U.S. patent application number 13/693347 was filed with the patent office on 2013-09-26 for antibodies for epidermal growth factor receptor 3 (her3) directed to domain iii and domain iv of her3.
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is NOVARTIS AG. Invention is credited to Winfried ELIS, Seth ETTENBERG, Andrew Paul GARNER, Nicole HAUBST, Heather Adkins HUET, Christian Carsten Silvester KUNZ, Elizabeth Anne REISINGER SPRAGUE, Qing SHENG.
Application Number | 20130251703 13/693347 |
Document ID | / |
Family ID | 47557417 |
Filed Date | 2013-09-26 |
United States Patent
Application |
20130251703 |
Kind Code |
A1 |
ELIS; Winfried ; et
al. |
September 26, 2013 |
ANTIBODIES FOR EPIDERMAL GROWTH FACTOR RECEPTOR 3 (HER3) DIRECTED
TO DOMAIN III AND DOMAIN IV OF HER3
Abstract
The present invention relates to antibodies or fragments thereof
that bind to a non-linear epitope within domain 3 of the HER3
receptor and inhibit both ligand-dependent and ligand-independent
signal transduction. The invention also relates antibodies or
fragments thereof that bind to amino acid residues within domains
3-4 of HER3 and inhibit both ligand-dependent and
ligand-independent signal transduction; and compositions and
methods of use of such antibodies or fragments thereof.
Inventors: |
ELIS; Winfried;
(Munchen-Pasing, DE) ; ETTENBERG; Seth; (Melrose,
MA) ; GARNER; Andrew Paul; (Arlington, MA) ;
HAUBST; Nicole; (Munchen, DE) ; HUET; Heather
Adkins; (Arlington, MA) ; KUNZ; Christian Carsten
Silvester; (Munchen, DE) ; REISINGER SPRAGUE;
Elizabeth Anne; (Concord, MA) ; SHENG; Qing;
(Sharon, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
47557417 |
Appl. No.: |
13/693347 |
Filed: |
December 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61566890 |
Dec 5, 2011 |
|
|
|
Current U.S.
Class: |
424/133.1 ;
424/139.1; 530/387.3; 530/387.9 |
Current CPC
Class: |
A61P 35/00 20180101;
C07K 2317/92 20130101; C07K 16/2863 20130101; A61K 45/06 20130101;
A61K 31/4439 20130101; C07K 16/28 20130101; A61K 39/3955 20130101;
C07K 2317/21 20130101; C07K 2317/73 20130101; A61K 39/39558
20130101; A61K 2039/505 20130101; A61P 15/00 20180101; C07K 16/32
20130101; C07K 2317/55 20130101; A61K 2039/507 20130101; A61P 13/08
20180101; A61P 5/24 20180101; C07K 2317/76 20130101; A61K 31/4439
20130101; A61K 2300/00 20130101; A61K 39/3955 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/133.1 ;
530/387.9; 530/387.3; 424/139.1 |
International
Class: |
C07K 16/28 20060101
C07K016/28; A61K 45/06 20060101 A61K045/06; A61K 39/395 20060101
A61K039/395 |
Claims
1. An isolated antibody or fragment thereof that recognizes a
non-linear epitope of a HER3 receptor, wherein the non-linear
epitope comprises amino acid residues within domain 3 of the HER3
receptor, wherein the antibody or fragment thereof binds to a
binding surface comprising at least one amino acid residue selected
from binding surface B, and wherein the antibody or fragment
thereof blocks both ligand-dependent and ligand-independent signal
transduction.
2. The isolated antibody or fragment thereof of claim 1, wherein
binding surface B comprises at least one amino acid residue
selected from amino acid residues 335-342, 398, 400, 424-428, 431,
433-434 and 455.
3. The isolated antibody or fragment thereof of claim 1, wherein
the antibody or fragment further binds to binding surface A.
4. The isolated antibody or fragment thereof of claim 3, wherein
binding surface A comprises at least one amino acid residue
selected from the group consisting of amino acid residues
362-376.
5. An isolated antibody or fragment thereof that recognizes a
non-linear epitope of a HER3 receptor, wherein the non-linear
epitope comprises amino acid residues within domain 3 of the HER3
receptor, wherein the antibody or fragment thereof binds to a
binding surface comprising at least one amino acid residue selected
from binding surface A and at least one amino acid residue selected
from binding surface B, and wherein the antibody or fragment
thereof blocks both ligand-dependent and ligand-independent signal
transduction.
6. The isolated antibody or fragment thereof of claim 5, wherein
the antibody or fragment thereof blocks HER3 ligand binding on the
HER3 receptor.
7. The isolated antibody or fragment thereof of claim 6, wherein
the HER3 ligand is selected from the group consisting of neuregulin
1 (NRG), neuregulin 2, betacellulin, heparin-binding epidermal
growth factor, and epiregulin. 8. The isolated antibody or fragment
thereof of claim 5, wherein the antibody or fragment thereof has
any one of the characteristics selected from the group consisting
of binding to the inactive state of the HER3 receptor, preventing
HER3 adopting an active conformation due to steric hindrance
between the antibody or fragment thereof and domains of HER3,
preventing HER3 adopting an active conformation by reducing the
degree of flexibility in domain 3, inducing a conformational change
in domain 3 residues 371-377 that prevents HER3 from adopting an
active conformation, destabilizing HER3 such that it is susceptible
to degradation, accelerating down regulation of cell surface HER3,
and generating an un-natural HER3 dimer that is susceptible to
proteolytic degradation or unable to dimerize with other receptor
tyrosine kinases.
9. The isolated antibody or fragment thereof of claim 5, wherein
the binding surface A comprises amino acid residues 362-376.
10. The isolated antibody or fragment thereof of claim 5, wherein
the binding surface B comprises amino acid residues 335-342, 398,
400, 424-428, 431, 433-434 and 455.
11. The isolated antibody of claim 5, wherein the non-linear
epitope comprises amino acid residues 335-342, 362-376, 398, 400,
424-428, 431, 433-434 and 455 (within domain 3), or a subset
thereof.
12. The isolated antibody of claim 5, wherein the VH of the
antibody or fragment thereof binds to at least one of the following
HER3 residues: Ile365, Thr366, Asn369, Gly370, Asp371, Pro372,
Trp373, His374, Lys375, Gln400, and Lys434.
13. The isolated antibody of claim 5, wherein the VL of the
antibody or fragment thereof binds to at least one of the following
HER3 residues: Gly335, Ser336, Gly337, Ser338, Phe340, Gln341,
Asp362, Leu364, Ile365, Thr366, His374, Ile376, Asn398, Gln400,
Tyr424, Asn425, Arg426, Phe428, Leu431, Met433, Lys434, Tyr455.
14. The isolated antibody or fragment of claim 5, wherein binding
of the antibody or fragment thereof to the HER3 receptor in the
absence of a HER3 ligand reduces ligand-independent formation of a
HER2-HER3 protein complex in a cell which expresses HER2 and
HER3.
15. The isolated antibody or fragment thereof of claim 5, wherein
the antibody or fragment thereof inhibits phosphorylation of HER3
as assessed by a HER3 ligand-independent phosphorylation assay.
16. The isolated antibody or fragment thereof of claim 15, wherein
the HER3 ligand-independent phosphorylation assay uses HER2
amplified cells, wherein the HER2 amplified cells are SK-Br-3 cells
and BT-474.
17. The isolated antibody or fragment of claim 5, wherein binding
of the antibody or fragment thereof to the HER3 receptor in the
presence of a HER3 ligand reduces ligand-dependent formation of a
HER2-HER3 protein complex in a cell which expresses HER2 and
HER3.
18. The isolated antibody or fragment thereof of claim 5, wherein
the antibody or fragment thereof inhibits phosphorylation of HER3
as assessed by HER3 ligand-dependent phosphorylation assay.
19. The isolated antibody or fragment thereof of claim 18, wherein
the HER3 ligand-dependent phosphorylation assay uses stimulated
MCF7 cells in the presence of neuregulin (NRG).
20. The isolated antibody or fragment thereof of claim 5, wherein
the antibody is selected from the group consisting of a monoclonal
antibody, a polyclonal antibody, a chimeric antibody, a humanized
antibody, and a synthetic antibody.
21. An isolated antibody or fragment thereof that recognizes an
epitope of a HER3 receptor, wherein the epitope comprises amino
acid residues within domains 3-4 of the HER3 receptor, and wherein
the antibody or fragment thereof blocks both ligand-dependent and
ligand-independent signal transduction.
22. The isolated antibody of claim 21, wherein the epitope
comprises at least one amino acid residue selected from the group
consisting of amino acid residues: 329-498 (domain 3) of SEQ ID NO:
1, and at least one amino acid residue selected from the group
consisting of amino acid residues 499-642 (domain 4) of SEQ ID NO:
1.
23. The isolated antibody of claim 21, wherein the epitope
comprising amino acid residues within domains 3-4 is selected from
the group consisting of a linear epitope, a non-linear epitope, and
a conformational epitope.
24. The isolated antibody of claim 21, wherein binding of the
antibody or fragment thereof to the HER3 receptor in the absence of
a HER3 ligand reduces ligand-independent formation of a HER2-HER3
protein complex in a cell which expresses HER2 and HER3.
25. The isolated antibody or fragment thereof of claim 21, wherein
the antibody or fragment thereof inhibits phosphorylation of HER3
as assessed by a HER3 ligand-independent phosphorylation assay.
26. The isolated antibody or fragment thereof of claim 25, wherein
the HER3 ligand-independent phosphorylation assay uses HER2
amplified cells, wherein the HER2 amplified cells are SK-Br-3 cells
and BT-474.
27. The isolated antibody or fragment thereof of claim 21, wherein
binding of the antibody or fragment thereof to the HER3 receptor in
the presence of a HER3 ligand reduces ligand-dependent formation of
a HER2-HER3 protein complex in a cell which expresses HER2 and
HER3.
28. The isolated antibody or fragment thereof of claim 21, wherein
the antibody or fragment thereof inhibits phosphorylation of HER3
as assessed by HER3 ligand-dependent phosphorylation assay.
29. The isolated antibody or fragment thereof of claim 28, wherein
the HER3 ligand-dependent phosphorylation assay uses stimulated
MCF7 cells in the presence of neuregulin (NRG).
30. An isolated antibody or fragment thereof to a HER3 receptor,
having a dissociation (K.sub.D) of at least 1.times.10.sup.7
M.sup.-, 10.sup.8 M.sup.-1, 10.sup.9 M.sup.-1, 10.sup.10 M.sup.-1,
10.sup.11 M.sup.-1, 10.sup.12 M.sup.-1, 10.sup.13 M.sup.-1, wherein
the antibody or fragment thereof blocks both ligand-dependent and
ligand-independent signal transduction.
31. The isolated antibody or fragment thereof of claim 30, wherein
the antibody or fragment thereof inhibits phosphorylation of HER3
as measured by an in vitro phosphorylation assay selected from the
group consisting of phospho-HER3 and phospho-Akt.
32. The isolated antibody or fragment thereof of claim 30, wherein
the antibody or fragment thereof binds to the same non-linear
epitope within domain 3 of HER3 as an antibody described in Table
1.
33. The isolated antibody or fragment thereof of claim 30, wherein
the antibody or fragment thereof, binds to the same amino acid
residues within domains 3-4 of HER3 as an antibody described in
Table 2.
34. A fragment of an antibody that binds to HER3 selected from the
group consisting of; Fab, F(ab.sub.2)', F(ab).sub.2', scFv, VHH,
VH, VL, dAbs, wherein the fragment of the antibody blocks both
ligand-dependent and ligand-independent signal transduction.
35. A pharmaceutical composition comprising an antibody or fragment
thereof and a pharmaceutically acceptable carrier.
36. The pharmaceutical composition of claim 35, further comprising
an additional therapeutic agent.
37. The pharmaceutical composition of claim 36, wherein the
additional therapeutic agent is selected from the group consisting
of an HER1 inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4
inhibitor, an mTOR inhibitor and a PI3 Kinase inhibitor.
38. The pharmaceutical composition of claim 37, wherein the
additional therapeutic agent is a HER1 inhibitor selected from the
group consisting of Matuzumab (EMD72000), Erbitux.RTM./Cetuximab,
Vectibix.RTM./Panitumumab, mAb 806, Nimotuzumab,
Iressa.RTM./Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016),
Tykerb.RTM./Lapatinib Ditosylate, Tarceva.RTM./Erlotinib HCL
(OSI-774), PKI-166, and Tovok.RTM.; a HER2 inhibitor selected from
the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib,
lapatinib or lapatinib ditosylate/Tykerb.RTM.; a HER3 inhibitor
selected from the group consisting of, MM-121, MM-111, IB4C3,
2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945A
(Genentech), MOR10703 (Novartis) and small molecules that inhibit
HER3; and a HER4 inhibitor.
39. The pharmaceutical composition of claim 37, wherein the
additional therapeutic agent is a HER3 inhibitor, wherein the HER3
inhibitor is MOR10703.
40. The pharmaceutical composition of claim 37, wherein the
additional therapeutic agent is an mTOR inhibitor selected from the
group consisting of Temsirolimus/Torisel.RTM.,
ridaforolimus/Deforolimus, AP23573, MK8669,
everolimus/Affinitor.RTM..
41. The pharmaceutical composition of claim 37, wherein the
additional therapeutic agent is a PI3 Kinase inhibitor selected
from the group consisting of GDC 0941, BEZ235, BKM120 and
BYL719.
42. A method of treating a cancer comprising selecting a subject
having an HER3 expressing cancer, administering to the subject an
effective amount of a composition comprising an antibody or
fragment thereof disclosed in Table 1 or Table 2.
43. The method of claim 42, wherein the subject is a human and the
cancer is selected from the group consisting of breast cancer,
colorectal cancer, lung cancer, multiple myeloma, ovarian cancer,
liver cancer, gastric cancer, acute myeloid leukemia, chronic
myeloid leukemia, osteosarcoma, squamous cell carcinoma, peripheral
nerve sheath tumors, schwannoma, head and neck cancer, bladder
cancer, esophageal cancer, Barretts esophageal cancer,
glioblastoma, clear cell sarcoma of soft tissue, malignant
mesothelioma, neurofibromatosis, renal cancer, and melanoma,
prostate cancer, benign prostatic hyperplasia (BPH), gynacomastica,
and endometriosis.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/566,912 filed on Dec. 5, 2011, the contents of
which are incorporated herein by reference in their entirety.
SEQUENCE LISTING
[0002] The instant application contains a Sequence Listing which
has been submitted in ASCII format via EFS-Web and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Apr. 2, 2013, is named PAT054914-US-NP_SL.txt and is 561,528
bytes in size.
FIELD OF THE INVENTION
[0003] The present invention relates to antibodies or fragments
thereof that bind to a non-linear epitope within domain 3 of the
HER3 receptor and inhibit both ligand-dependent and
ligand-independent signal transduction. The invention also relates
antibodies or fragments thereof that bind to amino acid residues
within domains 3-4 of HER3 and inhibit both ligand-dependent and
ligand-independent signal transduction; and compositions and
methods of use of such antibodies or fragments thereof.
BACKGROUND OF THE INVENTION
[0004] The human epidermal growth factor receptor 3 (ErbB3, also
known as HER3) is a receptor protein tyrosine kinase and belongs to
the epidermal growth factor receptor (EGFR) subfamily of receptor
protein tyrosine kinases, which also includes EGFR (HER1, ErbB1),
HER2 (ErbB2, Neu), and HER4 (ErbB4) (Plowman et al., (1990) Proc.
Natl. Acad. Sci. U.S.A. 87:4905-4909; Kraus et al., (1989) Proc.
Natl. Acad. Sci. U.S.A. 86:9193-9197; and Kraus et al., (1993)
Proc. Natl. Acad. Sci. U.S.A. 90:2900-2904). Like the prototypical
epidermal growth factor receptor, the transmembrane receptor HER3
consists of an extracellular ligand-binding domain (ECD), a
dimerization domain within the ECD, a transmembrane domain, an
intracellular protein tyrosine kinase-like domain (TKD) and a
C-terminal phosphorylation domain. Unlike the other HER family
members, the kinase domain of HER3 displays very low intrinsic
kinase activity.
[0005] The ligands neuregulin 1 (NRG) or neuregulin 2 bind to the
extracellular domain of HER3 and activate receptor-mediated
signaling pathway by promoting dimerization with other dimerization
partners such as HER2. Heterodimerization results in activation and
transphosphorylation of HER3's intracellular domain and is a means
not only for signal diversification but also signal amplification.
In addition, HER3 heterodimerization can also occur in the absence
of activating ligands and this is commonly termed
ligand-independent HER3 activation. For example, when HER2 is
expressed at high levels as a result of gene amplification (e.g. in
breast, lung, ovarian or gastric cancer) spontaneous HER2/HER3
dimers can be formed. In this situation the HER2/HER3 is considered
the most active ErbB signaling dimer and is therefore highly
transforming.
[0006] Increased HER3 has been found in several types of cancer
such as breast, lung, gastrointestinal and pancreatic cancers.
Interestingly, a correlation between the expression of HER2/HER3
and the progression from a non-invasive to an invasive stage has
been shown (Alimandi et al., (1995) Oncogene 10:1813-1821; DeFazio
et al., (2000) Cancer 87:487-498; Naidu et al., (1988) Br. J.
Cancer 78:1385-1390). Accordingly, agents that interfere with HER3
mediated signaling are needed.
SUMMARY OF THE INVENTION
[0007] The invention is based on the surprising discovery of
antibodies or fragments thereof that bind to a non-linear epitope
of HER3 receptor comprising amino acid residues within domain 3 of
HER3 and block both ligand-dependent (e.g. neuregulin) and
ligand-independent HER3 signaling pathways. The invention is also
based on the discovery of antibodies or fragments thereof that bind
to amino acid residues within domains 3-4 of HER3 and block both
ligand-dependent (e.g. neuregulin) and ligand-independent HER3
signaling pathways.
[0008] Accordingly, in one aspect, the invention pertains to an
isolated antibody or fragment thereof that recognizes a non-linear
epitope of a HER3 receptor, wherein the non-linear epitope
comprises amino acid residues within domain 3 of the HER3 receptor,
wherein the antibody or fragment thereof binds to binding surface
B, and wherein the antibody or fragment thereof blocks both
ligand-dependent and ligand-independent signal transduction.
[0009] In one embodiment, binding surface B comprises at least one
amino acid residue selected from a group consisting of amino acid
residues 335-342, 398, 400, 424-428, 431, 433-434 and 455. In
another embodiment, the antibody or fragment thereof further binds
to binding surface A. In one embodiment, binding surface A
comprises at least one amino acid residue selected from a group
consisting of amino acid residues 362-376.
[0010] In another aspect, the invention pertains to an isolated
antibody or fragment thereof that recognizes a non-linear epitope
of a HER3 receptor, wherein the non-linear epitope comprises amino
acid residues within domain 3 of the HER3 receptor, wherein the
antibody or fragment thereof binds to a binding surface comprising
at least one amino acid residue selected from binding surface A and
at least one amino acid residue selected from binding surface B,
and wherein the antibody or fragment thereof blocks both
ligand-dependent and ligand-independent signal transduction.
[0011] In one embodiment, the antibody or fragment thereof blocks
HER3 ligand binding on the HER3 receptor. In one embodiment, the
HER3 ligand is selected from the group consisting of neuregulin 1
(NRG), neuregulin 2, betacellulin, heparin-binding epidermal growth
factor, and epiregulin. In one embodiment, the antibody or fragment
thereof has any one of the characteristics selected from the group
consisting of binding to the inactive state of the HER3 receptor,
preventing HER3 adopting an active conformation due to steric
hindrance between the antibody or fragment thereof and domains of
HER3, preventing HER3 adopting an active conformation by reducing
the degree of flexibility in domain 3, inducing a conformational
change in domain 3 residues 371-377 that prevents HER3 from
adopting an active conformation, destabilizing HER3 such that it is
susceptible to degradation, accelerating down regulation of cell
surface HER3, and generating an un-natural HER3 dimer that is
susceptible to proteolytic degradation or unable to dimerize with
other receptor tyrosine kinases. In one embodiment, binding surface
A comprises amino acid residues 362-376. In one embodiment, binding
surface B comprises amino acid residues 335-342, 398, 400, 424-428,
431, 433-434 and 455.
[0012] In one embodiment, the non-linear epitope comprises amino
acid residues 335-342, 362-376, 398, 400, 424-428, 431, 433-434 and
455 (within domain 3), or a subset thereof. In one embodiment, the
VH of the antibody or fragment thereof binds to at least one of the
following HER3 residues: Ile365, Thr366, Asn369, Gly370, Asp371,
Pro372, Trp373, His374, Lys375, Gln400, and Lys434. In one
embodiment, the VL of the antibody or fragment thereof binds to at
least one of the following HER3 residues: Gly335, Ser336, Gly337,
Ser338, Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374,
Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431,
Met433, Lys434, Tyr455. In one embodiment, binding of the antibody
or fragment thereof to the HER3 receptor in the absence of a HER3
ligand reduces ligand-independent formation of a HER2-HER3 protein
complex in a cell which expresses HER2 and HER3. In one embodiment,
the antibody or fragment thereof inhibits phosphorylation of HER3
as assessed by a HER3 ligand-independent phosphorylation assay. In
one embodiment, the HER3 ligand-independent phosphorylation assay
uses HER2 amplified cells, wherein the HER2 amplified cells are
SK-Br-3 cells and BT-474. In one embodiment, binding of the
antibody or fragment thereof to the HER3 receptor in the presence
of a HER3 ligand reduces ligand-dependent formation of a HER2-HER3
protein complex in a cell which expresses HER2 and HER3. In one
embodiment, the antibody or fragment thereof inhibits
phosphorylation of HER3 as assessed by HER3 ligand-dependent
phosphorylation assay. In one embodiment, the HER3 ligand-dependent
phosphorylation assay uses stimulated MCF7 cells in the presence of
neuregulin (NRG). In one embodiment, the antibody is selected from
the group consisting of a monoclonal antibody, a polyclonal
antibody, a chimeric antibody, a humanized antibody, and a
synthetic antibody.
[0013] In another aspect, the invention pertains to isolated
antibody or fragment thereof that recognizes an epitope of a HER3
receptor, wherein the epitope comprises amino acid residues within
domains 3-4 of the HER3 receptor, and wherein the antibody or
fragment thereof blocks both ligand-dependent and
ligand-independent signal transduction.
[0014] In one embodiment, the epitope comprises at least one amino
acid residue selected from the group consisting of amino acid
residues: 329-498 (domain 3) of SEQ ID NO: 1, and at least one
amino acid residue selected from the group consisting of amino acid
residues 499-642 (domain 4) of SEQ ID NO: 1. In one embodiment, the
epitope comprising amino acid residues within domains 3-4 is
selected from the group consisting of a linear epitope, a
non-linear epitope, and a conformational epitope. In one
embodiment, binding of the antibody or fragment thereof to the HER3
receptor in the absence of a HER3 ligand reduces ligand-independent
formation of a HER2-HER3 protein complex in a cell which expresses
HER2 and HER3. In one embodiment, the antibody or fragment thereof
inhibits phosphorylation of HER3 as assessed by a HER3
ligand-independent phosphorylation assay. In one embodiment, the
HER3 ligand-independent phosphorylation assay uses HER2 amplified
cells, wherein the HER2 amplified cells are SK-Br-3 cells and
BT-474. In one embodiment, binding of the antibody or fragment
thereof to the HER3 receptor in the presence of a HER3 ligand
reduces ligand-dependent formation of a HER2-HER3 protein complex
in a cell which expresses HER2 and HER3. In one embodiment, the
antibody or fragment thereof inhibits phosphorylation of HER3 as
assessed by HER3 ligand-dependent phosphorylation assay. In one
embodiment, the HER3 ligand-dependent phosphorylation assay uses
stimulated MCF7 cells in the presence of neuregulin (NRG).
