctggca gatctgacaa tata 54 <210> SEQ
ID NO 559 <211> LENGTH: 260 <212> TYPE: PRT <213>
ORGANISM: Artificial Sequence <220> FEATURE: <223>
OTHER INFORMATION: chemically synthesized <400> SEQUENCE: 559
Cys Ile Ser Pro Arg Gly Cys Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5
10 15 Ser Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ile Ser Ser
Gly 20 25 30 Leu Leu Ser Gly Arg Ser Asp Asn Ile Gly Ser Ser Gly
Thr Gln Ile 35 40 45 Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val
Ser Pro Gly Glu Arg 50 55 60 Val Ser Phe Ser Cys Arg Ala Ser Gln
Ser Ile Gly Thr Asn Ile His 65 70 75 80 Trp Tyr Gln Gln Arg Thr Asn
Gly Ser Pro Arg Leu Leu Ile Lys Tyr 85 90 95 Ala Ser Glu Ser Ile
Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly 100 105 110 Ser Gly Thr
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp 115 120 125 Ile
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe 130 135
140 Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro Ser
145 150 155 160 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
Gly Thr Ala 165 170 175 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
Arg Glu Ala Lys Val 180 185 190 Gln Trp Lys Val Asp Asn Ala Leu Gln
Ser Gly Asn Ser Gln Glu Ser 195 200 205 Val Thr Glu Gln Asp Ser Lys
Asp Ser Thr Tyr Ser Leu Ser Ser Thr 210 215 220 Leu Thr Leu Ser Lys
Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 225 230 235 240 Glu Val
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 245 250 255
Arg Gly Glu Cys 260 <210> SEQ ID NO 560 <211> LENGTH:
265 <212> TYPE: PRT <213> ORGANISM: Artificial
Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 560 Cys Ile Ser Pro Arg Gly Cys
Pro Asp Gly Pro Tyr Val Met Tyr Gly 1 5 10 15 Ser Ser Gly Gly Ser
Gly Gly Ser Gly Gly Ser Gly Ala Val Gly Leu 20 25 30 Leu Ala Pro
Pro Gly Gly Leu Ser Gly Arg Ser Asp Asn Ile Gly Ser 35 40 45 Ser
Gly Thr Gln Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val 50 55
60 Ser Pro Gly Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile
65 70 75 80 Gly Thr Asn Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser
Pro Arg 85 90 95 Leu Leu Ile Lys Tyr Ala Ser Glu Ser Ile Ser Gly
Ile Pro Ser Arg 100 105 110 Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser Ile Asn Ser 115 120 125 Val Glu Ser Glu Asp Ile Ala Asp
Tyr Tyr Cys Gln Gln Asn Asn Asn 130 135 140 Trp Pro Thr Thr Phe Gly
Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr 145 150 155 160 Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu 165 170 175 Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 180 185
190 Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
195 200 205 Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
Thr Tyr 210 215 220 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr Glu Lys His 225 230 235 240 Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser Ser Pro Val 245 250 255 Thr Lys Ser Phe Asn Arg Gly
Glu Cys 260 265 <210> SEQ ID NO 561 <211> LENGTH: 252
<212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 561 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ile Ser Ser Gly Leu Leu Ser Gly Arg Ser Asp 20 25 30 Asn Ile Gly
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 35 40 45 Leu
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 50 55
60 Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
65 70 75 80 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu Gln Ser
Gly Val 85 90 95 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr 100 105 110 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln 115 120 125 Thr Val Val Ala Pro Pro Leu Phe
Gly Gln Gly Thr Lys Val Glu Ile 130 135 140 Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 145 150 155 160 Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 165 170 175 Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 180 185
190 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
195 200 205 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 210 215 220 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 225 230 235 240 Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 245 250 <210> SEQ ID NO 562 <211> LENGTH:
257 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence
<220> FEATURE: <223> OTHER INFORMATION: chemically
synthesized <400> SEQUENCE: 562 Cys Asn Ile Trp Leu Val Gly
Gly Asp Cys Arg Gly Trp Gln Gly Gly 1 5 10 15 Ser Ser Gly Gly Ser
Ala Val Gly Leu Leu Ala Pro Pro Gly Gly Leu 20 25 30 Ser Gly Arg
Ser Asp Asn Ile Gly Gly Gly Ser Asp Ile Gln Met Thr 35 40 45 Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile 50 55
60 Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
65 70 75 80 Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Ser 85 90 95 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr 100 105 110 Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr 115 120 125 Tyr Tyr Cys Gln Gln Thr Val Val
Ala Pro Pro Leu Phe Gly Gln Gly 130 135 140 Thr Lys Val Glu Ile Lys
Arg Thr Val Ala Ala Pro Ser Val Phe Ile 145 150 155 160 Phe Pro Pro
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val 165 170 175 Cys
Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys 180 185
190 Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
195 200 205 Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu 210 215 220 Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr 225 230 235 240 His Gln Gly Leu Ser Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu 245 250 255 Cys
* * * * *