[0015] In another aspect, the invention pertains to an isolated
antibody or fragment thereof to a HER3 receptor, having a
dissociation (K.sub.D) of at least 1.times.10.sup.7 M.sup.-1,
10.sup.8 M.sup.-1, 10.sup.9 M.sup.-1, 10.sup.10 M.sup.-1, 10.sup.11
M.sup.-1, 10.sup.12 M.sup.-1, 10.sup.13 M.sup.-1, wherein the
antibody or fragment thereof blocks both ligand-dependent and
ligand-independent signal transduction. In one embodiment, the
antibody or fragment thereof inhibits phosphorylation of HER3 as
measured by an in vitro phosphorylation assay selected from the
group consisting of phospho-HER3 and phospho-Akt.
[0016] In another aspect, the invention pertains to an isolated
antibody or fragment thereof binds to the same non-linear epitope
within domain 3 of HER3 as an antibody described in Table 1.
[0017] In another aspect, the invention pertains to an isolated
antibody or fragment thereof, binds to the same amino acid residues
within domains 3-4 of HER3 as an antibody described in Table 2.
[0018] In another aspect, the invention pertains to a fragment of
an antibody that binds to HER3 selected from the group consisting
of; Fab, F(ab.sub.2)', F(ab).sub.2', scFv, VHH, VH, VL, dAbs,
wherein the fragment of the antibody blocks both ligand-dependent
and ligand-independent signal transduction.
[0019] In another aspect, the invention pertains to a
pharmaceutical composition comprising an antibody or fragment
thereof and a pharmaceutically acceptable carrier. In one
embodiment, the pharmaceutical composition further comprises an
additional therapeutic agent. In one embodiment, the additional
therapeutic agent is selected from the group consisting of an HER1
inhibitor, a HER2 inhibitor, a HER3 inhibitor, a HER4 inhibitor, an
mTOR inhibitor and a PI3 Kinase inhibitor. In one embodiment, the
additional therapeutic agent is a HER1 inhibitor selected from the
group consisting of Matuzumab (EMD72000), Erbitux.RTM./Cetuximab,
Vectibix.RTM./Panitumumab, mAb 806, Nimotuzumab,
Iressa.RTM./Gefitinib, CI-1033 (PD183805), Lapatinib (GW-572016),
Tykerb.RTM./Lapatinib Ditosylate, Tarceva.RTM./Erlotinib HCL
(OSI-774), PKI-166, and Tovok.RTM.; a HER2 inhibitor selected from
the group consisting of Pertuzumab, Trastuzumab, MM-111, neratinib,
lapatinib or lapatinib ditosylate/Tykerb.RTM.; a HER3 inhibitor
selected from the group consisting of, MM-121, MM-111, IB4C3,
2DID12 (U3 Pharma AG), AMG888 (Amgen), AV-203 (Aveo), MEHD7945A
(Genentech), MOR10703 (Novartis) and small molecules that inhibit
HER3; and a HER4 inhibitor. In one embodiment, the additional
therapeutic agent is a HER3 inhibitor, wherein the HER3 inhibitor
is MOR10703. In one embodiment, the additional therapeutic agent is
an mTOR inhibitor selected from the group consisting of
Temsirolimus/Torisel.RTM., ridaforolimus/Deforolimus, AP23573,
MK8669, everolimus/Affinitor.RTM.. In one embodiment, the
additional therapeutic agent is a PI3 Kinase inhibitor selected
from the group consisting of GDC 0941, BEZ235, BKM120 and
BYL719.
[0020] In one aspect, the invention pertains to a method of
treating a cancer comprising selecting a subject having an HER3
expressing cancer, administering to the subject an effective amount
of a composition comprising an antibody or fragment thereof
disclosed in Table 1 or Table 2. In one embodiment, the subject is
a human and the cancer is selected from the group consisting of
breast cancer, colorectal cancer, lung cancer, multiple myeloma,
ovarian cancer, liver cancer, gastric cancer, acute myeloid
leukemia, chronic myeloid leukemia, osteosarcoma, squamous cell
carcinoma, peripheral nerve sheath tumors, schwannoma, head and
neck cancer, bladder cancer, esophageal cancer, Barretts esophageal
cancer, glioblastoma, clear cell sarcoma of soft tissue, malignant
mesothelioma, neurofibromatosis, renal cancer, and melanoma,
prostate cancer, benign prostatic hyperplasia (BPH), gynacomastica,
and endometriosis. In one embodiment, the cancer is breast
cancer.
[0021] In one aspect, the invention pertains to use of the antibody
or fragment thereof for use as a medicament. In one aspect, the
invention pertains to use of the antibody or fragment thereof for
use in treating a cancer mediated by a HER3 ligand-dependent signal
transduction or ligand-independent signal transduction pathway. In
one aspect, the invention pertains to use of the antibody or
fragment thereof for the manufacture of a medicament for the
treatment of a cancer mediated by a HER3 ligand-dependent signal
transduction or ligand-independent signal transduction pathway
selected from the group consisting of breast cancer, colorectal
cancer, lung cancer, multiple myeloma, ovarian cancer, liver
cancer, gastric cancer, pancreatic cancer, acute myeloid leukemia,
chronic myeloid leukemia, osteosarcoma, squamous cell carcinoma,
peripheral nerve sheath tumors, schwannoma, head and neck cancer,
bladder cancer, esophageal cancer, Barretts esophageal cancer,
glioblastoma, clear cell sarcoma of soft tissue, malignant
mesothelioma, neurofibromatosis, renal cancer, melanoma, prostate
cancer, benign prostatic hyperplasia (BPH), gynacomastica, and
endometriosis.
BRIEF DESCRIPTION OF FIGURES
[0022] FIG. 1 Representative MOR12615 SET curves obtained with
human HER3;
[0023] FIG. 2 SK-Br-3 cell binding determination by FACS
titration;
[0024] FIG. 3 HER3 domain binding ELISA;
[0025] FIG. 4 (A) Surface representation of the HER3/MOR12604 x-ray
crystal structure. HER3 (labeled by domains: D2, D3 & D4) is in
the closed conformation, and MOR12604 binds to domain 3. (B)
C.alpha.-superposition of HER3 from the HER3/MOR12064 structure
(dark gray) with an unbound HER3 structure (light gray; Cho et al.,
(2003) Nature 421:756-760) aligned by domain 3. (C) View of the
domain 3 epitope recognized by 12604. Highlighted HER3 residues are
within 5A of MOR12604 in the x-ray crystal structure (all positions
disclosed in FIG. 4C are residues of SEQ ID NO: 1). (D) View of
domain 3/MOR12604 interaction. The MOR12604 binding surface is
highlighted in dark gray with surface A (solid line) and surface B
(dashed line) indicated;
[0026] FIG. 5 Inhibition of ligand induced (A) HER3 and (B) Akt
phosphorylation in MCF7 cells;
[0027] FIG. 6 Inhibition of ligand independent (A) HER3 and (B) Akt
phosphorylation in HER2 amplified SKBr3 cells;
[0028] FIG. 7 Inhibition of ligand independent (A) HER3 and (B) Akt
phosphorylation in HER2 amplified BT474 cells;
[0029] FIG. 8 Inhibition of ligand stimulated proliferation of MCF7
cells;
[0030] FIG. 9 Inhibition of ligand-independent proliferation of
SKBr3 cells;
[0031] FIG. 10 Inhibition of ligand-independent proliferation of
BT474 cells;
[0032] FIG. 11 Data showing inhibition of tumor growth in vivo in
BxPC3 (A) and BT474 (B) using MOR12606 and MOR13655; and
[0033] FIG. 12 Data showing improved inhibition of tumor growth in
vivo in BxPC3 using a combination of MOR12606 (DIII binder) and
MOR10703 (DII+IV binder).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0034] In order that the present invention may be more readily
understood, certain terms are first defined. Additional definitions
are set forth throughout the detailed description.
[0035] The phrase "signal transduction" or "signaling activity" as
used herein refers to a biochemical causal relationship generally
initiated by a protein-protein interaction such as binding of a
growth factor to a receptor, resulting in transmission of a signal
from one portion of a cell to another portion of a cell. For HER3,
the transmission involves specific phosphorylation of one or more
tyrosine, serine, or threonine residues on one or more proteins in
the series of reactions causing signal transduction. Penultimate
processes typically include nuclear events, resulting in a change
in gene expression.
[0036] The term "HER3" or "HER3 receptor" also known as "ErbB3" as
used herein refers to mammalian HER3 protein and "her3" or "erbB3"
refers to mammalian her3 gene. The preferred HER3 protein is human
HER3 protein present in the cell membrane of a cell. The human her3
gene is described in U.S. Pat. No. 5,480,968 and Plowman et al.,
(1990) Proc. Natl. Acad. Sci. USA, 87:4905-4909.
[0037] Human HER3 as defined in Accession No. NP.sub.--001973
(human), and represented below as SEQ ID NO: 1. All nomenclature is
for full length, immature HER3 (amino acids 1-1342). The immature
HER3 is cleaved between positions 19 and 20, resulting in the
mature HER3 protein (20-1342 amino acids).
TABLE-US-00001 (SEQ ID NO: 1) mrandalqvl gllfslargs evgnsqavcp
gtlnglsvtg daenqyqtly klyercevvm gnleivltgh nadlsflqwi revtgyvlva
mnefstlplp nlrvvrgtqv ydgkfaifvm lnyntnssha lrqlrltqlt eilsggvyie
kndklchmdt idwrdivrdr daeivvkdng rscppchevc kgrcwgpgse dcqtltktic
apqcnghcfg pnpnqcchde caggcsgpqd tdcfacrhfn dsgacvprcp qplvynkltf
qlepnphtky qyggvcvasc phnfvvdqts cvracppdkm evdknglkmc epcgglcpka
cegtgsgsrf qtvdssnidg fvnctkilgn ldflitglng dpwhkipald peklnvfrtv
reitgylniq swpphmhnfs vfsnlttigg rslynrgfsl limknlnvts lgfrslkeis
agriyisanr qlcyhhslnw tkvlrgptee rldikhnrpr rdcvaegkvc dplcssggcw
gpgpgqclsc rnysrggvcv thcnflngep refaheaecf schpecqpme gtatcngsgs
dtcaqcahfr dgphcvsscp hgvlgakgpi ykypdvqnec rpchenctqg ckgpelqdcl
gqtlvligkt hltmaltvia glvvifmmlg gtflywrgrr iqnkramrry lergesiepl
dpsekankvl arifketelr klkvlgsgvf gtvhkgvwip egesikipvc ikviedksgr
qsfqavtdhm laigsldhah ivrllglcpg sslqlvtqyl plgslldhvr qhrgalgpql
llnwgvqiak gmyyleehgm vhrnlaarnv llkspsqvqv adfgvadllp pddkqllyse
aktpikwmal esihfgkyth qsdvwsygvt vwelmtfgae pyaglrlaev pdllekgerl
aqpqictidv ymvmvkcwmi denirptfke laneftrmar dpprylvikr esgpgiapgp
ephgltnkkl eevelepeld ldldleaeed nlatttlgsa lslpvgtlnr prgsqsllsp
ssgympmnqg nlgescqesa vsgssercpr pvslhpmprg clasessegh vtgseaelqe
kvsmcrsrsr srsprprgds ayhsqrhsll tpvtplsppg leeedvngyv mpdthlkgtp
ssregtlssv glssvlgtee ededeeyeym nrrrrhspph pprpssleel gyeymdvgsd
lsaslgstqs cplhpvpimp tagttpdedy eymnrqrdgg gpggdyaamg acpaseqgye
emrafqgpgh qaphvhyarl ktlrsleatd safdnpdywh srlfpkanaq rt
[0038] The term "HER3 ligand" as used herein refers to polypeptides
which bind and activate HER3. Examples of HER3 ligands include, but
are not limited to neuregulin 1 (NRG) and neuregulin 2,
betacellulin, heparin-binding epidermal growth factor, and
epiregulin. The term includes biologically active fragments and/or
variants of a naturally occurring polypeptide.
[0039] The "HER2-HER3 protein complex" is a noncovalently
associated oligomer containing HER2 receptor and the HER3 receptor.
This complex can form when a cell expressing both of these
receptors is exposed to a HER3 ligand e.g., NRG or when HER2 is
active/overexpressed
[0040] The phrase "HER3 activity" or "HER3 activation" as used
herein refers to an increase in oligomerization (e.g. an increase
in HER3 containing complexes), HER3 phosphorylation, conformational
rearrangements (for example those induced by ligands), and HER3
mediated downstream signaling.
[0041] The term "stabilization" or "stabilized" used in the context
of HER3 refers to an antibody or fragment thereof that directly
maintains (locks, tethers, holds, preferentially binds, favors) the
inactive state or conformation of HER3 without blocking ligand
binding to HER3, such that ligand binding is no longer able to
activate HER3.
[0042] The term "ligand-dependent signaling" as used herein refers
to the activation of HER3 via ligand. HER3 activation is evidenced
by increased heterodimerization and/or HER3 phosphorylation such
that downstream signaling pathways (e.g. PI3K) are activated. The
antibody or fragment thereof can statistically significantly reduce
the amount of phosphorylated HER3 in a stimulated cell exposed to
an antibody or fragment thereof relative to an untreated (control)
cell, as measured using the assays described in the Examples. The
cell which expresses HER3 can be a naturally occurring cell line
(e.g. MCF7) or can be recombinantly produced by introducing nucleic
acids encoding HER3 protein into a host cell. Cell stimulation can
occur either via the exogenous addition of an activating HER3
ligand or by the endogenous expression of an activating ligand.
[0043] The antibody or fragment thereof which "reduces
neregulin-induced HER3 activation in a cell" is one which
statistically significantly reduces HER3 tyrosine phosphorylation
relative to an untreated (control) cell, as measured using the
assays described in the Examples. This can be determined based on
HER3 phosphotyrosine levels following exposure of HER3 to NRG and
the antibody of interest. The cell which expresses HER3 protein can
be a naturally occurring cell or cell line (e.g. MCF7) or can be
recombinantly produced.
[0044] The term "ligand-independent signaling" as used herein
refers to cellular HER3 activity (e.g phosphorylation) in the
absence of a requirement for ligand binding. For example,
ligand-independent HER3 activation can be a result of HER2
overexpression or activating mutations in HER3 heterodimer partners
such as EGFR and HER2. The antibody or fragment thereof can
statistically significantly reduce the amount of phosphorylated
HER3 in a cell exposed to an antibody or fragment thereof relative
to an untreated (control) cell. The cell which expresses HER3 can
be a naturally occurring cell line (e.g. SK-Br-3) or can be
recombinantly produced by introducing nucleic acids encoding HER3
protein into a host cell.
[0045] The term "blocks" as used herein refers to stopping or
preventing an interaction or a process, e.g., stopping
ligand-dependent or ligand-independent signaling.
[0046] The term "recognize" as used herein refers to an antibody or
fragment thereof that finds and interacts (e.g., binds) with its
epitope in domain 3 of HER3; domain 4 of HER3; or both domain 3 and
domain 4 of HER3. The epitope can be a linear, non-linear, or
conformational epitope. For example, an antibody or fragment
thereof interacts with amino acid residues: 335-342, 362-376, 398,
400, 424-428, 431, 433-434 and 455 (within domain 3), or a subset
thereof of HER3. In another example, the antibody or fragment
thereof interacts with at least one amino acid residue selected
from amino acid residues: 329-498 (domain 3), or a subset thereof.
In another example, the antibody or fragment thereof interacts with
at least one amino acid residue selected from amino acid residues:
499-642 (domain 4), or a subset thereof. In another example, the
antibody or fragment thereof interacts with at least one amino acid
residue selected from domain 3 of HER3 (amino acid residues 329-498
of SEQ ID NO: 1), and at least one amino acid residue selected from
domain 4 (amino acid residues 499-642 of SEQ ID NO: 1), or a subset
thereof.
[0047] The phrase "concurrently binds" as used herein refers to a
HER3 ligand that can bind to a ligand binding site on the HER3
receptor along with the HER3 antibody or fragment thereof. This
means that both the antibody and ligand can bind to the HER3
receptor together. For the sake of illustration only, the HER3
ligand NRG, can bind to the HER3 receptor along with the HER3
antibody. Assay to measure concurrent binding of the ligand and
antibody are described in the Examples section.
[0048] The term "fails" as used herein refers to an antibody or
fragment thereof that does not do a particular event. For example,
an antibody or fragment thereof that "fails to activate signal
transduction" is one that does not trigger signal transduction.
[0049] The term "antibody" as used herein refers to whole
antibodies that interact with (e.g., by binding, steric hindrance,
stabilizing/destabilizing, spatial distribution) an HER3 epitope
and inhibit signal transduction. A naturally occurring "antibody"
is a glycoprotein comprising at least two heavy (H) chains and two
light (L) chains inter-connected by disulfide bonds. Each heavy
chain is comprised of a heavy chain variable region (abbreviated
herein as VH) and a heavy chain constant region. The heavy chain
constant region is comprised of three domains, CH1, CH2 and CH3.
Each light chain is comprised of a light chain variable region
(abbreviated herein as VL) and a light chain constant region. The
light chain constant region is comprised of one domain, CL. The VH
and VL regions can be further subdivided into regions of
hypervariability, termed complementarity determining regions (CDR),
interspersed with regions that are more conserved, termed framework
regions (FR). Each VH and VL is composed of three CDRs and four FRs
arranged from amino-terminus to carboxy-terminus in the following
order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions
of the heavy and light chains contain a binding domain that
interacts with an antigen. The constant regions of the antibodies
may mediate the binding of the immunoglobulin to host tissues or
factors, including various cells of the immune system (e.g.,
effector cells) and the first component (C1q) of the classical
complement system. The term "antibody" includes for example,
monoclonal antibodies, human antibodies, humanized antibodies,
camelised antibodies, chimeric antibodies, single-chain Fvs (scFv),
disulfide-linked Fvs (sdFv), Fab fragments, F (ab') fragments, and
anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id
antibodies to antibodies of the invention), and epitope-binding
fragments of any of the above. The antibodies can be of any isotype
(e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2,
IgG3, IgG4, IgA1 and IgA2) or subclass.
[0050] Both the light and heavy chains are divided into regions of
structural and functional homology. The terms "constant" and
"variable" are used functionally. In this regard, it will be
appreciated that the variable domains of both the light (VL) and
heavy (VH) chain portions determine antigen recognition and
specificity. Conversely, the constant domains of the light chain
(CL) and the heavy chain (CH1, CH2 or CH3) confer important
biological properties such as secretion, transplacental mobility,
Fc receptor binding, complement binding, and the like. By
convention the numbering of the constant region domains increases
as they become more distal from the antigen binding site or
amino-terminus of the antibody. The N-terminus is a variable region
and at the C-terminus is a constant region; the CH3 and CL domains
actually comprise the carboxy-terminus of the heavy and light
chain, respectively.
[0051] The phrase "antibody fragment", as used herein, refers to
one or more portions of an antibody that retain the ability to
specifically interact with (e.g., by binding, steric hindrance,
stabilizing/destabilizing, spatial distribution) an HER3 epitope
and inhibit signal transduction. Examples of binding fragments
include, but are not limited to, a Fab fragment, a monovalent
fragment consisting of the VL, VH, CL and CH1 domains; a
F(ab).sub.2 fragment, a bivalent fragment comprising two Fab
fragments linked by a disulfide bridge at the hinge region; a Fd
fragment consisting of the VH and CH1 domains; a Fv fragment
consisting of the VL and VH domains of a single arm of an antibody;
a dAb fragment (Ward et al., (1989) Nature 341:544-546), which
consists of a VH domain; and an isolated complementarity
determining region (CDR).
[0052] Furthermore, although the two domains of the Fv fragment, VL
and VH, are coded for by separate genes, they can be joined, using
recombinant methods, by a synthetic linker that enables them to be
made as a single protein chain in which the VL and VH regions pair
to form monovalent molecules (known as single chain Fv (scFv); see
e.g., Bird et al., (1988) Science 242:423-426; and Huston et al.,
(1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain
antibodies are also intended to be encompassed within the term
"antibody fragment". These antibody fragments are obtained using
conventional techniques known to those of skill in the art, and the
fragments are screened for utility in the same manner as are intact
antibodies.
[0053] Antibody fragments can also be incorporated into single
domain antibodies, maxibodies, minibodies, intrabodies, diabodies,
triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger
and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody
fragments can be grafted into scaffolds based on polypeptides such
as Fibronectin type 111 (Fn3) (see U.S. Pat. No. 6,703,199, which
describes fibronectin polypeptide monobodies).
[0054] Antibody fragments can be incorporated into single chain
molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1)
which, together with complementary light chain polypeptides, form a
pair of antigen binding regions (Zapata et al., (1995) Protein Eng.
8:1057-1062; and U.S. Pat. No. 5,641,870).
[0055] The term "epitope" includes any protein determinant capable
of specific binding to an immunoglobulin or otherwise interacting
with a molecule. Epitopic determinants generally consist of
chemically active surface groupings of molecules such as amino
acids or carbohydrate or sugar side chains and can have specific
three-dimensional structural characteristics, as well as specific
charge characteristics. An epitope may be "linear," "non-linear" or
"conformational."
[0056] The term "linear epitope" refers to an epitope with all of
the points of interaction between the protein and the interacting
molecule (such as an antibody) occur linearly along the primary
amino acid sequence of the protein (continuous). Once a desired
epitope on an antigen is determined, it is possible to generate
antibodies to that epitope, e.g., using the techniques described in
the present invention. Alternatively, during the discovery process,
the generation and characterization of antibodies may elucidate
information about desirable epitopes. From this information, it is
then possible to competitively screen antibodies for binding to the
same epitope. An approach to achieve this is to conduct
cross-competition studies to find antibodies that competitively
bind with one another, e.g., the antibodies compete for binding to
the antigen. A high throughput process for "binning" antibodies
based upon their cross-competition is described in International
Patent Application No. WO 2003/48731. As will be appreciated by one
of skill in the art, practically anything to which an antibody can
specifically bind could be an epitope. An epitope can comprises
those residues to which the antibody binds.
[0057] The term "non-linear epitope" refers to epitope with
non-contiguous amino acids that form a three-dimensional structure
within a particular domain (e.g., within domain 1, within domain 2,
within domain 3, or within domain 4). In one embodiment, the
non-linear epitope is within domain 2. The non-linear epitope may
also occur between two or more domains (e.g., the interface between
domains 3-4). Non-linear epitope also refers to non-contiguous
amino acids that are a result of a three-dimensional structure
within a particular domain.
[0058] The term "conformational epitope" refers to an epitope in
which discontinuous amino acids come together in a three
dimensional configuration. In a conformational epitope, the points
of interaction occur across amino acid residues on the protein that
are separated from one another in the sequence. As will be
appreciated by one of skill in the art, the space that is occupied
by a residue or side chain that creates the shape of a molecule
helps to determine what an epitope is.
[0059] In one embodiment, the epitope is within domain 3 of HER3.
In one embodiment, the epitope is a non-linear epitope comprising
amino acids residues within domain 3 of HER3. In one embodiment,
the non-linear epitope comprises amino acid residues: 335-342,
362-376, 398, 400, 424-428, 431, 433-434 and 455 (within domain 3),
or a subset thereof of SEQ ID NO:1.
[0060] In another embodiment, the epitope is within domain 4 of
HER3. In one embodiment, the epitope comprises at least one amino
acid residue selected from domain 4 (amino acid residues 499-642 of
SEQ ID NO: 1), or a subset thereof. In one embodiment, the epitope
is a linear epitope within domain 4 of HER3. In one embodiment, the
epitope is a non-linear epitope within domain 4 of HER3. In another
embodiment, the epitope is a conformational epitope within domain 4
of HER3.
[0061] In another embodiment, the epitope is within domains 3-4 of
HER3. In one embodiment, the epitope comprises at least one amino
acid residue selected from domain 3 (amino acid residues 329-498 of
SEQ ID NO: 1), or a subset thereof. In one embodiment, the epitope
comprises at least one amino acid residue selected from domain 4
(amino acid residues 499-642 of SEQ ID NO: 1), or a subset thereof.
In one embodiment, the epitope comprises at least one amino acid
residue selected from domain 3 (amino acid residues 329-498 of SEQ
ID NO: 1) and least one amino acid residue selected from domain 4
(amino acid residues 499-642 of SEQ ID NO: 1) or a subset thereof.
In one embodiment, the epitope is a linear epitope. In one
embodiment, the epitope is a non-linear epitope. In another
embodiment, the epitope is a conformational epitope.
[0062] Generally, antibodies specific for a particular target
antigen will preferentially recognize an epitope on the target
antigen in a complex mixture of proteins and/or macromolecules.
Regions of a given polypeptide that include an epitope can be
identified using any number of epitope mapping techniques, well
known in the art. See, e.g., Epitope Mapping Protocols in Methods
in Molecular Biology, Vol. 66 (Glenn E. Morris, Ed., 1996) Humana
Press, Totowa, N.J. For example, linear epitopes may be determined
by e.g., concurrently synthesizing large numbers of peptides on
solid supports, the peptides corresponding to portions of the
protein molecule, and reacting the peptides with antibodies while
the peptides are still attached to the supports. Such techniques
are known in the art and described in, e.g., U.S. Pat. No.
4,708,871; Geysen et al., (1984) Proc. Natl. Acad. Sci. USA
8:3998-4002; Geysen et al., (1985) Proc. Natl. Acad. Sci. USA
82:78-182; Geysen et al., (1986) Mol. Immunol. 23:709-715.
Similarly, non-linear and conformational epitopes are readily
identified by determining spatial conformation of amino acids such
as by, e.g., hydrogen/deuterium exchange, x-ray crystallography and
two-dimensional nuclear magnetic resonance. See, e.g., Epitope
Mapping Protocols, supra. Antigenic regions of proteins can also be
identified using standard antigenicity and hydropathy plots, such
as those calculated using, e.g., the Omiga version 1.0 software
program available from the Oxford Molecular Group. This computer
program employs the Hopp/Woods method, Hopp et al., (1981) Proc.
Natl. Acad. Sci. USA 78:3824-3828; for determining antigenicity
profiles, and the Kyte-Doolittle technique, Kyte et al., (1982) J.
Mol. Biol. 157:105-132; for hydropathy plots.
[0063] The term "binding surface" as used herein refers to multiple
contiguous or non-contiguous surfaces in a 3D configuration on
HER3, e.g., domain 3 of HER3. These surfaces form part of the
epitope and interact with an antibody or fragment thereof. For
example, a binding surface can comprise at least two surfaces
(e.g., surface A and surface B, see FIG. 4D), at least three
surfaces (e.g., surface A, surface B, and surface C), at least four
surfaces (e.g., surface A, surface B, surface C, and surface D), at
least five surfaces (e.g., surface A, surface B, surface C, surface
D, and surface E), at least six surfaces (e.g., surface A, surface
B, surface C, surface D, surface E, and surface F), at least seven
surfaces (e.g., surface A, surface B, surface C, surface D, surface
E, surface F, and surface G), at least eight surfaces (e.g.,
surface A, surface B, surface C, surface D, surface E, surface F,
surface G, and surface H), at least nine surfaces (e.g., surface A,
surface B, surface C, surface D, surface E, surface F, surface G,
surface H, and surface I), or at least ten surfaces (e.g., surface
A, surface B, surface C, surface D, surface E, surface F, surface
G, surface H, surface I, and surface J).
[0064] The term "binding surface A" as used herein refers to a
surface on domain 3 of HER3 comprising at least one amino acid
residue selected from a group consisting of amino acid residues
362-376.
[0065] The term "binding surface B" as used herein refers to a
surface on domain 3 of HER3 comprising at least one amino acid
residue selected from a group consisting of amino acid residues
335-342, 398, 400, 424-428, 431, 433-434 and 455.
[0066] The phrases "monoclonal antibody" or "monoclonal antibody
composition" as used herein refers to polypeptides, including
antibodies, antibody fragments, bispecific antibodies, etc. that
have substantially identical to amino acid sequence or are derived
from the same genetic source. This term also includes preparations
of antibody molecules of single molecular composition. A monoclonal
antibody composition displays a single binding specificity and
affinity for a particular epitope.
[0067] The phrase "human antibody", as used herein, includes
antibodies having variable regions in which both the framework and
CDR regions are derived from sequences of human origin.
Furthermore, if the antibody contains a constant region, the
constant region also is derived from such human sequences, e.g.,
human germline sequences, or mutated versions of human germline
sequences or antibody containing consensus framework sequences
derived from human framework sequences analysis, for example, as
described in Knappik et al., (2000) J Mol Biol 296:57-86). The
structures and locations of immunoglobulin variable domains, e.g.,
CDRs, may be defined using well known numbering schemes, e.g., the
Kabat numbering scheme, the Chothia numbering scheme, or a
combination of Kabat and Chothia (see, e.g., Sequences of Proteins
of Immunological Interest, U.S. Department of Health and Human
Services (1991), eds. Kabat et al.; Lazikani et al., (1997) J. Mol.
Bio. 273:927-948); Kabat et al., (1991) Sequences of Proteins of
Immunological Interest, 5th edit., NIH Publication no. 91-3242 U.S.
Department of Health and Human Services; Chothia et al., (1987) J.
Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883;
and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948.
[0068] The human antibodies of the invention may include amino acid
residues not encoded by human sequences (e.g., mutations introduced
by random or site-specific mutagenesis in vitro or by somatic
mutation in vivo, or a conservative substitution to promote
stability or manufacturing).
[0069] The phrase "human monoclonal antibody" as used herein refers
to antibodies displaying a single binding specificity which have
variable regions in which both the framework and CDR regions are
derived from human sequences. In one embodiment, the human
monoclonal antibodies are produced by a hybridoma which includes a
B cell obtained from a transgenic nonhuman animal, e.g., a
transgenic mouse, having a genome comprising a human heavy chain
transgene and a light chain transgene fused to an immortalized
cell.
[0070] The phrase "recombinant human antibody", as used herein,
includes all human antibodies that are prepared, expressed, created
or isolated by recombinant means, such as antibodies isolated from
an animal (e.g., a mouse) that is transgenic or transchromosomal
for human immunoglobulin genes or a hybridoma prepared therefrom,
antibodies isolated from a host cell transformed to express the
human antibody, e.g., from a transfectoma, antibodies isolated from
a recombinant, combinatorial human antibody library, and antibodies
prepared, expressed, created or isolated by any other means that
involve splicing of all or a portion of a human immunoglobulin
gene, sequences to other DNA sequences. Such recombinant human
antibodies have variable regions in which the framework and CDR
regions are derived from human germline immunoglobulin sequences.
In certain embodiments, however, such recombinant human antibodies
can be subjected to in vitro mutagenesis (or, when an animal
transgenic for human Ig sequences is used, in vivo somatic
mutagenesis) and thus the amino acid sequences of the V.sub.H and
V.sub.L regions of the recombinant antibodies are sequences that,
while derived from and related to human germline V.sub.H and
V.sub.L sequences, may not naturally exist within the human
antibody germline repertoire in vivo.
[0071] Specific binding between two entities means a binding with
an equilibrium constant (K.sub.A) (k.sub.on/k.sub.off) of at least
10.sup.2M.sup.-1, at least 5.times.10.sup.3M.sup.-1, at least
10.sup.3M.sup.-1, at least 5.times.10.sup.3M.sup.-1, at least
10.sup.4M.sup.-1 at least 5.times.10.sup.4M.sup.-1, at least
10.sup.5M.sup.-1, at least 5.times.10.sup.5M.sup.-1, at least
10.sup.6M.sup.-1, at least 5.times.10.sup.6M.sup.-1, at least
10.sup.7M.sup.-1, at least 5.times.10.sup.7M.sup.-1, at least
10M.sup.-1, at least 5.times.10M.sup.-1, at least 10.sup.9M.sup.-1,
at least 5.times.10.sup.9M.sup.-1, at least 10.sup.10M.sup.-1, at
least 5.times.10.sup.10M.sup.-1, at least 10.sup.11M.sup.-1, at
least 5.times.10.sup.11M.sup.-1, at least 10.sup.12M.sup.-1, at
least 5.times.10.sup.12M.sup.-1, at least 10.sup.13M.sup.-1, at
least 5.times.10.sup.13M.sup.-1, at least 10.sup.14M.sup.-1, at
least 5.times.10.sup.14M.sup.-1, at least 10.sup.15M.sup.-1, or at
least 5.times.10.sup.15M.sup.-1.
[0072] The phrase "specifically (or selectively) binds" refers to a
binding reaction of a HER3 binding antibody and HER3 receptor in a
heterogeneous population of proteins and other biologics. In
addition to the equilibrium constant (K.sub.A) noted above, an HER3
binding antibody of the invention typically also has a dissociation
rate constant (K.sub.D) (k.sub.off/k.sub.on) of less than
5.times.10.sup.-2M, less than 10.sup.-2M, less than
5.times.10.sup.-3M, less than 10.sup.-3M, less than
5.times.10.sup.-4M, less than 10.sup.-4M, less than
5.times.10.sup.-5M, less than 10.sup.-5M, less than
5.times.10.sup.-6M, less than 10.sup.-6M, less than
5.times.10.sup.-7M, less than 10.sup.-7M, less than
5.times.10.sup.-10M, less than 10.sup.-8M, less than
5.times.10.sup.-9M, less than 10.sup.-9M, less than
5.times.10.sup.-10M, less than 10.sup.-10M, less than
5.times.10.sup.-11M, less than 1011M, less than
5.times.10.sup.-12M, less than 10.sup.-12M, less than
5.times.10.sup.-13M, less than 10.sup.-13M, less than
5.times.10.sup.-14M, less than 10.sup.-14M, less than
5.times.10.sup.-15M, or less than 10.sup.-15M or lower, and binds
to HER3 with an affinity that is at least two-fold greater than its
affinity for binding to a non-specific antigen (e.g., HSA).
[0073] In one embodiment, the antibody or fragment thereof has
dissociation constant (K.sub.d) of less than 3000 pM, less than
2500 pM, less than 2000 pM, less than 1500 pM, less than 1000 pM,
less than 750 pM, less than 500 pM, less than 250 pM, less than 200
pM, less than 150 pM, less than 100 pM, less than 75 pM, less than
10 pM, less than 1 pM as assessed using a method described herein
or known to one of skill in the art (e.g., a BIAcore assay, ELISA,
FACS, SET) (Biacore International AB, Uppsala, Sweden).
[0074] The term "K.sub.assoc" or "K.sub.a", as used herein, refers
to the association rate of a particular antibody-antigen
interaction, whereas the term "K.sub.dis" or "K.sub.d," as used
herein, refers to the dissociation rate of a particular
antibody-antigen interaction. The term "K.sub.D", as used herein,
refers to the dissociation constant, which is obtained from the
ratio of K.sub.d to K.sub.a (i.e. K.sub.d/K.sub.a) and is expressed
as a molar concentration (M). K.sub.D values for antibodies can be
determined using methods well established in the art. A method for
determining the K.sub.D of an antibody is by using surface plasmon
resonance, or using a biosensor system such as a Biacore.RTM.
system.
[0075] The term "affinity" as used herein refers to the strength of
interaction between antibody and antigen at single antigenic sites.
Within each antigenic site, the variable region of the antibody
"arm" interacts through weak non-covalent forces with antigen at
numerous sites; the more interactions, the stronger the
affinity.
[0076] The term "avidity" as used herein refers to an informative
measure of the overall stability or strength of the
antibody-antigen complex. It is controlled by three major factors:
antibody epitope affinity; the valence of both the antigen and
antibody; and the structural arrangement of the interacting parts.
Ultimately these factors define the specificity of the antibody,
that is, the likelihood that the particular antibody is binding to
a precise antigen epitope.
[0077] The term "valency" as used herein refers to the number of
potential target binding sites in a polypeptide. Each target
binding site specifically binds one target molecule or specific
site (i.e, epitope) on a target molecule. When a polypeptide
comprises more than one target binding site, each target binding
site may specifically bind the same or different molecules (e.g.,
may bind to different molecules, e.g., different antigens, or
different epitopes on the same molecule).
[0078] The phrase "inhibiting antibody" as used herein refers to an
antibody that binds with HER3 and inhibits the biological activity
of HER3 signaling, e.g., reduces, decreases and/or inhibits HER3
induced signaling activity, e.g., in a phospho-HER3 or phospho-Akt
assay. Examples of assays are described in more details in the
examples below. Accordingly, an antibody that "inhibits" one or
more of these HER3 functional properties (e.g., biochemical,
immunochemical, cellular, physiological or other biological
activities, or the like) as determined according to methodologies
known to the art and described herein, will be understood to relate
to a statistically significant decrease in the particular activity
relative to that seen in the absence of the antibody (e.g., or when
a control antibody of irrelevant specificity is present). An
antibody that inhibits HER3 activity effects such a statistically
significant decrease by at least 10% of the measured parameter, by
at least 50%, 80% or 90%, and in certain embodiments an antibody of
the invention may inhibit greater than 95%, 98% or 99% of HER3
functional activity as evidenced by a reduction in the level of
cellular HER3 phosphorylation.
[0079] The phrase "isolated antibody" refers to an antibody that is
substantially free of other antibodies having different antigenic
specificities (e.g., an isolated antibody that specifically binds
HER3 is substantially free of antibodies that specifically bind
antigens other than HER3). An isolated antibody that specifically
binds HER3 may, however, have cross-reactivity to other antigens.
Moreover, an isolated antibody may be substantially free of other
cellular material and/or chemicals.
[0080] The phrase "conservatively modified variant" applies to both
amino acid and nucleic acid sequences. With respect to particular
nucleic acid sequences, conservatively modified variants refers to
those nucleic acids which encode identical or essentially identical
amino acid sequences, or where the nucleic acid does not encode an
amino acid sequence, to essentially identical sequences. Because of
the degeneracy of the genetic code, a large number of functionally
identical nucleic acids encode any given protein. For instance, the
codons GCA, GCC, GCG and GCU all encode the amino acid alanine.
Thus, at every position where an alanine is specified by a codon,
the codon can be altered to any of the corresponding codons
described without altering the encoded polypeptide. Such nucleic
acid variations are "silent variations," which are one species of
conservatively modified variations. Every nucleic acid sequence
herein which encodes a polypeptide also describes every possible
silent variation of the nucleic acid. One of skill will recognize
that each codon in a nucleic acid (except AUG, which is ordinarily
the only codon for methionine, and TGG, which is ordinarily the
only codon for tryptophan) can be modified to yield a functionally
identical molecule. Accordingly, each silent variation of a nucleic
acid that encodes a polypeptide is implicit in each described
sequence.
[0081] For polypeptide sequences, "conservatively modified
variants" include individual substitutions, deletions or additions
to a polypeptide sequence which result in the substitution of an
amino acid with a chemically similar amino acid. Conservative
substitution tables providing functionally similar amino acids are
well known in the art. Such conservatively modified variants are in
addition to and do not exclude polymorphic variants, interspecies
homologs, and alleles of the invention. The following eight groups
contain amino acids that are conservative substitutions for one
another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D),
Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine
(R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M),
Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7)
Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M)
(see, e.g., Creighton, Proteins (1984)). In some embodiments, the
term "conservative sequence modifications" are used to refer to
amino acid modifications that do not significantly affect or alter
the binding characteristics of the antibody containing the amino
acid sequence.
[0082] The terms "cross-compete" and "cross-competing" are used
interchangeably herein to mean the ability of an antibody or
fragment thereof to interfere with the binding of other antibodies
or fragments thereof to HER3 in a standard competitive binding
assay.
[0083] The ability or extent to which an antibody of fragment
thereof is able to interfere with the binding of another antibody
or fragment thereof to HER3, and therefore whether it can be said
to cross-compete according to the invention, can be determined
using standard competition binding assays. One suitable assay
involves the use of the Biacore technology (e.g. by using the
BIAcore 3000 instrument (Biacore, Uppsala, Sweden)), which can
measure the extent of interactions using surface plasmon resonance
technology. Another assay for measuring cross-competing uses an
ELISA-based approach.
[0084] The term "optimized" as used herein refers to a nucleotide
sequence has been altered to encode an amino acid sequence using
codons that are preferred in the production cell or organism,
generally a eukaryotic cell, for example, a cell of Pichia, a cell
of Trichoderma, a Chinese Hamster Ovary cell (CHO) or a human cell.
The optimized nucleotide sequence is engineered to retain
completely or as much as possible the amino acid sequence
originally encoded by the starting nucleotide sequence, which is
also known as the "parental" sequence.
[0085] Standard assays to evaluate the binding ability of the
antibodies toward HER3 of various species are known in the art,
including for example, ELISAs, western blots and RIAs. Suitable
assays are described in detail in the Examples. The binding
kinetics (e.g., binding affinity) of the antibodies also can be
assessed by standard assays known in the art, such as by Biacore
analysis, or FACS relative affinity (Scatchard). Assays to evaluate
the effects of the antibodies on functional properties of HER3
(e.g., receptor binding assays, modulating the HER3 signal pathway)
are described in further detail in the Examples.
[0086] The phrases "percent identical" or "percent identity," in
the context of two or more nucleic acids or polypeptide sequences,
refers to two or more sequences or subsequences that are the same.
Two sequences are "substantially identical" if two sequences have a
specified percentage of amino acid residues or nucleotides that are
the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%,
90%, 95%, or 99% identity over a specified region, or, when not
specified, over the entire sequence), when compared and aligned for
maximum correspondence over a comparison window, or designated
region as measured using one of the following sequence comparison
algorithms or by manual alignment and visual inspection.
Optionally, the identity exists over a region that is at least
about 50 nucleotides (or 10 amino acids) in length, or more
preferably over a region that is 100 to 500 or 1000 or more
nucleotides (or 20, 50, 200 or more amino acids) in length.
[0087] For sequence comparison, typically one sequence acts as a
reference sequence, to which test sequences are compared. When
using a sequence comparison algorithm, test and reference sequences
are entered into a computer, subsequence coordinates are
designated, if necessary, and sequence algorithm program parameters
are designated. Default program parameters can be used, or
alternative parameters can be designated. The sequence comparison
algorithm then calculates the percent sequence identities for the
test sequences relative to the reference sequence, based on the
program parameters.
[0088] A "comparison window", as used herein, includes reference to
a segment of any one of the number of contiguous positions selected
from the group consisting of from 20 to 600, usually about 50 to
about 200, more usually about 100 to about 150 in which a sequence
may be compared to a reference sequence of the same number of
contiguous positions after the two sequences are optimally aligned.
Methods of alignment of sequences for comparison are well known in
the art. Optimal alignment of sequences for comparison can be
conducted, e.g., by the local homology algorithm of Smith and
Waterman, (1970) Adv. Appl. Math. 2:482c, by the homology alignment
algorithm of Needleman and Wunsch, (1970) J. Mol. Biol. 48:443, by
the search for similarity method of Pearson and Lipman, (1988)
Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized
implementations of these algorithms (GAP, BESTFIT, FASTA, and
TFASTA in the Wisconsin Genetics Software Package, Genetics
Computer Group, 575 Science Dr., Madison, Wis.), or by manual
alignment and visual inspection (see, e.g., Brent et al., (2003)
Current Protocols in Molecular Biology).
[0089] Two examples of algorithms that are suitable for determining
percent sequence identity and sequence similarity are the BLAST and
BLAST 2.0 algorithms, which are described in Altschul et al.,
(1977) Nuc. Acids Res. 25:3389-3402; and Altschul et al., (1990) J.
Mol. Biol. 215:403-410, respectively. Software for performing BLAST
analyses is publicly available through the National Center for
Biotechnology Information. This algorithm involves first
identifying high scoring sequence pairs (HSPs) by identifying short
words of length W in the query sequence, which either match or
satisfy some positive-valued threshold score T when aligned with a
word of the same length in a database sequence. T is referred to as
the neighborhood word score threshold (Altschul et al., supra).
These initial neighborhood word hits act as seeds for initiating
searches to find longer HSPs containing them. The word hits are
extended in both directions along each sequence for as far as the
cumulative alignment score can be increased. Cumulative scores are
calculated using, for nucleotide sequences, the parameters M
(reward score for a pair of matching residues; always >0) and N
(penalty score for mismatching residues; always <0). For amino
acid sequences, a scoring matrix is used to calculate the
cumulative score. Extension of the word hits in each direction are
halted when: the cumulative alignment score falls off by the
quantity X from its maximum achieved value; the cumulative score
goes to zero or below, due to the accumulation of one or more
negative-scoring residue alignments; or the end of either sequence
is reached. The BLAST algorithm parameters W, T, and X determine
the sensitivity and speed of the alignment. The BLASTN program (for
nucleotide sequences) uses as defaults a wordlength (W) of 11, an
expectation (E) or 10, M=5, N=-4 and a comparison of both strands.
For amino acid sequences, the BLASTP program uses as defaults a
wordlength of 3, and expectation (E) of 10, and the BLOSUM62
scoring matrix (see Henikoff and Henikoff, (1989) Proc. Natl. Acad.
Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10,
M=5, N=-4, and a comparison of both strands.
[0090] The BLAST algorithm also performs a statistical analysis of
the similarity between two sequences (see, e.g., Karlin and
Altschul, (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One
measure of similarity provided by the BLAST algorithm is the
smallest sum probability (P(N)), which provides an indication of
the probability by which a match between two nucleotide or amino
acid sequences would occur by chance. For example, a nucleic acid
is considered similar to a reference sequence if the smallest sum
probability in a comparison of the test nucleic acid to the
reference nucleic acid is less than about 0.2, more preferably less
than about 0.01, and most preferably less than about 0.001.
[0091] The percent identity between two amino acid sequences can
also be determined using the algorithm of E. Meyers and W. Miller,
(1988) Comput. Appl. Biosci. 4:11-17) which has been incorporated
into the ALIGN program (version 2.0), using a PAM120 weight residue
table, a gap length penalty of 12 and a gap penalty of 4. In
addition, the percent identity between two amino acid sequences can
be determined using the Needleman and Wunsch (1970) J. Mol. Biol.
48:444-453) algorithm which has been incorporated into the GAP
program in the GCG software package (available at www.gcg.com),
using either a Blossom 62 matrix or a PAM250 matrix, and a gap
weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2,
3, 4, 5, or 6.
[0092] Other than percentage of sequence identity noted above,
another indication that two nucleic acid sequences or polypeptides
are substantially identical is that the polypeptide encoded by the
first nucleic acid is immunologically cross reactive with the
antibodies raised against the polypeptide encoded by the second
nucleic acid, as described below. Thus, a polypeptide is typically
substantially identical to a second polypeptide, for example, where
the two peptides differ only by conservative substitutions. Another
indication that two nucleic acid sequences are substantially
identical is that the two molecules or their complements hybridize
to each other under stringent conditions, as described below. Yet
another indication that two nucleic acid sequences are
substantially identical is that the same primers can be used to
amplify the sequence.
[0093] The phrase "nucleic acid" is used herein interchangeably
with the term "polynucleotide" and refers to deoxyribonucleotides
or ribonucleotides and polymers thereof in either single- or
double-stranded form. The term encompasses nucleic acids containing
known nucleotide analogs or modified backbone residues or linkages,
which are synthetic, naturally occurring, and non-naturally
occurring, which have similar binding properties as the reference
nucleic acid, and which are metabolized in a manner similar to the
reference nucleotides. Examples of such analogs include, without
limitation, phosphorothioates, phosphoramidates, methyl
phosphonates, chiral-methyl phosphonates, 2-O-methyl
ribonucleotides, peptide-nucleic acids (PNAs).
[0094] Unless otherwise indicated, a particular nucleic acid
sequence also implicitly encompasses conservatively modified
variants thereof (e.g., degenerate codon substitutions) and
complementary sequences, as well as the sequence explicitly
indicated. Specifically, as detailed below, degenerate codon
substitutions may be achieved by generating sequences in which the
third position of one or more selected (or all) codons is
substituted with mixed-base and/or deoxyinosine residues (Batzer et
al., (1991) Nucleic Acid Res. 19:5081; Ohtsuka et al., (1985) J.
Biol. Chem. 260:2605-2608; and Rossolini et al., (1994) Mol. Cell.
Probes 8:91-98).
[0095] The phrase "operably linked" refers to a functional
relationship between two or more polynucleotide (e.g., DNA)
segments. Typically, it refers to the functional relationship of a
transcriptional regulatory sequence to a transcribed sequence. For
example, a promoter or enhancer sequence is operably linked to a
coding sequence if it stimulates or modulates the transcription of
the coding sequence in an appropriate host cell or other expression
system. Generally, promoter transcriptional regulatory sequences
that are operably linked to a transcribed sequence are physically
contiguous to the transcribed sequence, i.e., they are cis-acting.
However, some transcriptional regulatory sequences, such as
enhancers, need not be physically contiguous or located in close
proximity to the coding sequences whose transcription they
enhance.
[0096] The terms "polypeptide" and "protein" are used
interchangeably herein to refer to a polymer of amino acid
residues. The terms apply to amino acid polymers in which one or
more amino acid residue is an artificial chemical mimetic of a
corresponding naturally occurring amino acid, as well as to
naturally occurring amino acid polymers and non-naturally occurring
amino acid polymer. Unless otherwise indicated, a particular
polypeptide sequence also implicitly encompasses conservatively
modified variants thereof.
[0097] The term "subject" as used herein includes human and
non-human animals. Non-human animals include all vertebrates, e.g.,
mammals and non-mammals, such as non-human primates, sheep, dog,
cow, chickens, amphibians, and reptiles. Except when noted, the
terms "patient" or "subject" are used herein interchangeably.
[0098] The term "anti-cancer agent" as used herein refers to any
agent that can be used to treat a cell proliferative disorder such
as cancer, including cytotoxic agents, chemotherapeutic agents,
radiotherapy and radiotherapeutic agents, targeted anti-cancer
agents, and immunotherapeutic agents.
[0099] The term "tumor" as used herein refers to neoplastic cell
growth and proliferation, whether malignant or benign, and all
pre-cancerous and cancerous cells and tissues.
[0100] The term "anti-tumor activity" as used herein refers to a
reduction in the rate of tumor cell proliferation, viability, or
metastatic activity. A possible way of showing anti-tumor activity
is show a decline in growth rate of abnormal cells that arises
during therapy or tumor size stability or reduction. Such activity
can be assessed using accepted in vitro or in vivo tumor models,
including but not limited to xenograft models, allograft models,
MMTV models, and other known models known in the art to investigate
anti-tumor activity.
[0101] The term "malignancy" as used herein refers to a non-benign
tumor or a cancer.
[0102] The term "cancer" as used herein refers to a malignancy
characterized by deregulated or uncontrolled cell growth. Exemplary
cancers include: carcinomas, sarcomas, leukemias, and lymphomas.
The term "cancer" includes primary malignant tumors (e.g., those
whose cells have not migrated to sites in the subject's body other
than the site of the original tumor) and secondary malignant tumors
(e.g., those arising from metastasis, the migration of tumor cells
to secondary sites that are different from the site of the original
tumor).
[0103] Various aspects of the invention are described in further
detail in the following sections and subsections.
Structure and Mechanism of Activation of the HER Receptors
[0104] All four HER receptors have an extracellular ligand-binding
domain, a single trans-membrane domain and a cytoplasmic tyrosine
kinase-containing domain. The intracellular tyrosine kinase domain
of HER receptors is highly conserved, although the kinase domain of
HER3 contains substitutions of critical amino acids and therefore
lacks kinase activity (Guy et al., (1994): PNAS 91, 8132-8136).
Ligand-induced dimerisation of the HER receptors induces activation
of the kinase, receptor transphosphorylation on tyrosine residues
in the C-terminal tail, followed by recruitment and activation of
intracellular signalling effectors (Yarden and Sliwkowski, (2001)
Nature Rev 2, 127-137; Jorissen et al., (2003) Exp Cell Res 284,
31-53.
[0105] The crystal structures of the extracellular domains of HERs
have provided some insight into the process of ligand-induced
receptor activation (Schlessinger, (2002) Cell 110, 669-672). The
extracellular domain of each HER receptor consists of four
subdomains: Subdomain I and III cooperate in forming the
ligand-binding site, whereas subdomain II (and perhaps also
subdomain IV) participates in receptor dimerisation via direct
receptor-receptor interactions. In the structures of ligand-bound
HER1, a .beta. hairpin (termed the dimerisation loop) in subdomain
II interacts with the dimerisation loop of the partner receptor,
mediating receptor dimerisation (Garrett et al, (2002) Cell 110,
763-773; Ogiso et al., (2002) Cell 110, 775-787). In contrast, in
the structures of the inactive HER1, HER3 and HER4, the
dimerisation loop is engaged in intramolecular interactions with
subdomain IV, which prevents receptor dimerisation in the absence
of ligand (Cho and Leahy, (2002) Science 297, 1330-1333; Ferguson
et al., (2003) Mol Cell 12, 541-552; Bouyan et al., (2005) PNAS
102, 15024-15029). The structure of HER2 is unique among the HERs.
In the absence of a ligand, HER2 has a conformation that resembles
the ligand-activated state of HER1 with a protruding dimerisation
loop, available to interact with other HER receptors (Cho et al.,
(2003) Nature 421, 756-760; Garrett et al., (2003) Mol Cell 11,
495-505). This may explain the enhanced heterodimerisation capacity
of HER2.
[0106] Although the HER receptor crystal structures provide a model
for HER receptor homo- and heterodimerisation, the background for
the prevalence of some HER homo- and heterodimers over others
(Franklin et al., (2004) Cancer Cell 5, 317-328) as well as the
role of each of the domain in receptor dimerisation and
autoinhibition (Burgess et al., (2003) Mol Cell 12, 541-552;
Mattoon et al., (2004) PNAS 101, 923-928) remains somewhat
unclear.
HER3 Structure and Epitopes
[0107] A conformational epitope to which anti-HER3 antibodies bind,
has previously been described in PCT/EP2011/064407, and U.S. Ser.
No. 61/375,408, both filed Aug. 22, 2011, and which are
incorporated herein by reference in their entirety. The three
dimensional structure of a truncated form of HER3 complexed with a
HER3 antibody fragment, showed conformational epitope comprising
domain 2 and domain 4 of HER3.
[0108] The present invention provides an additional class of
antibodies or fragments thereof that bind a non-linear epitope
within domain 3 of HER3. These antibodies or fragments thereof bind
with HER3 to inhibit both ligand dependent and ligand independent
signal transduction.
[0109] The present invention further provides a class of antibodies
or fragments thereof that bind within domains 3-4 of HER3 to
inhibit both ligand dependent and ligand independent signal
transduction. In one embodiment, the class of antibodies or
fragments thereof binds to domain 3 or domain 4 of HER3 to inhibit
both ligand dependent and ligand independent signal transduction.
In another embodiment, the class of antibodies or fragments thereof
binds to domain 3 and domain 4 of HER3 to inhibit both ligand
dependent and ligand independent signal transduction.
[0110] The present Examples present the crystal structure of HER3
bound to the Fab fragment of MOR12604 determined at 3.38 .ANG.
resolution.
[0111] The three dimensional structure of a truncated form
(residues 20-640) of the extracellular domain of HER3 complexed
with an antibody have been shown. The HER3-MOR12604 Fab complex was
determined at 3.38 .ANG. resolution, and shown in FIG. 4.
[0112] Although not bound to provide a theory, one possible model
for the mechanism of action is that HER3 typically exists in an
inactive (closed, tethered) or active (open) state. Ligand binding
induces a conformational change such that HER3 exists in the active
(open) state which is capable of binding heterodimer partners
resulting in activation in downstream signaling. Antibodies such as
MOR12604 bind the inactive (tethered) state of HER3 and apparently
block the ligand binding site.
[0113] Binding within domain 3 by MOR12604 suggests that MOR12604
could function by a mechanisms selected from the group consisting
of blocking HER3 residues required for ligand binding, preventing
HER3 adopting the active conformation due to steric hindrance
between the antibody and domains of HER3, preventing HER3 adopting
the active conformation by reducing the degree of flexibility in
HER3 hinge regions (e.g. domain 3), inducing a conformational
change in domain 3 loop 371-377 that prevents HER3 from
transitioning to the open conformation, destabilizing HER3 such
that it is prone to degradation, acting as a partial agonist to
accelerate the down regulation of HER3, and by each arm of MOR12604
binding a molecule of HER3 such that the antibody generates an
un-natural HER3 dimer that is either prone to proteolytic
degradation or cannot dimerize with other receptor tyrosine
kinases
[0114] To examine the crystal structure of domain 3 antibodies or
fragments thereof bound to HER3, crystals of HER3 were prepared by
expressing a nucleotide sequence encoding HER3 or a variant thereof
in a suitable host cell, and then crystallising the purified
protein(s) in the presence of the relevant HER3 targeted Fab.
Preferably the HER3 polypeptide contains the extracellular domain
(amino acids 20 to 640 of the human polypeptide (SEQ ID NO: 1) or a
truncated version thereof, preferably comprising amino acids
20-640) but lacks the transmembrane and intracellular domains.
[0115] HER3 polypeptides may also be produced as fusion proteins,
for example to aid in extraction and purification. Examples of
fusion protein partners include glutathione-5-transferase (GST),
histidine (HIS), hexahistidine (6HIS) (SEQ ID NO: 702), GAL4 (DNA
binding and/or transcriptional activation domains) and
beta-galactosidase. It may also be convenient to include a
proteolytic cleavage site between the fusion protein partner and
the protein sequence of interest to allow removal of fusion protein
sequences.
[0116] After expression, the proteins may be purified and/or
concentrated, for example by immobilised metal affinity
chromatography, ion-exchange chromatography, and/or gel
filtration.
[0117] The protein(s) may be crystallised using techniques
described herein. Commonly, in a crystallisation process, a drop
containing the protein solution is mixed with the crystallisation
buffer and allowed to equilibrate in a sealed container.
Equilibration may be achieved by known techniques such as the
"hanging drop" or the "sitting drop" method. In these methods, the
drop is hung above or sitting beside a much larger reservoir of
crystallization buffer and equilibration is reached through vapor
diffusion. Alternatively, equilibration may occur by other methods,
for example under oil, through a semi-permeable membrane, or by
free-interface diffusion (See e.g., Chayen et al., (2008) Nature
Methods 5, 147-153.
[0118] Once the crystals have been obtained, the structure may be
solved by known X-ray diffraction techniques. Many techniques use
chemically modified crystals, such as those modified by heavy atom
derivatization to approximate phases. In practice, a crystal is
soaked in a solution containing heavy metal atom salts, or
organometallic compounds, e.g., lead chloride, gold thiomalate,
thimerosal or uranyl acetate, which can diffuse through the crystal
and bind to the surface of the protein. The location(s) of the
bound heavy metal atom(s) can then be determined by X-ray
diffraction analysis of the soaked crystal. The patterns obtained
on diffraction of a monochromatic beam of X-rays by the atoms
(scattering centres) of the crystal can be solved by mathematical
equations to give mathematical coordinates. The diffraction data
are used to calculate an electron density map of the repeating unit
of the crystal. Another method of obtaining phase information is
using a technique known as molecular replacement.
[0119] In this method, rotational and translational algorithms are
applied to a search model derived from a related structure,
resulting in an approximate orientation for the protein of interest
(See Rossmann, (1990) Acta Crystals A 46, 73-82). The electron
density maps are used to establish the positions of the individual
atoms within the unit cell of the crystal (Blundel et al., (1976)
Protein Crystallography, Academic Press).
[0120] The present disclosure describes the three-dimensional
structure of HER3 and a Fab of an anti-HER3 antibody. The
approximate domain boundaries of extracellular domain of HER3 are
as follows; domain 1: amino acids 20-207; domain 2: amino acids
208-328; domain 3: amino acids 329-498; and domain 4: amino acids
499-642. The three-dimensional structure of HER3 and the antibody
allows the identification of target binding sites for potential
HER3 modulators. Preferred target binding sites are those involved
in the activation of HER3. In one embodiment, the target binding
site is located within domain 3 of HER3. Thus an antibody or
fragment thereof which binds to domain 3 can, for example, modulate
HER3 activation by modifying the relative position of the domain
relative to itself or other HER3 domains. Thus binding an antibody
or fragment thereof to amino acid residues within domain 3 may
cause the protein to adopt a configuration that prevents
activation.
[0121] In some embodiments, the antibody or fragment thereof binds
to a binding surface of HER3. This binding surface comprises
multiple contiguous or non-contiguous surfaces in a 3D
configuration that form part of the epitope which interacts with
the antibody or fragment thereof. For example, a binding surface
can comprise at least two surfaces (e.g., surface A and surface B,
see FIG. 4D), at least three surfaces (e.g., surface A, surface B,
and surface C), at least four surfaces (e.g., surface A, surface B,
surface C, and surface D), at least five surfaces (e.g., surface A,
surface B, surface C, surface D, and surface E), at least six
surfaces (e.g., surface A, surface B, surface C, surface D, surface
E, and surface F), at least seven surfaces (e.g., surface A,
surface B, surface C, surface D, surface E, surface F, and surface
G), at least eight surfaces (e.g., surface A, surface B, surface C,
surface D, surface E, surface F, surface G, and surface H), at
least nine surfaces (e.g., surface A, surface B, surface C, surface
D, surface E, surface F, surface G, surface H, and surface I), or
at least ten surfaces (e.g., surface A, surface B, surface C,
surface D, surface E, surface F, surface G, surface H, surface I,
and surface J).
[0122] In one embodiment, the antibody or fragment thereof binds to
binding surface A. In one embodiment, the antibody or fragment
thereof binds to binding surface B. In another embodiment, the
antibody or fragment thereof binds to both binding surface A and
binding surface B. In one embodiment, binding surface A comprises
at least one amino acid residue selected from amino acid residues
362-376. In one embodiment, binding surface B comprises at least
one amino acid residue selected from amino acid residues 335-342,
398, 400, 424-428, 431, 433-434 and 455. In another embodiment, the
antibody or fragment thereof binds to binding surface A, wherein at
least one amino acid residue is selected from amino acid residues
362-376; and binding surface B, wherein at least one amino acid
residue is selected from amino acid residues 335-342, 398, 400,
424-428, 431, 433-434 and 455.
[0123] In some embodiments, the antibody or fragment thereof binds
to human HER3 protein having a non-linear epitope comprising HER3
amino acid residues 335-342, 362-376, 398, 400, 424-428, 431,
433-434 and 455 (within domain 3), of SEQ ID NO: 1, or a subset
thereof. In some embodiments, the antibody or fragment thereof
binds to amino acids within or overlapping amino acid residues
335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455 (within
domain 3), of SEQ ID NO: 1, or a subset thereof. In some
embodiments, the antibody or fragment thereof binds to amino acids
within (and/or amino acid sequences consisting of) amino acids
335-342, 362-376, 398, 400, 424-428, 431, 433-434 and 455 (within
domain 3), of SEQ ID NO: 1, or a subset thereof.
[0124] In some embodiments, the antibody or fragment thereof binds
to human HER3 protein having an epitope (linear, non-linear,
conformational) comprising HER3 amino acid residues 499-642 (of
domain 4) of SEQ ID NO: 1, or a subset thereof. In some
embodiments, the antibody or fragment thereof binds to amino acids
within or overlapping amino acid residues 499-642 (of domain 4) of
SEQ ID NO: 1, or a subset thereof. In some embodiments, the
antibody or fragment thereof binds to amino acids within (and/or
amino acid sequences consisting of) amino acids residues 499-642
(of domain 4) of SEQ ID NO: 1, or a subset thereof, or a subset
thereof.
[0125] In some embodiments, the antibody or fragment thereof binds
to human HER3 protein having a non-linear epitope comprising HER3
amino acid residues 335-342, 362-376, 398,400,424-428, 431, 433-434
and 455 (within domain 3) and an epitope (linear, non-linear,
conformational) comprising HER3 amino acid residues 499-642 (of
domain 4) of SEQ ID NO: 1, or a subset thereof. In some
embodiments, the antibody or fragment thereof binds to amino acids
within or overlapping amino acid residues 335-342, 362-376, 398,
400, 424-428, 431, 433-434 and 455 (within domain 3), of SEQ ID NO:
1 and an epitope (linear, non-linear, conformational) comprising
HER3 amino acid residues 499-642 (of domain 4) of SEQ ID NO: 1 or a
subset thereof. In some embodiments, the antibody or fragment
thereof binds to amino acids within (and/or amino acid sequences
consisting of) amino acids 335-342, 362-376, 398, 400, 424-428,
431, 433-434 and 455 (within domain 3), and an epitope (linear,
non-linear, conformational) comprising HER3 amino acid residues
499-642 (of domain 4) of SEQ ID NO: 1 of SEQ ID NO: 1, or a subset
thereof.
[0126] In some embodiments, the antibody or fragment thereof binds
to human HER3 protein having a epitope (linear, non-linear,
conformational) comprising HER3 amino acid residues within domain 3
and an epitope (linear, non-linear, conformational) comprising HER3
amino acid residues within of domain 4 of SEQ ID NO: 1, or a subset
thereof. In some embodiments, the antibody or fragment thereof
binds to amino acids within or overlapping amino acid residues of
domain 3 and amino acids of domain 4 of SEQ ID NO: 1, or a subset
thereof.
[0127] In some embodiments, the antibody or fragment thereof binds
to the inactive state of the HER3 receptor, thereby preventing HER3
adopting an active conformation. In some embodiments, the antibody
or fragment thereof prevents HER3 adopting an active conformation
due to steric hindrance between the antibody or fragment thereof
and domains of HER3 (e.g., with MOR12604, steric interference with
domain 1 of HER3). In some embodiments, the antibody or fragment
thereof prevents HER3 adopting an active conformation by reducing
the degree of flexibility in domain 3. In some embodiments, the
antibody or fragment thereof induces a conformational change in
domain 3 loop 371-377 of SEQ ID NO:1 that prevents HER3 from
adopting an active conformation. In some embodiments, the antibody
or fragment thereof destabilizes HER3 such that it is susceptible
to degradation. In some embodiments, the antibody or fragment
thereof accelerates down regulation of cell surface HER3. In some
embodiments, the antibody or fragment thereof generates an
un-natural HER3 dimer that is susceptible to proteolytic
degradation or unable to dimerize with other receptor tyrosine
kinases.
[0128] In some embodiments, the antibody or fragment thereof can
bind to either the active or inactive state of HER3. In some
embodiments, the antibody or fragment thereof stabilizes the HER3
receptor in an inactive state such that the HER3 receptor fails to
dimerize with a co-receptor to form a receptor-receptor complex.
The failure to form a receptor-receptor complex prevents activation
of both ligand-dependent and ligand-independent signal
transduction.
[0129] In some embodiments, the antibody or fragment thereof
induces dimerization of HER3 with HER3 to form an inactive
receptor-receptor complex. The formation of the inactive
receptor-receptor complex prevents activation of HER3 mediated
signal transduction since HER3 is sequestered in inactive
receptor-receptor complexes.
[0130] The depicted structure also allows one to identify specific
HER3 amino acid residues for the interaction interface of an
antibody or fragment thereof (e.g., MOR12604) with HER3. This was
defined as residues that are within 5 .ANG. of the MOR12604 protein
VH chain. The residues are as follows: Ile365, Thr366, Asn369,
Gly370, Asp371, Pro372, Trp373, His374, Lys375, Gln400, and Lys434.
The depicted structure also allows one to identify specific HER3
amino acid residues for the interaction interface of an antibody or
fragment thereof (e.g., MOR12604) with HER3. This was defined as
residues that are within 5 .ANG. of the MOR12604 protein VL chain.
The residues are as follows: Gly335, Ser336, Gly337, Ser338,
Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374, Ile376,
Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431, Met433,
Lys434, Tyr455. As can be seen in Tables 5 and 6 (MOR12604),
respectively, both the light and heavy chains are involved in the
antigen binding protein's binding to amino acid residues within
domain 3 of the epitope.
[0131] As such, one of skill in the art, given the present
teachings, can predict which residues and areas of the antigen
binding proteins can be varied without unduly interfering with the
antigen binding protein's ability to bind to domains 3 and 4 of
HER3.
[0132] Core interaction interface amino acids were determined as
being all amino acid residues with at least one atom less than or
equal to 5 .ANG. from the HER3 partner protein. 5 .ANG. was chosen
as the core region cutoff distance to allow for atoms within a van
der Waals radius plus a possible water-mediated hydrogen bond.
[0133] In some embodiments, any antigen binding protein that binds
to, covers, or prevents MOR12604 from interacting with any of the
above residues can be employed to bind to or neutralize HER3. In
some embodiments, the antibodies or fragments thereof binds to or
interacts with at least one of the following HER3 residues (SEQ ID
NO: 1): Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373,
His374, Lys375, Gln400, and Lys434. In some embodiments, the
antibodies and fragments thereof binds to or interacts with at
least one of the following HER3 residues (SEQ ID NO: 1): Gly335,
Ser336, Gly337, Ser338, Phe340, Gln341, Asp362, Leu364, Ile365,
Thr366, His374, Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426,
Phe428, Leu431, Met433, Lys434, Tyr455. In some embodiments, the
antibodies or fragments thereof binds to or interacts with at least
one of the following HER3 residues (SEQ ID NO: 1): Ile365, Thr366,
Asn369, Gly370, Asp371, Pro372, Trp373, His374, Lys375, Gln400,
Lys434, Gly335, Ser336, Gly337, Ser338, Phe340, Gln341, Asp362,
Leu364, Ile365, Thr366, His374, Ile376, Asn398, Gln400, Tyr424,
Asn425, Arg426, Phe428, Leu431, Met433, Lys434, Tyr455. In some
embodiments, the antibodies or fragments thereof binds to or
interacts with a combination of the following HER3 residues (SEQ ID
NO: 1): Ile365, Thr366, Asn369, Gly370, Asp371, Pro372, Trp373,
His374, Lys375, Gln400, Lys434, Gly335, Ser336, Gly337, Ser338,
Phe340, Gln341, Asp362, Leu364, Ile365, Thr366, His374, Ile376,
Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428, Leu431, Met433,
Lys434, Tyr455. In some embodiments, the antibodies or fragments
thereof binds to or interacts with all of the following HER3
residues (SEQ ID NO: 1): Ile365, Thr366, Asn369, Gly370, Asp371,
Pro372, Trp373, His374, Lys375, Gln400, Lys434, Gly335, Ser336,
Gly337, Ser338, Phe340, Gln341, Asp362, Leu364, Ile365, Thr366,
His374, Ile376, Asn398, Gln400, Tyr424, Asn425, Arg426, Phe428,
Leu431, Met433, Lys434, Tyr455. In some embodiments, the antibody
or fragment thereof is within 5 angstroms of one or more of the
above residues. In some embodiments, the antibody or fragment
thereof is 5 to 8 angstroms from one or more of the above residues.
In some embodiments, the antibody or fragment thereof interacts,
blocks, or is within 8 angstroms of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 20, 25, 28, 30, 35, 40, 45, or 50 of the above
residues.
[0134] The availability of 3D structures for the HER3 and the
complex of HER3: MOR12604, for example, provides the framework to
explore other HER3 antibodies in more detail. The 3D structure of
HER3 allows the epitopes for monoclonal antibodies to be mapped and
their mode of action inferred, since some inhibit, some stimulate
and others have no effect on cell growth. The non-linearepitope for
MOR12604 has been located to the domain 3 of HER3. The availability
of the 3D structures of this receptor will facilitate the
determination of the precise mechanism of action of these
inhibitory agents and the design of new approaches to interfering
with HER3 receptor function. In one embodiment, the antibodies of
the invention bind to the same non-linear epitope as MOR12604.
[0135] In some embodiments, the non-linear epitope bound by any of
the antibodies listed in Table 1 is especially useful. In certain
embodiments, a HER3 non-linear epitope can be utilized to isolate
antibodies of fragments thereof that bind to HER3. In certain
embodiments, a HER3 non-linear epitope can be utilized to generate
antibodies or fragments thereof which bind to HER3. In certain
embodiments, a HER3 non-linear epitope can be utilized as an
immunogen to generate antibodies of fragments thereof that bind to
the HER3 non-linear epitope. In certain embodiments, a HER3
non-linear epitope can be administered to an animal, and antibodies
that bind to HER3 can subsequently be obtained from the animal.
[0136] The present invention also provides a class of antibodies
that bind to an epitope (linear, non-linear, or conformational)
within domains 3-4 of HER3. Examples of such antibodies or
fragments thereof that bind within domains 3-4 are shown in Table
2. The above methodology and the methods described in the Example
section below, can be also used to generate domain 3-4 antibodies
or fragments thereof complexed to HER3.
[0137] In some embodiments, the domain(s)/region(s) containing
residues that are in contact with or are buried by an antibody can
be identified by mutating specific residues in HER3 (e.g., a
wild-type antigen) and determining whether antibody or fragment
thereof can bind the mutated or variant HER3 protein or measure
changes of affinity from wild-type. By making a number of
individual mutations, residues that play a direct role in binding
or that are in sufficiently close proximity to the antibody such
that a mutation can affect binding between the antibody and antigen
can be identified. From a knowledge of these amino acids, the
domain(s) or region(s) of the antigen (HER3) that contain residues
in contact with the antibody or covered by the antibody can be
elucidated. Mutagenesis using known techniques such as
alanine-scanning can help define functionally relevant epitopes.
Mutagenesis utilizing an arginine/glutamic acid scanning protocol
can also be employed (see, e.g., Nanevicz et al., (1995), J. Biol.
Chem. 270(37):21619-21625 and Zupnick et al., (2006), J. Biol.
Chem. 281(29):20464-20473). In general, arginine and glutamic acids
are substituted (typically individually) for an amino acid in the
wild-type polypeptide because these amino acids are charged and
bulky and thus have the potential to disrupt binding between an
antigen binding protein and an antigen in the region of the antigen
where the mutation is introduced. Arginines that exist in the
wild-type antigen are replaced with glutamic acid. A variety of
such individual mutants can be obtained and the collected binding
results analyzed to determine what residues affect binding. A
series of mutant HER3 antigens can be created, with each mutant
antigen having a single mutation. Binding of each mutant HER3
antigen with various HER3 antibodies or fragments thereof can be
measured and compared to the ability of the selected an antibody or
fragments thereof to bind wild-type HER3 (SEQ ID NO: 1).
[0138] An alteration (for example a reduction or increase) in
binding between an antibody or fragment thereof and a mutant or
variant HER3 as used herein means that there is a change in binding
affinity (e.g., as measured by known methods such as Biacore
testing or the bead based assay described below in the examples),
EC.sub.50, and/or a change (for example a reduction) in the total
binding capacity of the antigen binding protein (for example, as
evidenced by a decrease in B.sub.max in a plot of antigen binding
protein concentration versus antigen concentration). A significant
alteration in binding indicates that the mutated residue is
involved in binding to the antibody or fragment thereof.
[0139] In some embodiments, a significant reduction in binding
means that the binding affinity, EC.sub.50, and/or capacity between
an antibody or fragments thereof and a mutant HER3 antigen is
reduced by greater than 10%, greater than 20%, greater than 40%,
greater than 50%, greater than 55%, greater than 60%, greater than
65%, greater than 70%, greater than 75%, greater than 80%, greater
than 85%, greater than 90% or greater than 95% relative to binding
between the an antibody or fragment thereof and a wild type HER3
(e.g., SEQ ID NO: 1).
[0140] In some embodiments, binding of an antibody or fragments
thereof is significantly reduced or increased for a mutant HER3
protein having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more) mutations as compared to a wild-type HER3 protein (e.g., SEQ
ID NO: 1).
[0141] Although the variant forms are referenced with respect to
the wild-type sequence shown in SEQ ID NO: 1, it will be
appreciated that in an allelic or splice variants of HER3 the amino
acids could differ. Antibodies or fragments thereof showing
significantly altered binding (e.g., lower or higher binding) for
such allelic forms of HER3 are also contemplated.
[0142] In addition to the general structural aspects of antibodies,
the more specific interaction between the paratope and the epitope
may be examined through structural approaches. In one embodiment,
the structure of the CDRs contribute to a paratope, through which
an antibody is able to bind to an epitope. The shape of such a
paratope may be determined in a number of ways. Traditional
structural examination approaches can be used, such as NMR or x-ray
crystallography. These approaches can examine the shape of the
paratope alone, or while it is bound to the epitope. Alternatively,
molecular models may be generated in silico. A structure can be
generated through homology modeling, aided with a commercial
package, such as InsightII modeling package from Accelrys (San
Diego, Calif.). Briefly, one can use the sequence of the antibody
to be examined to search against a database of proteins of known
structures, such as the Protein Data Bank. After one identifies
homologous proteins with known structures, these homologous
proteins are used as modeling templates. Each of the possible
templates can be aligned, thus producing structure based sequence
alignments among the templates. The sequence of the antibody with
the unknown structure can then be aligned with these templates to
generate a molecular model for the antibody with the unknown
structure. As will be appreciated by one of skill in the art, there
are many alternative methods for generating such structures in
silico, any of which may be used. For instance, a process similar
to the one described in Hardman et al., issued U.S. Pat. No.
5,958,708 employing QUANTA (Polygen Corp., Waltham, Mass.) and
CHARM (Brooks et al., (1983), J. Comp. Chem. 4:187) may be used
(hereby incorporated in its entirety by reference).
[0143] Not only is the shape of the paratope important in
determining whether and how well a possible paratope will bind to
an epitope, but the interaction itself, between the epitope and the
paratope is a source of great information in the design of variant
antibodies. As appreciated by one of skill in the art, there are a
variety of ways in which this interaction can be studied. One way
is to use the structural model generated, perhaps as described
above, and then to use a program such as InsightII (Accelrys, San
Diego, Calif.), which has a docking module, which, among other
things, is capable of performing a Monte Carlo search on the
conformational and orientational spaces between the paratope and
its epitope. The result is that one is able to estimate where and
how the epitope interacts with the paratope. In one embodiment,
only a fragment, or variant, of the epitope is used to assist in
determining the relevant interactions. In one embodiment, the
entire epitope is used in the modeling of the interaction between
the paratope and the epitope.
[0144] Through the use of these modelled structures, one is able to
predict which residues are the most important in the interaction
between the epitope and the paratope. Thus, in one embodiment, one
is able to readily select which residues to change in order to
alter the binding characteristics of the antibody. For instance, it
may be apparent from the docking models that the side chains of
certain residues in the paratope may sterically hinder the binding
of the epitope, thus altering these residues to residues with
smaller side chains may be beneficial. One can determine this in
many ways. For example, one may simply look at the two models and
estimate interactions based on functional groups and proximity.
Alternatively, one may perform repeated pairings of epitope and
paratope, as described above, in order to obtain more favorable
energy interactions. One can also determine these interactions for
a variety of variants of the antibody to determine alternative ways
in which the antibody may bind to the epitope. One can also combine
the various models to determine how one should alter the structure
of the antibodies in order to obtain an antibody with the
particular characteristics that are desired.
[0145] The models determined above can be tested through various
techniques. For example, the interaction energy can determined with
the programs discussed above in order to determine which of the
variants to further examine. Also, coulumbic and van der Waals
interactions are used to determine the interaction energies of the
epitope and the variant paratopes. Also site directed mutagenesis
is used to see if predicted changes in antibody structure actually
result in the desired changes in binding characteristics.
Alternatively, changes may be made to the epitope to verify that
the models are correct or to determine general binding themes that
may be occurring between the paratope and the epitope.
[0146] As will be appreciated by one of skill in the art, while
these models will provide the guidance necessary to make the
antibodies and variants thereof of the present embodiments, it may
still be desirable to perform routine testing of the in silico
models, perhaps through in vitro studies. In addition, as will be
apparent to one of skill in the art, any modification may also have
additional side effects on the activity of the antibody. For
instance, while any alteration predicted to result in greater
binding, may induce greater binding, it may also cause other
structural changes which might reduce or alter the activity of the
antibody. The determination of whether or not this is the case is
routine in the art and can be achieved in many ways. For example,
the activity can be tested through an ELISA test. Alternatively,
the samples can be tested through the use of a surface plasmon
resonance device.
HER3 Antibodies
[0147] The present invention provides a class of antibodies that
recognize a non-linear epitope within domain 3 of HER3 and inhibit
both ligand-dependent and ligand-independent HER3 signal
transduction pathways as shown in Table 1. The present invention
also provides a class of antibodies that recognize an epitope
(linear, non-linear, conformational) within domains 3-4 of HER3
that inhibit both ligand-dependent and ligand-independent HER3
signal transduction pathways, as shown in Table 2
TABLE-US-00002 TABLE 1 Examples of HER3 antibodies that bind to a
non-linear epitope within domain 3 of HER3. MOR09627 SEQ ID NO: 2
(Kabat) HCDR1 SYAIS SEQ ID NO: 3 (Kabat) HCDR2 LIIPRYGKARYAQKFQG
SEQ ID NO: 4 (Kabat) HCDR3 NWPYYYMDF SEQ ID NO: 5 (Chothia) HCDR1
GGTFSSY SEQ ID NO: 6 (Chothia) HCDR2 IPRYGK SEQ ID NO: 7 (Chothia)
HCDR3 NWPYYYMDF SEQ ID NO: 8 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 9
(Kabat) LCDR2 DASNRAT SEQ ID NO: 10 (Kabat) LCDR3 QQHGSGPTT SEQ ID
NO: 11 (Chothia) LCDR1 SQNIVFN SEQ ID NO: 12 (Chothia) LCDR2 DAS
SEQ ID NO: 13 (Chothia) LCDR3 HGSGPT SEQ ID NO: 14 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 15
VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQHGSGPTTFGQGTKVEIK SEQ ID NO: 16 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 17 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTTTA
TTATTGCCAGCAGCATGGTTCTGGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 18 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE
VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ
ID NO: 19 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQHGSGPTTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA
SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKV
YACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 20 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 21 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTTTA
TTATTGCCAGCAGCATGGTTCTGGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAAC
GTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCAC
CGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGT
GGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGACT
CCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCG
AGTGT MOR12603 SEQ ID NO: 22 (Kabat) HCDR1 SYAIS SEQ ID NO: 23
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 24 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 25 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 26
(Chothia) HCDR2 IPRYGK SEQ ID NO: 27 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 28 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 29 (Kabat) LCDR2
DASNRAT SEQ ID NO: 30 (Kabat) LCDR3 QQTKNRPPT SEQ ID NO: 31
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 32 (Chothia) LCDR2 DAS SEQ ID
NO: 33 (Chothia) LCDR3 TKNRPP SEQ ID NO: 34 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 35
VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIK SEQ ID NO: 36 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 37 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 38 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH
NHYTQKSLSLSPGK SEQ ID NO: 39 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS
GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 40 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 41 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAA
ACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGC
ACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG
GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGA
CTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGT
GTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGT MOR12604 SEQ ID NO: 42 (Kabat) HCDR1 SYAIS SEQ ID NO: 43
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 44 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 45 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 46
(Chothia) HCDR2 IPRYGK SEQ ID NO: 47 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 48 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 49 (Kabat) LCDR2
DASNRAT SEQ ID NO: 50 (Kabat) LCDR3 QQKKSMPLT SEQ ID NO: 51
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 52 (Chothia) LCDR2 DAS SEQ ID
NO: 53 (Chothia) LCDR3 KKSMPL SEQ ID NO: 54 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 55
VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQKKSMPLTFGQGTKVEIK SEQ ID NO: 56 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 57 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGAAGAAGTCTATGCCTCTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 58 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 59 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQKKSMPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS
GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 60 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 61 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGAAGAAGTCTATGCCTCTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAA
ACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGC
ACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG
GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGA
CTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGT
GTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGT MOR12605 SEQ ID NO: 62 (Kabat) HCDR1 SYAIS SEQ ID NO: 63
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 64 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 65 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 66
(Chothia) HCDR2 IPRYGK SEQ ID NO: 67 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 68 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 69 (Kabat) LCDR2
DASNRAT SEQ ID NO: 70 (Kabat) LCDR3 QQFRRKSNT SEQ ID NO: 71
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 72 (Chothia) LCDR2 DAS SEQ ID
NO: 73 (Chothia) LCDR3 FRRKSN SEQ ID NO: 74 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 75
VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQFRRKSNTFGQGTKVEIK SEQ ID NO: 76 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 77 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGTTTCGTCGTAAGTCTAATACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 78 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF
PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVV
SVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
CSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 79 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQFRRKSNTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGT
ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK
VYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 80 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 81 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGTTTCGTCGTAAGTCTAATACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCA
CCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG
TGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGAC
TCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTG
TACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC
GAGTGT MOR12606 SEQ ID NO: 82 (Kabat) HCDR1 SYAIS SEQ ID NO: 83
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 84 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 85 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 86
(Chothia) HCDR2 IPRYGK SEQ ID NO: 87 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 88 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 89 (Kabat) LCDR2
DASNRAT SEQ ID NO: 90 (Kabat) LCDR3 QQTKSKPSPT SEQ ID NO: 91
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 92 (Chothia) LCDR2 DAS SEQ ID
NO: 93 (Chothia) LCDR3 TKSKPSP SEQ ID NO: 94 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO: 95
VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIK SEQ ID NO: 96 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 97 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT
AAA SEQ ID NO: 98 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL
FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 99 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIKRTVAAPSVFIFPPSDEQ
LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 100 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 101 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT
AAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCG
GCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGA
AGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAG
GACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG
GTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGG
GGCGAGTGT MOR12607 SEQ ID NO: 102 (Kabat) HCDR1 SYAIS SEQ ID NO:
103 (Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 104 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 105 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 106
(Chothia) HCDR2 IPRYGK SEQ ID NO: 107 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 108 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 109 (Kabat) LCDR2
DASNRAT SEQ ID NO: 110 (Kabat) LCDR3 QQVKKRPFT SEQ ID NO: 111
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 112 (Chothia) LCDR2 DAS SEQ ID
NO: 113 (Chothia) LCDR3 VKKRPF SEQ ID NO: 114 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO:
115 VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQVKKRPFTFGQGTKVEIK SEQ ID NO: 116 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 117 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGGTTAAGAAGCGTCCTTTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 118 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 119 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQVKKRPFTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS
GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 120 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 121 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGGTTAAGAAGCGTCCTTTTACCTTTGGCCAGGGTACGAAAGTTGAAATTAA
ACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGC
ACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG
GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGA
CTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGT
GTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGT MOR12608 SEQ ID NO: 122 (Kabat) HCDR1 SYAIS SEQ ID NO: 123
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 124 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 125 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 126
(Chothia) HCDR2 IPRYGK SEQ ID NO: 127 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 128 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 129 (Kabat) LCDR2
DASNRAT SEQ ID NO: 130 (Kabat) LCDR3 QQSYTRPTT SEQ ID NO: 131
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 132 (Chothia) LCDR2 DAS SEQ ID
NO: 133 (Chothia) LCDR3 SYTRPT SEQ ID NO: 134 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO:
135 VL
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQSYTRPTTFGQGTKVEIK SEQ ID NO: 136 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 137 DNA VL
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGTCTTATACTCGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 138 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTK
GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 139 Light Chain
DIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGVPARFSGSGS
GTDFTLTISSLEPEDFAVYYCQQSYTRPTTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS
GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD
YEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 140 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 141 DNA Light
GATATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGGTCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGTCTTATACTCGTCCTACTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCA
CCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG
TGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGAC
TCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTG
TACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC
GAGTGT MOR14533 SEQ ID NO: 142 (Kabat) HCDR1 SYAIS SEQ ID NO: 143
(Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 144 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 145 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 146
(Chothia) HCDR2 IPRYGK SEQ ID NO: 147 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 148 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 149 (Kabat) LCDR2
DASNRAT SEQ ID NO: 150 (Kabat) LCDR3 QQTKSKPSPT SEQ ID NO: 151
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 152 (Chothia) LCDR2 DAS SEQ ID
NO: 153 (Chothia) LCDR3 TKSKPSP SEQ ID NO: 154 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO:
155 VL
EIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFS
GSGSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIK SEQ ID NO: 156 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 157 DNA VL
GAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT
AAA SEQ ID NO: 158 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ
QGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 159 Light Chain
EIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSGS
GSGTDFTLTISSLEPEDFAVYYCQQTKSKPSPTFGQGTKVEIKRTVAAPSVFIFPPSDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 160 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 161 DNA Light
GAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGTCTAAGCCTTCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATT
AAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCG
GCACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGA
AGGTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAG
GACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAG
GTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGG
GGCGAGTGT MOR14534 SEQ ID NO: 162 (Kabat) HCDR1 SYAIS SEQ ID NO:
163 (Kabat) HCDR2 LIIPRYGKARYAQKFQG SEQ ID NO: 164 (Kabat) HCDR3
NWPYYYMDF SEQ ID NO: 165 (Chothia) HCDR1 GGTFSSY SEQ ID NO: 166
(Chothia) HCDR2 IPRYGK SEQ ID NO: 167 (Chothia) HCDR3 NWPYYYMDF SEQ
ID NO: 168 (Kabat) LCDR1 RASQNIVFNLA SEQ ID NO: 169 (Kabat) LCDR2
DASNRAT SEQ ID NO: 170 (Kabat) LCDR3 QQTKNRPPT SEQ ID NO: 171
(Chothia) LCDR1 SQNIVFN SEQ ID NO: 172 (Chothia) LCDR2 DAS SEQ ID
NO: 173 (Chothia) LCDR3 TKNRPP SEQ ID NO: 174 VH
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSS SEQ ID NO:
175 VL
EIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFS
GSGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIK SEQ ID NO: 176 DNA VH
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCA SEQ ID NO: 177 DNA VL
GAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAAA
SEQ ID NO: 178 Heavy Chain
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPRYGKARYAQKFQ
GRVTITADESTSTAYMELSSLRSEDTAVYYCARNWPYYYMDFWGQGTLVTVSSASTKG
PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL
FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR
VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 179 Light Chain
EIVLTQSPATLSLSPGERATLSCRASQNIVFNLAWYQQKPGQAPRLLIYDASNRATGIPARFSG
SGSGTDFTLTISSLEPEDFAVYYCQQTKNRPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQL
KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA
DYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 180 DNA Heavy
CAGGTGCAATTGGTTCAGTCTGGCGCGGAAGTGAAAAAACCGGGCAGCAGCGTGAAAGTGAG
Chain
CTGCAAAGCCTCCGGAGGCACTTTTAGCAGCTATGCGATTAGCTGGGTGCGCCAAGCCCCTGGG
CAGGGTCTCGAGTGGATGGGCCTTATTATTCCTCGTTATGGTAAGGCTCGTTATGCTCAGAAGTT
TCAGGGTCGGGTGACCATTACCGCGGATGAAAGCACCAGCACCGCGTATATGGAACTGAGCAG
CCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTAATTGGCCTTATTATTATATGGATT
TTTGGGGCCAAGGCACCCTGGTGACGGTTAGCTCAGCCTCCACCAAGGGTCCATCGGTCTTCCC
CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA
CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC
TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAG
CAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAC
TCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG
ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC
TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAA
CAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGA
GTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAG
AACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGG
AGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCT
CCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTC
ATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO: 181 DNA Light
GAGATCGTGCTGACCCAGAGCCCGGCGACCCTGAGCCTGTCTCCGGGCGAACGTGCGACCCTG
Chain
AGCTGCAGAGCGAGCCAGAATATTGTTTTTAATCTGGCTTGGTACCAGCAGAAACCAGGTCAAG
CACCGCGTCTATTAATTTATGATGCTTCTAATCGTGCAACTGGGATCCCGGCGCGTTTTAGCGGC
TCTGGATCCGGCACGGATTTTACCCTGACCATTAGCAGCCTGGAACCTGAAGACTTTGCGGTGT
ATTATTGCCAGCAGACTAAGAATCGTCCTCCTACCTTTGGCCAGGGTACGAAAGTTGAAATTAA
ACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGC
ACCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG
GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGA
CTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGT
GTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGG
CGAGTGT
TABLE-US-00003 TABLE 2 Examples of HER3 antibodies that bind to
amino acids within domains 3-4 of HER3. MOR12514 SEQ ID NO: 182
(Kabat) HCDR1 SYDIH SEQ ID NO: 183 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG
SEQ ID NO: 184 (Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 185 (Chothia)
HCDR1 GYTFTSY SEQ ID NO: 186 (Chothia) HCDR2 DPYSGN SEQ ID NO: 187
(Chothia) HCDR3 GSFYTRDSYFDV SEQ ID NO: 188 (Kabat) LCDR1
TGTSSDVGTYNQVS SEQ ID NO: 189 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 190
(Kabat) LCDR3 QVRDMSLFDV SEQ ID NO: 191 (Chothia) LCDR1 TSSDVGTYNQ
SEQ ID NO: 192 (Chothia) LCDR2 GVS SEQ ID NO: 193 (Chothia) LCDR3
RDMSLFD SEQ ID NO: 194 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 195 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVRDMSLFDVFGGGTKLTVL SEQ ID NO: 196 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 197 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTCGTGACATGTCTCTGTTCGACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 198 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 199 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVRDMSLFDVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKA
TLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH
EGSTVEKTVAPTECS SEQ ID NO: 200 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 201 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTCGTGACATGTCTCTGTTCGACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR12515 SEQ ID NO: 202 (Kabat) HCDR1 SYDIH SEQ ID
NO: 203 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 204 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 205 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 206 (Chothia) HCDR2 DPYSGN SEQ ID NO: 207 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 208 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
209 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 210 (Kabat) LCDR3 YSRDSPMDQV
SEQ ID NO: 211 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 212 (Chothia)
LCDR2 GVS SEQ ID NO: 213 (Chothia) LCDR3 RDSPMDQ SEQ ID NO: 214 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 215 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCYSRDSPMDQVFGGGTKLTVL SEQ ID NO: 216 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 217 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTACTCTCGTGACTCTCCGATGGACCAGGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 218 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP
VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ
ID NO: 219 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCYSRDSPMDQVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKA
TLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH
EGSTVEKTVAPTECS SEQ ID NO: 220 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 221 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTACTCTCGTGACTCTCCGATGGACCAGGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR12516 SEQ ID NO: 222 (Kabat) HCDR1 SYDIH SEQ ID
NO: 223 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 224 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 225 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 226 (Chothia) HCDR2 DPYSGN SEQ ID NO: 227 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 228 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
229 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 230 (Kabat) LCDR3 QSRDTYRPVKV
SEQ ID NO: 231 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 232 (Chothia)
LCDR2 GVS SEQ ID NO: 233 (Chothia) LCDR3 RDTYRPVK SEQ ID NO: 234 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 235 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQSRDTYRPVKVFGGGTKLTVL SEQ ID NO: 236 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 237 DNA
VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTCGTGACACTTACCGTCCGGTTAAAGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTA SEQ ID NO: 238 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYA
QKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH
YTQKSLSLSPGK SEQ ID NO: 239 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQSRDTYRPVKVFGGGTKLTVLGQPKAAPSVTLFPPSSEEL
QANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSH
RSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 240 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 241 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTCGTGACACTTACCGTCCGGTTAAAGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT
GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCC
GTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC
CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG
GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAG
TGGCCCCTACAGAATGTTCA MOR12615 SEQ ID NO: 242 (Kabat) HCDR1 SYDIH
SEQ ID NO: 243 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 244
(Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 245 (Chothia) HCDR1 GYTFTSY
SEQ ID NO: 246 (Chothia) HCDR2 DPYSGN SEQ ID NO: 247 (Chothia)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 248 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ
ID NO: 249 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 250 (Kabat) LCDR3
SSRDLIGHYV SEQ ID NO: 251 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 252
(Chothia) LCDR2 GVS SEQ ID NO: 253 (Chothia) LCDR3 RDLIGHY SEQ ID
NO: 254 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 255 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 256 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 257 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 258 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNY
AQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL
HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHN
HYTQKSLSLSPGK SEQ ID NO: 259 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSN
RFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSEEL
QANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSY
SCQVTHEGSTVEKTVAPTECS SEQ ID NO: 260 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 261 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR12920 SEQ ID NO: 262 (Kabat) HCDR1 GYYMH SEQ ID
NO: 263 (Kabat) HCDR2 DIEPYHGKPLYAQKFQG SEQ ID NO: 264 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 265 (Chothia) HCDR1 GYTFTGY SEQ ID
NO: 266 (Chothia) HCDR2 EPYHGK SEQ ID NO: 267 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 268 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
269 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 270 (Kabat) LCDR3 SSRDLIGHYV
SEQ ID NO: 271 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 272 (Chothia)
LCDR2 GVS SEQ ID NO: 273 (Chothia) LCDR3 RDLIGHY SEQ ID NO: 274 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIEPYHGKPLYAQK
FQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 275 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGNAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 276 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAG
CTGCAAAGGCTCCGGATATAGCTTCACTAACTCTTGGGTTGCTTGGGTGCGCCAGATGCCGGGC
AAAGGTCTCGAGTGGATGGGCATCATCTACCCGGGTAACAGCGACACCATCTATAGCCCGAGCT
TTCAGGGCCAGGTGACCATTAGCGCGGATAAAAGCATCAGCACCGCGTATCTGCAATGGAGCA
GCCTGAAAGCGAGCGATACCGCGATGTATTATTGCGCGCGTGTTCATATCATCCAGCCGCCGTC
TGCTTGGTCTTACAACGCTATGGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ
ID NO: 277 DNA VL
GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATT
ACCTGCAGAGCCAGCCAGTCTATTTCTACTTACCTGAACTGGTACCAGCAGAAACCGGGCAAAG
CGCCGAAACTATTAATCTTCGGTGCTTCTAACCTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGG
CAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCT
ATTATTGCCAGCAGTCTATCACTGAACTGTTCACCTTTGGCCAGGGCACGAAAGTTGAAATTAAA
SEQ ID NO: 278 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIEPYHGKP
LYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL
FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLT
CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 279 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGNAPKLMIYGVSKRPSGVSNR
FSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPPSSE
ELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWK
SHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 280 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGCGAAAGCCTGAAAATTAG
Chain
CTGCAAAGGCTCCGGATATAGCTTCACTAACTCTTGGGTTGCTTGGGTGCGCCAGATGCCGGGC
AAAGGTCTCGAGTGGATGGGCATCATCTACCCGGGTAACAGCGACACCATCTATAGCCCGAGCT
TTCAGGGCCAGGTGACCATTAGCGCGGATAAAAGCATCAGCACCGCGTATCTGCAATGGAGCA
GCCTGAAAGCGAGCGATACCGCGATGTATTATTGCGCGCGTGTTCATATCATCCAGCCGCCGTC
TGCTTGGTCTTACAACGCTATGGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCC
TCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG
CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG
GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC
AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATC
ACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACA
CATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAA
CCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCC
ACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGA
CAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGC
ACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC
CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT
ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTA
CACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 281 DNA Light
GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTGGGCGATCGCGTGACCATT
Chain
ACCTGCAGAGCCAGCCAGTCTATTTCTACTTACCTGAACTGGTACCAGCAGAAACCGGGCAAAG
CGCCGAAACTATTAATCTTCGGTGCTTCTAACCTGCAAAGCGGCGTGCCGAGCCGCTTTAGCGG
CAGCGGATCCGGCACCGATTTCACCCTGACCATTAGCTCTCTGCAACCGGAAGACTTTGCGACCT
ATTATTGCCAGCAGTCTATCACTGAACTGTTCACCTTTGGCCAGGGCACGAAAGTTGAAATTAAA
CGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCA
CCGCCAGCGTGGTGTGCCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGG
TGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAGCAGGACAGCAAGGAC
TCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTG
TACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGC
GAGTGT MOR12921 SEQ ID NO: 282 (Kabat) HCDR1 GYYMH SEQ ID NO: 283
(Kabat) HCDR2 DIDPHSGNAVYAQKFQG SEQ ID NO: 284 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 285 (Chothia) HCDR1 GYTFTGY SEQ ID NO: 286
(Chothia) HCDR2 DPHSGN SEQ ID NO: 287 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 288 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 289 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 290 (Kabat) LCDR3 SSRDLIGHYV SEQ ID NO:
291 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 292 (Chothia) LCDR2 GVS
SEQ ID NO: 293 (Chothia) LCDR3 RDLIGHY SEQ ID NO: 294 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIDPHSGNAVYAQ
KFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 295 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 296 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCGACATCGACCCGCATTCTGGCAACGCTGTTTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 297 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 298 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGDIDPHSG
NAVYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVS
SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
QKSLSLSPGK SEQ ID NO: 299 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYG
VSKRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAA
PSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASS
YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 300 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCGACATCGACCCGCATTCTGGCAACGCTGTTTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 301 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR12922 SEQ ID NO: 302 (Kabat) HCDR1 GYYMH SEQ ID
NO: 303 (Kabat) HCDR2 VIDPYSGWTEYAQKFQG SEQ ID NO: 304 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 305 (Chothia) HCDR1 GYTFTGY SEQ ID
NO: 306 (Chothia) HCDR2 DPYSGW SEQ ID NO: 307 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 308 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
309 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 310 (Kabat) LCDR3 SSRDLIGHYV
SEQ ID NO: 311 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 312 (Chothia)
LCDR2 GVS SEQ ID NO: 313 (Chothia) LCDR3 RDLIGHY SEQ ID NO: 314 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGVIDPYSGWTEYAQK
FQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 315 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVL SEQ ID NO: 316 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCGTTATTGACCCGTACTCTGGCTGGACTGAATACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 317 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 318 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGVIDPYS
GWTEYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR
EEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLP
PSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 319 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCSSRDLIGHYVFGGGTKLTVLGQPKAAPSVTLFPP
SSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQ
WKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 320 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACCGGCTATTACATGCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCGTTATTGACCCGTACTCTGGCTGGACTGAATACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 321 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTCGTGACCTGATCGGTCATTACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR13654 SEQ ID NO: 322 (Kabat) HCDR1 SYDIH SEQ ID
NO: 323 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 324 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 325 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 326 (Chothia) HCDR2 DPYSGN SEQ ID NO: 327 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 328 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
329 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 330 (Kabat) LCDR3 QSRGEYRPGWV
SEQ ID NO: 331 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 332 (Chothia)
LCDR2 GVS SEQ ID NO: 333 (Chothia) LCDR3 RGEYRPGW SEQ ID NO: 334 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 335 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQSRGEYRPGWVFGGGTKLTVL SEQ ID NO: 336 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 337 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTCGTGGTGAATACCGTCCGGGTTGGGTGTTTGGCGGCGGC
ACGAAGTTAACCGTCCTA SEQ ID NO: 338 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGN
TNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA
VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 339 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSVVYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCQSRGEYRPGWVFGGGTKLTVLGQPKAAPSVTLF
PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPE
QWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 340 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 341 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTCGTGGTGAATACCGTCCGGGTTGGGTGTTTGGCGGCGGC
ACGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTC
TGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCC
GTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC
CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG
GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAG
TGGCCCCTACAGAATGTTCA MOR13655 SEQ ID NO: 342 (Kabat) HCDR1 SYDIH
SEQ ID NO: 343 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 344
(Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 345 (Chothia) HCDR1 GYTFTSY
SEQ ID NO: 346 (Chothia) HCDR2 DPYSGN SEQ ID NO: 347 (Chothia)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 348 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ
ID NO: 349 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 350 (Kabat) LCDR3
SSATQKPDVTV SEQ ID NO: 351 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO:
352 (Chothia) LCDR2 GVS SEQ ID NO: 353 (Chothia) LCDR3 ATQKPDVT SEQ
ID NO: 354 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 355 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVL SEQ ID NO: 356 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 357 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTA SEQ ID NO: 358 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP
APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 359 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPS
GVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVLGQPKA
APSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 360 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 361 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT
GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCC
GTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC
CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG
GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAG
TGGCCCCTACAGAATGTTCA MOR13656 SEQ ID NO: 362 (Kabat) HCDR1 SYDIH
SEQ ID NO: 363 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 364
(Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 365 (Chothia) HCDR1 GYTFTSY
SEQ ID NO: 366 (Chothia) HCDR2 DPYSGN SEQ ID NO: 367 (Chothia)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 368 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ
ID NO: 368 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 370 (Kabat) LCDR3
AVRDSVWHV SEQ ID NO: 371 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 372
(Chothia) LCDR2 GVS SEQ ID NO: 373 (Chothia) LCDR3 RDSVWH SEQ ID
NO: 374 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 375 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCAVRDSVWHVFGGGTKLTVL SEQ ID NO: 376 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 377 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTGTTCGTGACTCCGTTTGGCATGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTA SEQ ID NO: 378 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYS
GNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWG
QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT
CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE
VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG
QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD
SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 379
Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRDSVWHVFGGGTKLTVLGQPKAA
PSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYA
ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 380 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 381 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTGTTCGTGACTCCGTTTGGCATGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG
CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAG
TGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAAC
AAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT
ACAGAATGTTCA MOR13657 SEQ ID NO: 382 (Kabat) HCDR1 SYDIH SEQ ID NO:
383 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 384 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 385 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 386
(Chothia) HCDR2 DPYSGN SEQ ID NO: 387 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 388 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 389 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 390 (Kabat) LCDR3 SARDGWSEYV SEQ ID NO:
391 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 392 (Chothia) LCDR2 GVS
SEQ ID NO: 393 (Chothia) LCDR3 RDGWSEY SEQ ID NO: 394 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 395 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSARDGWSEYVFGGGTKLTVL SEQ ID NO: 396 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 397 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGCTCGTGACGGTTGGTCTGAATACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 398 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNT
NYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP
KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD
WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDI
AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
LSLSPGK SEQ ID NO: 399 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCSARDGWSEYVFGGGTKLTVLGQPKAAPSVTLF
PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTP
EQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 400 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 401 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGCTCGTGACGGTTGGTCTGAATACGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR13658 SEQ ID NO: 402 (Kabat) HCDR1 SYDIH SEQ ID
NO: 403 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 404 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 405 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 406 (Chothia) HCDR2 DPYSGN SEQ ID NO: 407 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 408 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
409 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 410 (Kabat) LCDR3 ASADHSYHTV
SEQ ID NO: 411 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 412 (Chothia)
LCDR2 GVS SEQ ID NO: 413 (Chothia) LCDR3 ADHSYHT SEQ ID NO: 414 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 415 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVL SEQ ID NO: 416 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 417 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTA SEQ ID NO: 418 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYS
GNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS
SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRV
VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL
TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 419 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVLGQPKAAPSV
TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLS
LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 420 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 421 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGG
AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGAC
AGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAA
ACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTC
CCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCC
CTACAGAATGTTCA MOR13659 SEQ ID NO: 422 (Kabat) HCDR1 SYDIH SEQ ID
NO: 423 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 424 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 425 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 426 (Chothia) HCDR2 DPYSGN SEQ ID NO: 427 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 428 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
429 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 430 (Kabat) LCDR3 GSRTSHNWV
SEQ ID NO: 431 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 432 (Chothia)
LCDR2 GVS SEQ ID NO: 433 (Chothia) LCDR3 RTSHNW SEQ ID NO: 434 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 435 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCGSRTSHNWVFGGGTKLTVL SEQ ID NO: 436 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 437 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGGTTCTCGTACTTCTCATAACTGGGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTA SEQ ID NO: 438 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRID
PYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVW
GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG
VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP
PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE
PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 439 Light
Chain DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPS
GVSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRTSHNWVFGGGTKLTVLGQPKAAPS
VTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 440 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 441 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGGTTCTCGTACTTCTCATAACTGGGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG
CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAG
TGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAAC
AAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT
ACAGAATGTTCA MOR13660 SEQ ID NO: 442 (Kabat) HCDR1 SYDIH SEQ ID NO:
443 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 444 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 445 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 446
(Chothia) HCDR2 DPYSGN SEQ ID NO: 447 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 448 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 449 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 450 (Kabat) LCDR3 AVRGSQTLV SEQ ID NO: 451
(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 452 (Chothia) LCDR2 GVS SEQ
ID NO: 453 (Chothia) LCDR3 RGSQTL SEQ ID NO: 454 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 455 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCAVRGSQTLVFGGGTKLTVL SEQ ID NO: 456 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 457 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTGTTCGTGGTTCTCAGACTCTGGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTA SEQ ID NO: 458 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYS
GNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR
EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 459 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCAVRGSQTLVFGGGTKLTVLGQPKAAPS
VTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAA
SSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 460 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 461 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTGTTCGTGGTTCTCAGACTCTGGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG
CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAG
TGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAAC
AAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT
ACAGAATGTTCA MOR13661 SEQ ID NO: 462 (Kabat) HCDR1 SYDIH SEQ ID NO:
463 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 464 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 465 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 466
(Chothia) HCDR2 DPYSGN SEQ ID NO: 467 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 468 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 469 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 470 (Kabat) LCDR3 GSRDSWAHV SEQ ID NO: 471
(Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 472 (Chothia) LCDR2 GVS SEQ
ID NO: 473 (Chothia) LCDR3 RDSWAH SEQ ID NO: 474 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 475 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCGSRDSWAHVFGGGTKLTVL SEQ ID NO: 476 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 477 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGGTTCTCGTGACTCTTGGGCTCATGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTA SEQ ID NO: 478 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 479 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCGSRDSWAHVFGGGTKLTVLGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLS
LTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 480 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 481 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGGTTCTCGTGACTCTTGGGCTCATGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG
CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAG
TGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAAC
AAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT
ACAGAATGTTCA MOR13662 SEQ ID NO: 482 (Kabat) HCDR1 SYDIH SEQ ID NO:
483 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 484 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 485 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 486
(Chothia) HCDR2 DPYSGN SEQ ID NO: 487 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 488 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 489 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 490 (Kabat) LCDR3 YSRAKTHWTDV SEQ ID NO:
491 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 492 (Chothia) LCDR2 GVS
SEQ ID NO: 493 (Chothia) LCDR3 RAKTHWTD SEQ ID NO: 494 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 495 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCYSRAKTHWTDVFGGGTKLTVL SEQ ID NO: 496 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 497 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTACTCTCGTGCTAAAACTCATTGGACTGACGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTA SEQ ID NO: 498 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYS
GNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGT
LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVF
SCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 499 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCYSRAKTHWTDVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANK
ATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT
HEGSTVEKTVAPTECS SEQ ID NO: 500 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 501 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTACTCTCGTGCTAAAACTCATTGGACTGACGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT
GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCC
GTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC
CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG
GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAG
TGGCCCCTACAGAATGTTCA MOR13663 SEQ ID NO: 502 (Kabat) HCDR1 SYDIH
SEQ ID NO: 503 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 504
(Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 505 (Chothia) HCDR1 GYTFTSY
SEQ ID NO: 506 (Chothia) HCDR2 DPYSGN SEQ ID NO: 507 (Chothia)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 508 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ
ID NO: 509 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 510 (Kabat) LCDR3
SVWTSIKVFV SEQ ID NO: 511 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 512
(Chothia) LCDR2 GVS SEQ ID NO: 513 (Chothia) LCDR3 WTSIKVF SEQ ID
NO: 514 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 515 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSVWTSIKVFVFGGGTKLTVL SEQ ID NO: 516 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 517 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGTTTGGACTTCTATCAAAGTTTTCGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTA SEQ ID NO: 518 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGN
TNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTV
SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF
PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL
TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV
KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
ALHNHYTQKSLSLSPGK SEQ ID NO: 519 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGV
SNRFSGSKSGNTASLTISGLQAEDEADYYCSVWTSIKVFVFGGGTKLTVLGQPKAAPSV
TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAA
SSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 520 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 521 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGTTTGGACTTCTATCAAAGTTTTCGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGG
AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGAC
AGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAA
ACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTC
CCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCC
CTACAGAATGTTCA MOR13664 SEQ ID NO: 522 (Kabat) HCDR1 SYDIH SEQ ID
NO: 523 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 524 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 525 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 526 (Chothia) HCDR2 DPYSGN SEQ ID NO: 527 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 528 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
529 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 530 (Kabat) LCDR3
SAYDASTQVV
SEQ ID NO: 531 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 532 (Chothia)
LCDR2 GVS SEQ ID NO: 533 (Chothia) LCDR3 YDASTQV SEQ ID NO: 534 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 535 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSAYDASTQVVFGGGTKLTVL SEQ ID NO: 536 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 537 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGCTTACGACGCTTCTACTCAGGTTGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTA SEQ ID NO: 538 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGN
TNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL
QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE
EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 539 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGV
SNRFSGSKSGNTASLTISGLQAEDEADYYCSAYDASTQVVFGGGTKLTVLGQPKAAPS
VTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYA
ASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 540 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 541 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTGCTTACGACGCTTCTACTCAGGTTGTGTTTGGCGGCGGCACGA
AGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG
GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGA
CAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCA
AACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGT
CCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR13665 SEQ ID NO: 542 (Kabat) HCDR1 SYDIH SEQ ID
NO: 543 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 544 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 545 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 546 (Chothia) HCDR2 DPYSGN SEQ ID NO: 547 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 548 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
549 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 550 (Kabat) LCDR3 QSAAIATSV
SEQ ID NO: 551 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 552 (Chothia)
LCDR2 GVS SEQ ID NO: 553 (Chothia) LCDR3 AAIATS SEQ ID NO: 554 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 555 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQSAAIATSVFGGGTKLTVL SEQ ID NO: 556 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 557 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTGCTGCTATCGCTACTTCTGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTA SEQ ID NO: 558 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 559 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCQSAAIATSVFGGGTKLTVLGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL
SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 560 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 561 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGTCTGCTGCTATCGCTACTTCTGTGTTTGGCGGCGGCACGAAGT
TAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAG
CTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAG
TGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAAC
AAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCC
ACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCT
ACAGAATGTTCA MOR13666 SEQ ID NO: 562 (Kabat) HCDR1 SYDIH SEQ ID NO:
563 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 564 (Kabat) HCDR3
GSFYTRDSYFDV SEQ ID NO: 565 (Chothia) HCDR1 GYTFTSY SEQ ID NO: 566
(Chothia) HCDR2 DPYSGN SEQ ID NO: 567 (Chothia) HCDR3 GSFYTRDSYFDV
SEQ ID NO: 568 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 569 (Kabat)
LCDR2 GVSKRPS SEQ ID NO: 570 (Kabat) LCDR3 STTTYSFHMV SEQ ID NO:
571 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 572 (Chothia) LCDR2 GVS
SEQ ID NO: 573 (Chothia) LCDR3 TTYSFHM SEQ ID NO: 574 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 575 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSTTTYSFHMVFGGGTKLTVL SEQ ID NO: 576 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 577 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTACTACTACTTACTCTTTCCATATGGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTA SEQ ID NO: 578 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLV
TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ
SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN
QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 579 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCSTTTYSFHMVFGGGTKLTVLGQPKAAPSVT
LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL
SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 580 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 581 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTACTACTACTTACTCTTTCCATATGGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGG
AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGAC
AGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAA
ACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTC
CCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCC
CTACAGAATGTTCA MOR13667 SEQ ID NO: 582 (Kabat) HCDR1 SYDIH SEQ ID
NO: 583 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 584 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 585 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 586 (Chothia) HCDR2 DPYSGN SEQ ID NO: 587 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 588 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
589 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 590 (Kabat) LCDR3 QAWDYRQTIV
SEQ ID NO: 591 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 592 (Chothia)
LCDR2 GVS SEQ ID NO: 593 (Chothia) LCDR3 WDYRQTI SEQ ID NO: 594 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 595 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQAWDYRQTIVFGGGTKLTVL SEQ ID NO: 596 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 597 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGCTTGGGACTACCGTCAGACTATCGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTA SEQ ID NO: 598 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP
AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE
EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP
SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 599 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQAWDYRQTIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKA
TLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTH
EGSTVEKTVAPTECS SEQ ID NO: 600 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 601 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGCTTGGGACTACCGTCAGACTATCGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGA
GGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTG
ACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCC
AAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAG
TCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR13668 SEQ ID NO: 602 (Kabat) HCDR1 SYDIH SEQ ID
NO: 603 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 604 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 605 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 606 (Chothia) HCDR2 DPYSGN SEQ ID NO: 607 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 608 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
609 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 610 (Kabat) LCDR3 QVWDSDQAMV
SEQ ID NO: 611 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 612 (Chothia)
LCDR2 GVS SEQ ID NO: 613 (Chothia) LCDR3 WDSDQAM SEQ ID NO: 614 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 615 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVWDSDQAMVFGGGTKLTVL SEQ ID NO: 616 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 617 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTTGGGACTCTGACCAGGCTATGGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTA SEQ ID NO: 618 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVT
VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC
LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM
HEALHNHYTQKSLSLSPGK SEQ ID NO: 619 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVWDSDQAMVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANK
ATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT
HEGSTVEKTVAPTECS SEQ ID NO: 620 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 621 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTTGGGACTCTGACCAGGCTATGGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGA
GGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTG
ACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCC
AAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAG
TCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR13669 SEQ ID NO: 622 (Kabat) HCDR1 SYDIH SEQ ID
NO: 623 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 624 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 625 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 626 (Chothia) HCDR2 DPYSGN
SEQ ID NO: 627 (Chothia) HCDR3 GSFYTRDSYFDV SEQ ID NO: 628 (Kabat)
LCDR1 TGTSSDVGTYNQVS SEQ ID NO: 629 (Kabat) LCDR2 GVSKRPS SEQ ID
NO: 630 (Kabat) LCDR3 STATAMTVSLV SEQ ID NO: 631 (Chothia) LCDR1
TSSDVGTYNQ SEQ ID NO: 632 (Chothia) LCDR2 GVS SEQ ID NO: 633
(Chothia) LCDR3 ATAMTVSL SEQ ID NO: 634 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 635 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCSTATAMTVSLVFGGGTKLTVL SEQ ID NO: 636 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 637 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTACTGCTACTGCTATGACTGTTTCTCTGGTGTTTGGCGGCGGCAC
GAAGTTAACCGTCCTA SEQ ID NO: 638 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYS
GNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT
LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK
LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 639 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYCSTATAMTVSLVFGGGTKLTVLGQPKAAPSVTL
FPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSL
TPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 640 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 641 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTACTGCTACTGCTATGACTGTTTCTCTGGTGTTTGGCGGCGGCAC
GAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTG
AGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGT
GACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCT
CCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGA
AGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG
GCCCCTACAGAATGTTCA MOR13670 SEQ ID NO: 642 (Kabat) HCDR1 SYDIH SEQ
ID NO: 643 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 644 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 645 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 646 (Chothia) HCDR2 DPYSGN SEQ ID NO: 647 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 648 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
649 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 650 (Kabat) LCDR3 QVADQGWHQV
SEQ ID NO: 651 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 652 (Chothia)
LCDR2 GVS SEQ ID NO: 653 (Chothia) LCDR3 ADQGWHQ SEQ ID NO: 654 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 655 VL
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVADQGWHQVFGGGTKLTVL SEQ ID NO: 656 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 657 DNA VL
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTGCTGACCAGGGTTGGCATCAGGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTA SEQ ID NO: 658 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARGSFYTRDSYFDVWGQGTL
VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV
LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL
GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY
NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM
TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 659 Light Chain
DIALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSGS
KSGNTASLTISGLQAEDEADYYCQVADQGWHQVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANK
ATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT
HEGSTVEKTVAPTECS SEQ ID NO: 660 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGAAGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 661 DNA Light
GATATCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCCAGGTTGCTGACCAGGGTTGGCATCAGGTGTTTGGCGGCGGCACG
AAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGA
GGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTG
ACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCC
AAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAG
TCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCC
CCTACAGAATGTTCA MOR14537 SEQ ID NO: 662 (Kabat) HCDR1 SYDIH SEQ ID
NO: 663 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 664 (Kabat)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 665 (Chothia) HCDR1 GYTFTSY SEQ ID
NO: 666 (Chothia) HCDR2 DPYSGN SEQ ID NO: 667 (Chothia) HCDR3
GSFYTRDSYFDV SEQ ID NO: 668 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ ID NO:
669 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 670 (Kabat) LCDR3 SSATQKPDVTV
SEQ ID NO: 671 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 672 (Chothia)
LCDR2 GVS SEQ ID NO: 673 (Chothia) LCDR3 ATQKPDVT SEQ ID NO: 674 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 675 VL
QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSG
SKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVL SEQ ID NO: 676 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 677 DNA VL
CAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTA SEQ ID NO: 678 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRID
PYSGNTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDV
WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH
TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV
HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS
FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 679 Light Chain
QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSK
RPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSATQKPDVTVFGGGTKLTVLGQPK
AAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 680 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 681 DNA Light
CAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCTCTTCTGCTACTCAGAAACCGGACGTTACTGTGTTTGGCGGCGGCA
CGAAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT
GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCC
GTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC
CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG
GAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAG
TGGCCCCTACAGAATGTTCA MOR14538 SEQ ID NO: 682 (Kabat) HCDR1 SYDIH
SEQ ID NO: 683 (Kabat) HCDR2 RIDPYSGNTNYAQKFQG SEQ ID NO: 684
(Kabat) HCDR3 GSFYTRDSYFDV SEQ ID NO: 685 (Chothia) HCDR1 GYTFTSY
SEQ ID NO: 686 (Chothia) HCDR2 DPYSGN SEQ ID NO: 687 (Chothia)
HCDR3 GSFYTRDSYFDV SEQ ID NO: 688 (Kabat) LCDR1 TGTSSDVGTYNQVS SEQ
ID NO: 689 (Kabat) LCDR2 GVSKRPS SEQ ID NO: 690 (Kabat) LCDR3
ASADHSYHTV SEQ ID NO: 691 (Chothia) LCDR1 TSSDVGTYNQ SEQ ID NO: 692
(Chothia) LCDR2 GVS SEQ ID NO: 693 (Chothia) LCDR3 ADHSYHT SEQ ID
NO: 694 VH
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSGNTNYAQKF
QGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQGTLVTVSS SEQ ID
NO: 695 VL
QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPSGVSNRFSG
SKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVL SEQ ID NO: 696 DNA VH
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 697 DNA VL
CAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTA SEQ ID NO: 698 Heavy Chain
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDIHWVRQAPGQGLEWMGRIDPYSG
NTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGSFYTRDSYFDVWGQG
TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL
PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL
TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 699 Light Chain
QSALTQPASVSGSPGQSITISCTGTSSDVGTYNQVSWYQQHPGKAPKLMIYGVSKRPS
GVSNRFSGSKSGNTASLTISGLQAEDEADYYCASADHSYHTVFGGGTKLTVLGQPKAAPSVTLFPP
SSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQW
KSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 700 DNA Heavy
CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGTGCCAGCGTGAAAGTTAG
Chain
CTGCAAAGCGTCCGGATATACCTTCACTTCTTACGACATCCATTGGGTGCGCCAGGCCCCGGGC
CAGGGCCTCGAGTGGATGGGCCGTATCGACCCGTACTCTGGCAACACGAACTACGCGCAGAAA
TTTCAGGGCCGGGTGACCATGACCCGTGATACCAGCATTAGCACCGCGTATATGGAACTGAGCC
GTCTGCGTAGCGACGATACGGCCGTGTATTATTGCGCGCGTGGTTCTTTCTACACTCGTGACTCT
TACTTCGATGTTTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCAT
CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT
GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG
CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG
TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACAC
CAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCA
GCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCAT
GATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGT
CAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG
AGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA
ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGA
GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC
GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA
CTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG
GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAA SEQ ID NO: 701 DNA Light
CAGAGCGCGCTGACCCAGCCGGCGAGCGTGAGCGGTAGCCCGGGCCAGAGCATTACCATTAGC
Chain
TGCACCGGCACCAGCAGCGATGTGGGCACTTACAACCAGGTGTCTTGGTACCAGCAGCATCCG
GGCAAGGCGCCGAAACTGATGATCTACGGTGTTTCTAAACGTCCGAGCGGCGTGAGCAACCGT
TTTAGCGGATCCAAAAGCGGCAACACCGCGAGCCTGACCATTAGCGGCCTGCAAGCGGAAGAC
GAAGCGGATTATTACTGCGCTTCTGCTGACCATTCTTACCATACTGTGTTTGGCGGCGGCACGAA
GTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGG
AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGAC
AGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAA
ACAAAGCAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTC
CCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCC
CTACAGAATGTTCA
[0148] In one aspect, the present invention provides antibodies
that specifically bind to domain 3 of HER3 protein (e.g., human
and/or cynomologus HER3), the antibodies comprising a VH domain
having an amino acid sequence of SEQ ID NO: 14, 34, 54, 74, 94,
114, 134, 154, and 174. In another, the present invention provides
antibodies that specifically bind specifically bind to domain 3 of
HER3 protein (e.g., human and/or cynomologus HER3), the antibodies
comprising a VL domain having an amino acid sequence of SEQ ID NO:
15, 35, 55, 75, 95, 115, 135, 155, and 175.
[0149] In one aspect, the present invention provides antibodies
that specifically bind to domains 3-4 of HER3 protein (e.g., human
and/or cynomologus HER3), the antibodies comprising a VH domain
having an amino acid sequence of SEQ ID NO: 194, 214, 234, 254,
274, 294, 314, 334, 354, 374, 394, 414, 434, 454, 474, 494, 514,
534, 554, 574, 594, 614, 634, 654, 674, and 694. In another aspect,
the present invention provides antibodies that specifically bind
specifically bind to domain 3 of HER3 protein (e.g., human and/or
cynomologus HER3), the antibodies comprising a VL domain having an
amino acid sequence of SEQ ID NO: 195, 215, 235, 255, 275, 295,
315, 335, 355, 375, 395, 415, 435, 455, 475, 495, 515, 535, 555,
575, 595, 615, 635, 655, 675, and 695.
[0150] Since each of these antibodies or fragments thereof can bind
to HER3, the VH, VL, full length light chain, and full length heavy
chain sequences (amino acid sequences and the nucleotide sequences
encoding the amino acid sequences) can be "mixed and matched" to
create other HER3 antibodies of the invention. Such "mixed and
matched" HER3 antibodies can be tested using the binding assays
known in the art (e.g., ELISAs, and other assays described in the
Example section). When these chains are mixed and matched, a VH
sequence from a particular VH/VL pairing should be replaced with a
structurally similar VH sequence. Likewise a full length heavy
chain sequence from a particular full length heavy chain/full
length light chain pairing should be replaced with a structurally
similar full length heavy chain sequence. Likewise, a VL sequence
from a particular VH/VL pairing should be replaced with a
structurally similar VL sequence. Likewise a full length light
chain sequence from a particular full length heavy chain/full
length light chain pairing should be replaced with a structurally
similar full length light chain sequence.
[0151] Accordingly, in one aspect, the invention provides an
isolated monoclonal antibody or fragment thereof having: a heavy
chain variable region comprising an amino acid sequence selected
from the group consisting of SEQ ID NO: 14, 34, 54, 74, 94, 114,
134, 154, and 174; and a light chain variable region comprising an
amino acid sequence selected from the group consisting of SEQ ID
NOs: 15, 35, 55, 75, 95, 115, 135, 155, and 175; wherein the
antibody specifically binds to domain 3 of HER3 (e.g., human and/or
cynomologus).
[0152] Accordingly, in one aspect, the invention provides an
isolated monoclonal antibody or fragment thereof having: a heavy
chain variable region comprising an amino acid sequence selected
from the group consisting of SEQ ID NO: 194, 214, 234, 254, 274,
294, 314, 334, 354, 374, 394, 414, 434, 454, 474, 494, 514, 534,
554, 574, 594, 614, 634, 654, 674, and 694; and a light chain
variable region comprising an amino acid sequence selected from the
group consisting of SEQ ID NOs: 195, 215, 235, 255, 275, 295, 315,
335, 355, 375, 395, 415, 435, 455, 475, 495, 515, 535, 555, 575,
595, 615, 635, 655, 675, and 695; wherein the antibody specifically
binds to domain 3 of HER3 (e.g., human and/or cynomologus).
[0153] In a specific embodiment, an antibody that binds to domain 3
of HER3 comprises a VH of SEQ ID NO. 14 and VL of SEQ ID NO: 15. In
a specific embodiment, an antibody that binds to domain 3 of HER3
comprises a VH of SEQ ID NO: 34 and VL of SEQ ID NO: 35. In a
specific embodiment, an antibody that binds to domain 3 of HER3
comprises a VH of SEQ ID NO: 54 and VL of SEQ ID NO: 55. In a
specific embodiment, an antibody that binds to domain 3 of HER3
comprises a SEQ ID NO: 74 and VL of SEQ ID NO: 75. In a specific
embodiment, an antibody that binds to domain 3 of HER3 comprises a
VH of SEQ ID NO: 94 and VL of SEQ ID NO: 95. In a specific
embodiment, an antibody that binds to domain 3 of HER3 comprises a
VH of SEQ ID NO: 114 and VL of SEQ ID NO: 115. In a specific
embodiment, an antibody that binds to domain 3 of HER3 comprises a
VH of SEQ ID NO: 134 and VL of SEQ ID NO: 135. In a specific
embodiment, an antibody that binds to domain 3 of HER3 comprises a
VH of SEQ ID NO: 154 and VL of SEQ ID NO: 155. In a specific
embodiment, an antibody that binds to domain 3 of HER3 comprises a
VH of SEQ ID NO: 174 and VL of SEQ ID NO: 175.
[0154] In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO. 194 and VL of SEQ ID NO:
195. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 214 and VL of SEQ ID NO:
215. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 234 and VL of SEQ ID NO:
235. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a SEQ ID NO: 254 and VL of SEQ ID NO:
255.
[0155] In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 274 and VL of SEQ ID NO:
275. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 294 and VL of SEQ ID NO:
295. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 314 and VL of SEQ ID NO:
315. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 334 and VL of SEQ ID NO:
335. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 354 and VL of SEQ ID NO:
355. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 374 and VL of SEQ ID NO:
375. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 394 and VL of SEQ ID NO:
395. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 414 and VL of SEQ ID NO:
415. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 434 and VL of SEQ ID NO:
435. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 454 and VL of SEQ ID NO:
255. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 474 and VL of SEQ ID NO:
475. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 494 and VL of SEQ ID NO:
495. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 514 and VL of SEQ ID NO:
515. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 534 and VL of SEQ ID NO:
535. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 554 and VL of SEQ ID NO:
555. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 574 and VL of SEQ ID NO:
575. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 594 and VL of SEQ ID NO:
595. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 614 and VL of SEQ ID NO:
615. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 634 and VL of SEQ ID NO:
635. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 654 and VL of SEQ ID NO:
655. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 674 and VL of SEQ ID NO:
675. In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a VH of SEQ ID NO: 694 and VL of SEQ ID NO:
695.
[0156] In another aspect, the present invention provides HER3
antibodies that bind to domain 3 that comprise the heavy chain and
light chain CDR1s, CDR2s and CDR3s as described in Table 1, or
combinations thereof. The amino acid sequences of the VH CDR1s of
the antibodies are shown in SEQ ID NOs: 2, 22, 42, 62, 82, 102,
122, 142, and 162. The amino acid sequences of the VH CDR2s of the
antibodies and are shown in SEQ ID NOs: 3, 23, 43, 63, 83, 103,
123, 143, and 163. The amino acid sequences of the VH CDR3s of the
antibodies are shown in SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124,
144, and 164. The amino acid sequences of the VL CDR1s of the
antibodies are shown in SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128,
148, and 168. The amino acid sequences of the VL CDR2s of the
antibodies are shown in SEQ ID NOs: 9, 29, 49, 69, 89, 109, 129,
149, and 169. The amino acid sequences of the VL CDR3s of the
antibodies are shown in SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130,
150, and 170. The CDR regions are delineated using the Kabat system
(Kabat et al., (1991) Sequences of Proteins of Immunological
Interest, Fifth Edition, U.S. Department of Health and Human
Services, NIH Publication No. 91-3242; Chothia et al., (1987) J.
Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342: 877-883;
and Al-Lazikani et al., (1997) J. Mol. Biol. 273, 927-948).
[0157] In a specific embodiment, an antibody that binds to domain 3
of HER3 comprises a heavy chain variable region CDR1 of SEQ ID NO:
142; a CDR2 of SEQ ID NO: 143; a CDR3 of SEQ ID NO: 144; a light
chain variable region CDR1 of SEQ ID NO: 148; a CDR2 of SEQ ID NO:
149; and a CDR3 of SEQ ID NO: 150.
[0158] In a specific embodiment, an antibody that binds to domain 3
of HER3 comprises a heavy chain variable region CDR1 of SEQ ID NO:
162; a CDR2 of SEQ ID NO: 163; a CDR3 of SEQ ID NO: 164; a light
chain variable region CDR1 of SEQ ID NO: 168; a CDR2 of SEQ ID NO:
169; and a CDR3 of SEQ ID NO: 170.
[0159] In another aspect, the present invention provides HER3
antibodies that bind to domains 3-4 that comprise the heavy chain
and light chain CDR1s, CDR2s and CDR3s as described in Table 2, or
combinations thereof. The amino acid sequences of the VH CDR1s of
the antibodies are shown in SEQ ID NOs: 182, 202, 222, 242, 262,
282, 302, 322, 342, 362, 382, 402, 422, 442, 462, 482, 502, 522,
542, 562, 582, 602, 622, 642, 662, and 682. The amino acid
sequences of the VH CDR2s of the antibodies and are shown in SEQ ID
NOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403,
423, 443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663,
and 683. The amino acid sequences of the VH CDR3s of the antibodies
are shown in SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324,
344, 364, 384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584,
604, 624, 644, 664, and 684. The amino acid sequences of the VL
CDR1s of the antibodies are shown in SEQ ID NOs: 188, 208, 228,
248, 268, 288, 308, 328, 348, 368, 388, 408, 428, 448, 468, 488,
508, 528, 548, 568, 588, 608, 628, 648, 668, and 688. The amino
acid sequences of the VL CDR2s of the antibodies are shown in SEQ
ID NOs: 189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409,
429, 449, 469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669,
and 689. The amino acid sequences of the VL CDR3s of the antibodies
are shown in SEQ ID NOs: 190, 210, 230, 250, 270, 290, 310, 330,
350, 370, 390, 410, 430, 450, 470, 490, 510, 530, 550, 570, 590,
610, 630, 650, 670, and 690. The CDR regions are delineated using
the Kabat system (Kabat et al., (1991) Sequences of Proteins of
Immunological Interest, Fifth Edition, U.S. Department of Health
and Human Services, NIH Publication No. 91-3242; Chothia et al.,
(1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature
342: 877-883; and Al-Lazikani et al., (1997) J. Mol. Biol. 273,
927-948).
[0160] In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a heavy chain variable region CDR1 of SEQ ID
NO: 662; a CDR2 of SEQ ID NO: 663; a CDR3 of SEQ ID NO: 664; a
light chain variable region CDR1 of SEQ ID NO: 668; a CDR2 of SEQ
ID NO: 669; and a CDR3 of SEQ ID NO: 670.
[0161] In a specific embodiment, an antibody that binds to domains
3-4 of HER3 comprises a heavy chain variable region CDR1 of SEQ ID
NO: 682; a CDR2 of SEQ ID NO: 683; a CDR3 of SEQ ID NO: 684; a
light chain variable region CDR1 of SEQ ID NO: 688; a CDR2 of SEQ
ID NO: 689; and a CDR3 of SEQ ID NO: 690.
[0162] Other antibodies of the invention include amino acids that
have been mutated, yet have at least 50%, 60%, 70%, 80%, 90%, 95%,
96%, 97%, 98% or 99% identity in the CDR regions with the CDR
regions depicted in the sequences described in Table 1 or Table 2.
In some embodiments, it includes mutant amino acid sequences
wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated
in the CDR regions when compared with the CDR regions depicted in
the sequence described Table 1 or Table 2, while still maintaining
their specificity for the original antibody's epitope
[0163] Other antibodies of the invention include amino acids that
have been mutated, yet have at least 50%, 60%, 70%, 80%, 90%, 95%,
96%, 97%, 98% or 99% identity in the framework regions with the
framework regions depicted in the sequences described in Table 1 or
Table 2. In some embodiments, it includes mutant amino acid
sequences wherein no more than 1, 2, 3, 4, 5, 6, or 7 amino acids
have been mutated in the framework regions when compared with the
framework regions depicted in the sequence described Table 1 or
Table 2, while still maintaining their specificity for the original
antibody's epitope. The present invention also provides nucleic
acid sequences that encode VH, VL, the full length heavy chain, and
the full length light chain of the antibodies that specifically
bind to a HER3 protein (e.g., human and/or cynomologus HER3).
[0164] Other antibodies of the invention include those where the
amino acids or nucleic acids encoding the amino acids have been
mutated, yet have at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,
98% or 99% identity to the sequences described in Table 1 or Table
2. In some embodiments, it include mutant amino acid sequences
wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated
in the variable regions when compared with the variable regions
depicted in the sequence described in Table 1 or Table 2, while
retaining substantially the same therapeutic activity.
[0165] As used herein, a human antibody comprises heavy or light
chain variable regions or full length heavy or light chains that
are "the product of" or "derived from" a particular germline
sequence if the variable regions or full length chains of the
antibody are obtained from a system that uses human germline
immunoglobulin genes. Such systems include immunizing a transgenic
mouse carrying human immunoglobulin genes with the antigen of
interest or screening a human immunoglobulin gene library displayed
on phage with the antigen of interest. A human antibody that is
"the product of" or "derived from" a human germline immunoglobulin
sequence can be identified as such by comparing the amino acid
sequence of the human antibody to the amino acid sequences of human
germline immunoglobulins and selecting the human germline
immunoglobulin sequence that is closest in sequence (i.e., greatest
% identity) to the sequence of the human antibody. A human antibody
that is "the product of" or "derived from" a particular human
germline immunoglobulin sequence may contain amino acid differences
as compared to the germline sequence, due to, for example,
naturally occurring somatic mutations or intentional introduction
of site-directed mutations. However, in the VH or VL framework
regions, a selected human antibody typically is at least 90%
identical in amino acids sequence to an amino acid sequence encoded
by a human germline immunoglobulin gene and contains amino acid
residues that identify the human antibody as being human when
compared to the germline immunoglobulin amino acid sequences of
other species (e.g., murine germline sequences). In certain cases,
a human antibody may be at least 50%, 60%, 70%, 80%, 90%, 95%, 96%,
97%, 98% or 99% identical in amino acid sequence to the amino acid
sequence encoded by the germline immunoglobulin gene. Typically, a
recombinant human antibody will display no more than 10 amino acid
differences from the amino acid sequence encoded by the human
germline immunoglobulin gene in the VH or VL framework regions. In
certain cases, the human antibody may display no more than 5, or
even no more than 4, 3, 2, or 1 amino acid difference from the
amino acid sequence encoded by the germline immunoglobulin
gene.
[0166] The antibodies disclosed herein can be derivatives of single
chain antibodies, diabodies, domain antibodies, nanobodies, and
unibodies. A "single-chain antibody" (scFv) consists of a single
polypeptide chain comprising a VL domain linked to a VH domain,
wherein VL domain and VH domain are paired to form a monovalent
molecule. Single chain antibody can be prepared according to method
known in the art (see, for example, Bird et al., (1988) Science
242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA
85:5879-5883). A "disbud" consists of two chains, each chain
comprising a heavy chain variable region connected to a light chain
variable region on the same polypeptide chain connected by a short
peptide linker, wherein the two regions on the same chain do not
pair with each other but with complementary domains on the other
chain to form a bispecific molecule. Methods of preparing diabodies
are known in the art (See, e.g., Holliger et al., (1993) Proc.
Natl. Acad. Sci. USA 90:6444-6448, and Poljak et al., (1994)
Structure 2:1121-1123). Domain antibodies (dAbs) are small
functional binding units of antibodies, corresponding to the
variable regions of either the heavy or light chains of antibodies.
Domain antibodies are well expressed in bacterial, yeast, and
mammalian cell systems. Further details of domain antibodies and
methods of production thereof are known in the art (see, for
example, U.S. Pat. Nos. 6,291,158; 6,582,915; 6,593,081; 6,172,197;
6,696,245; European Patents 0368684 & 0616640; WO05/035572,
WO04/101790, WO04/081026, WO04/058821, WO04/003019 and WO03/002609.
Nanobodies are derived from the heavy chains of an antibody. A
nanobody typically comprises a single variable domain and two
constant domains (CH2 and CH3) and retains antigen-binding capacity
of the original antibody. Nanobodies can be prepared by methods
known in the art (See e.g., U.S. Pat. No. 6,765,087, U.S. Pat. No.
6,838,254, WO 06/079372). Unibodies consist of one light chain and
one heavy chain of a IgG4 antibody. Unibodies may be made by the
removal of the hinge region of IgG4 antibodies. Further details of
unibodies and methods of preparing them may be found in
WO2007/059782.
Homologous Antibodies
[0167] In yet another embodiment, the present invention provides an
antibody or fragment thereof comprising amino acid sequences that
are homologous to the sequences described in Table 1 or Table 2,
and said antibody binds to a HER3 protein (e.g., human and/or
cynomologus HER3), and retains the desired functional properties of
those antibodies described in Table 1 or Table 2.
[0168] For example, the invention provides an isolated monoclonal
antibody (or a functional fragment thereof) comprising a heavy
chain variable region and a light chain variable region, wherein
the heavy chain variable region comprises an amino acid sequence
that is at least 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to
an amino acid sequence selected from the group consisting of SEQ ID
NOs: 14, 34, 54, 74, 94, 114, 134, 154, and 174; the light chain
variable region comprises an amino acid sequence that is at least
80%, 90%, 95%, 96%, 97%, 98% or 99% identical to an amino acid
sequence selected from the group consisting of SEQ ID NOs: 15, 35,
55, 75, 95, 115, 135, 155, and 175; wherein the antibody binds to
domain 3 of HER3 (e.g., human and/or cynomologus HER3) and inhibits
the signaling activity of HER3, which can be measured in a
phosphorylation assay or other measure of HER signaling (e.g.,
phospho-HER3 assays, phospho-Akt assays, cell proliferation, and
ligand blocking assays as described in the Examples). Also includes
within the scope of the invention are variable heavy and light
chain parental nucleotide sequences; and full length heavy and
light chain sequences optimized for expression in a mammalian cell.
Other antibodies of the invention include amino acids or nucleic
acids that have been mutated, yet have at least 60, 70, 80, 90, 95,
98, or 99% percent identity to the sequences described above. In
some embodiments, it include mutant amino acid sequences wherein no
more than 1, 2, 3, 4 or 5 amino acids have been mutated by amino
acid deletion, insertion or substitution in the variable regions
when compared with the variable regions depicted in the sequence
described above.
[0169] For example, the invention provides an isolated monoclonal
antibody (or a functional fragment thereof) comprising a heavy
chain variable region and a light chain variable region,
[0170] wherein the heavy chain variable region comprises an amino
acid sequence that is at least 80%, 90%, 95%, 96%, 97%, 98% or 99%
identical to an amino acid sequence selected from the group
consisting of SEQ ID NOs: 194, 214, 234, 254, 274, 294, 314, 334,
354, 374, 394, 414, 434, 454, 474, 494, 514, 534, 554, 574, 594,
614, 634, 654, 674, and 694; the light chain variable region
comprises an amino acid sequence that is at least 80%, 90%, 95%,
96%, 97%, 98% or 99% identical to an amino acid sequence selected
from the group consisting of SEQ ID NOs: 195, 215, 235, 255, 275,
295, 315, 335, 355, 375, 395, 415, 435, 455, 475, 495, 515, 535,
555, 575, 595, 615, 635, 655, 675, and 695; wherein the antibody
binds to domains 3-4 of HER3 (e.g., human and/or cynomologus HER3)
and inhibits the signaling activity of HER3, which can be measured
in a phosphorylation assay or other measure of HER signaling (e.g.,
phospho-HER3 assays, phospho-Akt assays, cell proliferation, and
ligand blocking assays as described in the Examples). Also includes
within the scope of the invention are variable heavy and light
chain parental nucleotide sequences; and full length heavy and
light chain sequences optimized for expression in a mammalian cell.
Other antibodies of the invention include amino acids or nucleic
acids that have been mutated, yet have at least 60, 70, 80, 90, 95,
98, or 99% percent identity to the sequences described above. In
some embodiments, it include mutant amino acid sequences wherein no
more than 1, 2, 3, 4 or 5 amino acids have been mutated by amino
acid deletion, insertion or substitution in the variable regions
when compared with the variable regions depicted in the sequence
described above.
[0171] In other embodiments, the VH and/or VL amino acid sequences
may be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical
to the sequences set forth in Table 1 or Table 2. In other
embodiments, the VH and/or VL amino acid sequences may be identical
except an amino acid substitution in no more than 1, 2, 3, 4 or 5
amino acid position. An antibody having VH and VL regions having
high (i.e., 80% or greater) identity to the VH and VL regions of
the antibodies described in Table 1 or Table 2 can be obtained by
mutagenesis (e.g., site-directed or PCR-mediated mutagenesis),
followed by testing of the encoded altered antibody for retained
function using the functional assays described herein.
[0172] In other embodiments, the variable regions of heavy chain
and/or light chain nucleotide sequences may be 60%, 70%, 80%, 90%,
95%, 96%, 97%, 98% or 99% identical to the sequences set forth
above.
[0173] As used herein, "percent identity" between the two sequences
is a function of the number of identical positions shared by the
sequences (i.e., % identity equals number of identical
positions/total number of positions.times.100), taking into account
the number of gaps, and the length of each gap, which needs to be
introduced for optimal alignment of the two sequences. The
comparison of sequences and determination of percent identity
between two sequences can be accomplished using a mathematical
algorithm, as described in the non-limiting examples below.
[0174] Additionally or alternatively, the protein sequences of the
present invention can further be used as a "query sequence" to
perform a search against public databases to, for example,
identifies related sequences. For example, such searches can be
performed using the BLAST program (version 2.0) of Altschul et al.,
(1990) J. Mol. Biol. 215:403-10.
Antibodies with Conservative Modifications
[0175] In certain embodiments, an antibody of the invention has a
heavy chain variable region comprising CDR1, CDR2, and CDR3
sequences and a light chain variable region comprising CDR1, CDR2,
and CDR3 sequences, wherein one or more of these CDR sequences have
specified amino acid sequences based on the antibodies described
herein or conservative modifications thereof, and wherein the
antibodies retain the desired functional properties of the HER3
antibodies of the invention.
[0176] Accordingly, the invention provides an isolated HER3
monoclonal antibody, or a fragment thereof that bind to domain 3 of
HER3, consisting of a heavy chain variable region comprising CDR1,
CDR2, and CDR3 sequences and a light chain variable region
comprising CDR1, CDR2, and CDR3 sequences, wherein: the heavy chain
variable region CDR1 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 2, 22, 42, 62, 82, 102, 122, 142,
and 162, and conservative modifications thereof; the heavy chain
variable region CDR2 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 3, 23, 43, 63, 83, 103, 123, 143,
and 163 and conservative modifications thereof; the heavy chain
variable region CDR3 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124, 144,
and 164 and conservative modifications thereof; the light chain
variable regions CDR1 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128, 148,
and 168 and conservative modifications thereof; the light chain
variable regions CDR2 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 9, 29, 49, 69, 89, 109, 129, 149,
and 169, and conservative modifications thereof; the light chain
variable regions of CDR3 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130, 150,
and 170, and conservative modifications thereof; the antibody or
fragment thereof specifically binds to HER3, and inhibits HER3
activity by inhibiting a HER3 signaling pathway, which can be
measured in a phosphorylation assay or other measure of HER
signaling (e.g., phospho-HER3 assays, phospho-Akt assays, cell
proliferation, and ligand blocking assays as described in the
Examples).
[0177] Accordingly, the invention provides an isolated HER3
monoclonal antibody, or a fragment thereof that bind to domains 3-4
of HER3, consisting of a heavy chain variable region comprising
CDR1, CDR2, and CDR3 sequences and a light chain variable region
comprising CDR1, CDR2, and CDR3 sequences, wherein: the heavy chain
variable region CDR1 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 182, 202, 222, 242, 262, 282, 302,
322, 342, 362, 382, 402, 422, 442, 462, 482, 502, 522, 542, 562,
582, 602, 622, 642, 662, and 682, and conservative modifications
thereof; the heavy chain variable region CDR2 amino acid sequences
are selected from the group consisting of SEQ ID NOs: 183, 203,
223, 243, 263, 283, 303, 323, 343, 363, 383, 403, 423, 443, 463,
483, 503, 523, 543, 563, 583, 603, 623, 643, 663, and 683 and
conservative modifications thereof; the heavy chain variable region
CDR3 amino acid sequences are selected from the group consisting of
SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324, 344, 364, 384,
404, 424, 444, 464, 484, 504, 524, 544, 564, 584, 604, 624, 644,
664, and 684 and conservative modifications thereof; the light
chain variable regions CDR1 amino acid sequences are selected from
the group consisting of SEQ ID NOs: 188, 208, 228, 248, 268, 288,
308, 328, 348, 368, 388, 408, 428, 448, 468, 488, 508, 528, 548,
568, 588, 608, 628, 648, 668, and 688 and conservative
modifications thereof; the light chain variable regions CDR2 amino
acid sequences are selected from the group consisting of SEQ ID
NOs: 189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409,
429, 449, 469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669,
and 689, and conservative modifications thereof; the light chain
variable regions of CDR3 amino acid sequences are selected from the
group consisting of SEQ ID NOs: 190, 210, 230, 250, 270, 290, 310,
330, 350, 370, 390, 410, 430, 450, 470, 490, 510, 530, 550, 570,
590, 610, 630, 650, 670, and 690, and conservative modifications
thereof; the antibody or fragment thereof specifically binds to
HER3, and inhibits HER3 activity by inhibiting a HER3 signaling
pathway, which can be measured in a phosphorylation assay or other
measure of HER signaling (e.g., phospho-HER3 assays, phospho-Akt
assays, cell proliferation, and ligand blocking assays as described
in the Examples).
Antibodies That Bind to the Same Epitope
[0178] The present invention provides antibodies that interacts
with (e.g., by binding, steric hindrance,
stabilizing/destabilizing, spatial distribution) the same epitope
as do the HER3 antibodies described in Table 1 or Table 2.
Additional antibodies can therefore be identified based on their
ability to cross-compete (e.g., to competitively inhibit the
binding of, in a statistically significant manner) with other
antibodies of the invention in HER3 binding assays. The ability of
a test antibody to inhibit the binding of antibodies of the present
invention to a HER3 protein (e.g., human and/or cynomologus HER3)
demonstrates that the test antibody can compete with that antibody
for binding to HER3; such an antibody may, according to
non-limiting theory, bind to the same or a related (e.g., a
structurally similar or spatially proximal) epitope on the HER3
protein as the antibody with which it competes. In a certain
embodiment, the antibody that binds to the same epitope on HER3 as
the antibodies of the present invention is a human monoclonal
antibody. Such human monoclonal antibodies can be prepared and
isolated as described herein.
[0179] In one embodiment, the antibody or fragments thereof binds
to domain 3 of HER3 and inhibits both ligand dependent and
ligand-independent HER3 signal transduction. In one embodiment, the
antibody or fragments thereof bind to domains 3-4 of HER3 and
inhibits both ligand dependent and ligand-independent HER3 signal
transduction.
[0180] The antibodies of the invention or fragments thereof inhibit
both ligand dependent and independent activation of HER3 without
preventing ligand binding. This is considered advantageous for the
following reasons:
[0181] (i) The therapeutic antibody would have clinical utility in
a broad spectrum of tumors than an antibody which targeted a single
mechanism of HER3 activation (i.e. ligand dependent or ligand
independent) since distinct tumor types are driven by each
mechanism.
[0182] (ii) The therapeutic antibody would be efficacious in tumor
types where both mechanisms of HER3 activation are simultaneously
involved. An antibody targeting a single mechanism of HER3
activation (i.e. ligand dependent or ligand independent) would
display little or no efficacy in these tumor types
[0183] (iii) The efficacy of an antibody which inhibits ligand
dependent activation of HER3 without preventing ligand binding
would be less likely to be adversely affected by increasing
concentrations of ligand. This would translate to either increased
efficacy in a tumor type driven by very high concentrations of HER3
ligand or a reduced drug resistance liability where resistance is
mediated by up-regulation of HER3 ligands.
[0184] (iv) An antibody which inhibits HER3 activation by
stabilizing the inactive form would be less prone to drug
resistance driven by alternative mechanisms of HER3 activation.
[0185] Consequently, the antibodies of the invention may be used to
treat conditions where existing therapeutic antibodies are
clinically ineffective.
Engineered and Modified Antibodies
[0186] An antibody of the invention further can be prepared using
an antibody having one or more of the VH and/or VL sequences shown
herein as starting material to engineer a modified antibody, which
modified antibody may have altered properties from the starting
antibody. An antibody can be engineered by modifying one or more
residues within one or both variable regions (i.e., VH and/or VL),
for example within one or more CDR regions and/or within one or
more framework regions. Additionally or alternatively, an antibody
can be engineered by modifying residues within the constant
region(s), for example to alter the effector function(s) of the
antibody.
[0187] One type of variable region engineering that can be
performed is CDR grafting. Antibodies interact with target antigens
predominantly through amino acid residues that are located in the
six heavy and light chain complementarity determining regions
(CDRs). For this reason, the amino acid sequences within CDRs are
more diverse between individual antibodies than sequences outside
of CDRs. Because CDR sequences are responsible for most
antibody-antigen interactions, it is possible to express
recombinant antibodies that mimic the properties of specific
naturally occurring antibodies by constructing expression vectors
that include CDR sequences from the specific naturally occurring
antibody grafted onto framework sequences from a different antibody
with different properties (see, e.g., Riechmann et al., (1998)
Nature 332:323-327; Jones et al., (1986) Nature 321:522-525; Queen
et al., (1989) Proc. Natl. Acad., U.S.A. 86:10029-10033; U.S. Pat.
No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089;
5,693,762 and 6,180,370 to Queen et al.)
[0188] Accordingly, another embodiment of the invention pertains to
an isolated HER3 monoclonal antibody, or fragment thereof that
binds to domain 3 of HER3, comprising a heavy chain variable region
comprising CDR1 sequences having an amino acid sequence selected
from the group consisting of SEQ ID NOs: 2, 22, 42, 62, 82, 102,
122, 142, and 162; CDR2 sequences having an amino acid sequence
selected from the group consisting of SEQ ID NOs: 33, 23, 43, 63,
83, 103, 123, 143, and 163; CDR3 sequences having an amino acid
sequence selected from the group consisting of SEQ ID NOs: 4, 24,
44, 64, 84, 104, 124, 144, and 164, respectively; and a light chain
variable region having CDR1 sequences having an amino acid sequence
selected from the group consisting of SEQ ID NOs: 8, 28, 48, 68,
88, 108, 128, 148, and 168; CDR2 sequences having an amino acid
sequence selected from the group consisting of SEQ ID NOs: 9, 29,
49, 69, 89, 109, 129, 149, and 169; and CDR3 sequences consisting
of an amino acid sequence selected from the group consisting of SEQ
ID NOs: 10, 30, 50, 70, 90, 110, 130, 150, and 170,
respectively.
[0189] Accordingly, another embodiment of the invention pertains to
an isolated HER3 monoclonal antibody, or fragment thereof that bind
to domains 3-4 of HER3, comprising a heavy chain variable region
comprising CDR1 sequences having an amino acid sequence selected
from the group consisting of SEQ ID NOs: 182, 202, 222, 242, 262,
282, 302, 322, 342, 362, 382, 402, 422, 442, 462, 482, 502, 522,
542, 562, 582, 602, 622, 642, 662, and 682; CDR2 sequences having
an amino acid sequence selected from the group consisting of SEQ ID
NOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403,
423, 443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663,
and 683; CDR3 sequences having an amino acid sequence selected from
the group consisting of SEQ ID NOs: 184, 204, 224, 244, 264, 284,
304, 324, 344, 364, 384, 404, 424, 444, 464, 484, 504, 524, 544,
564, 584, 604, 624, 644, 664, and 684, respectively; and a light
chain variable region having CDR1 sequences having an amino acid
sequence selected from the group consisting of SEQ ID NOs: 188,
208, 228, 248, 268, 288, 308, 328, 348, 368, 388, 408, 428, 448,
468, 488, 508, 528, 548, 568, 588, 608, 628, 648, 668, and 688;
CDR2 sequences having an amino acid sequence selected from the
group consisting of SEQ ID NOs: 189, 209, 229, 249, 269, 289, 309,
329, 349, 369, 389, 409, 429, 449, 469, 489, 509, 529, 549, 569,
589, 609, 629, 649, 669, and 689; and CDR3 sequences consisting of
an amino acid sequence selected from the group consisting of SEQ ID
NOs: 190, 210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410,
430, 450, 470, 490, 510, 530, 550, 570, 590, 610, 630, 650, 670,
and 690, respectively.
[0190] Such antibodies contain the VH and VL CDR sequences of
monoclonal antibodies, yet may contain different framework
sequences from these antibodies. Such framework sequences can be
obtained from public DNA databases or published references that
include germline antibody gene sequences. For example, germline DNA
sequences for human heavy and light chain variable region genes can
be found in the "Vbase" human germline sequence database (available
on the Internet at www.mrc-cpe.cam.ac.uk/vbase), as well as in
Kabat et al., (1991) Sequences of Proteins of Immunological
Interest, Fifth Edition, U.S. Department of Health and Human
Services, NIH Publication No. 91-3242; Chothia et al., (1987) J.
Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 342:877-883;
and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948; Tomlinson
et al., (1992) J. fol. Biol. 227:776-798; and Cox et al., (1994)
Eur. J. Immunol. 24:827-836; the contents of each of which are
expressly incorporated herein by reference.
[0191] An example of framework sequences for use in the antibodies
of the invention are those that are structurally similar to the
framework sequences used by selected antibodies of the invention,
e.g., consensus sequences and/or framework sequences used by
monoclonal antibodies of the invention. The VH CDR1, 2 and 3
sequences, and the VL CDR1, 2 and 3 sequences, can be grafted onto
framework regions that have the identical sequence as that found in
the germline immunoglobulin gene from which the framework sequence
derive, or the CDR sequences can be grafted onto framework regions
that contain one or more mutations as compared to the germline
sequences. For example, it has been found that in certain instances
it is beneficial to mutate residues within the framework regions to
maintain or enhance the antigen binding ability of the antibody
(see e.g., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and
6,180,370 to Queen et al).
[0192] Another type of variable region modification is to mutate
amino acid residues within the VH and/or VL CDR1, CDR2 and/or CDR3
regions to thereby improve one or more binding properties (e.g.,
affinity) of the antibody of interest, known as "affinity
maturation." Site-directed mutagenesis or PCR-mediated mutagenesis
can be performed to introduce the mutation(s) and the effect on
antibody binding, or other functional property of interest, can be
evaluated in in vitro or in vivo assays as described herein and
provided in the Examples. Conservative modifications (as discussed
above) can be introduced. The mutations may be amino acid
substitutions, additions or deletions. Moreover, typically no more
than one, two, three, four or five residues within a CDR region are
altered.
[0193] Accordingly, in another embodiment, the invention provides
isolated HER3 monoclonal antibodies, or fragment thereof that bind
to domain 3 of HER3, consisting of a heavy chain variable region
having: a VH CDR1 region consisting of an amino acid sequence
selected from the group having SEQ ID NOs: 22, 22, 42, 62, 82, 102,
122, 142, and 162 or an amino acid sequence having one, two, three,
four or five amino acid substitutions, deletions or additions as
compared to SEQ ID NOs: 2, 22, 42, 62, 82, 102, 122, 142, and 162;
a VH CDR2 region having an amino acid sequence selected from the
group consisting of SEQ ID NOs: 3, 23, 43, 63, 83, 103, 123, 143,
and 163 or an amino acid sequence having one, two, three, four or
five amino acid substitutions, deletions or additions as compared
to SEQ ID NOs: 3, 23, 43, 63, 83, 103, 123, 143, and 163; a VH CDR3
region having an amino acid sequence selected from the group
consisting of SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124, 144, and
164, or an amino acid sequence having one, two, three, four or five
amino acid substitutions, deletions or additions as compared to SEQ
ID NOs: 4, 24, 44, 64, 84, 104, 124, 144, and 164, and 370; a VL
CDR1 region having an amino acid sequence selected from the group
consisting of SEQ ID NOs: 8, 28, 48, 68, 88, 108, 128, 148, and
168, or an amino acid sequence having one, two, three, four or five
amino acid substitutions, deletions or additions as compared to SEQ
ID NOs: 8, 28, 48, 68, 88, 108, 128, 148, and 168; a VL CDR2 region
having an amino acid sequence selected from the group consisting of
SEQ ID NOs: 9, 29, 49, 69, 89, 109, 129, 149, and 169, or an amino
acid sequence having one, two, three, four or five amino acid
substitutions, deletions or additions as compared to SEQ ID NOs: 9,
29, 49, 69, 89, 109, 129, 149, and 169; and a VL CDR3 region having
an amino acid sequence selected from the group consisting of SEQ ID
NOs: 10, 30, 50, 70, 90, 110, 130, 150, and 170, and 373, or an
amino acid sequence having one, two, three, four or five amino acid
substitutions, deletions or additions as compared to SEQ ID NOs:
10, 30, 50, 70, 90, 110, 130, 150, and 170.
[0194] Accordingly, in another embodiment, the invention provides
isolated HER3 monoclonal antibodies, or fragment thereof bind to
domains 3-4 of HER3, consisting of a heavy chain variable region
having: a VH CDR1 region consisting of an amino acid sequence
selected from the group having SEQ ID NOs: 182, 202, 222, 242, 262,
282, 302, 322, 342, 362, 382, 402, 422, 442, 462, 482, 502, 522,
542, 562, 582, 602, 622, 642, 662, and 682 or an amino acid
sequence having one, two, three, four or five amino acid
substitutions, deletions or additions as compared to SEQ ID NOs:
182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402, 422,
442, 462, 482, 502, 522, 542, 562, 582, 602, 622, 642, 662, and
682; a VH CDR2 region having an amino acid sequence selected from
the group consisting of SEQ ID NOs: 183, 203, 223, 243, 263, 283,
303, 323, 343, 363, 383, 403, 423, 443, 463, 483, 503, 523, 543,
563, 583, 603, 623, 643, 663, and 683 or an amino acid sequence
having one, two, three, four or five amino acid substitutions,
deletions or additions as compared to SEQ ID NOs: 183, 203, 223,
243, 263, 283, 303, 323, 343, 363, 383, 403, 423, 443, 463, 483,
503, 523, 543, 563, 583, 603, 623, 643, 663, and 683; a VH CDR3
region having an amino acid sequence selected from the group
consisting of SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324,
344, 364, 384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584,
604, 624, 644, 664, and 684, or an amino acid sequence having one,
two, three, four or five amino acid substitutions, deletions or
additions as compared to SEQ ID NOs: 184, 204, 224, 244, 264, 284,
304, 324, 344, 364, 384, 404, 424, 444, 464, 484, 504, 524, 544,
564, 584, 604, 624, 644, 664, and 684; a VL CDR1 region having an
amino acid sequence selected from the group consisting of SEQ ID
NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348, 368, 388, 408,
428, 448, 468, 488, 508, 528, 548, 568, 588, 608, 628, 648, 668,
and 688, or an amino acid sequence having one, two, three, four or
five amino acid substitutions, deletions or additions as compared
to SEQ ID NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348, 368,
388, 408, 428, 448, 468, 488, 508, 528, 548, 568, 588, 608, 628,
648, 668, and 688; a VL CDR2 region having an amino acid sequence
selected from the group consisting of SEQ ID NOs: 189, 209, 229,
249, 269, 289, 309, 329, 349, 369, 389, 409, 429, 449, 469, 489,
509, 529, 549, 569, 589, 609, 629, 649, 669, and 689, or an amino
acid sequence having one, two, three, four or five amino acid
substitutions, deletions or additions as compared to SEQ ID NOs:
189, 209, 229, 249, 269, 289, 309, 329, 349, 369, 389, 409, 429,
449, 469, 489, 509, 529, 549, 569, 589, 609, 629, 649, 669, and
689; and a VL CDR3 region having an amino acid sequence selected
from the group consisting of SEQ ID NOs: 190, 210, 230, 250, 270,
290, 310, 330, 350, 370, 390, 410, 430, 450, 470, 490, 510, 530,
550, 570, 590, 610, 630, 650, 670, and 690, or an amino acid
sequence having one, two, three, four or five amino acid
substitutions, deletions or additions as compared to SEQ ID NOs:
190, 210, 230, 250, 270, 290, 310, 330, 350, 370, 390, 410, 430,
450, 470, 490, 510, 530, 550, 570, 590, 610, 630, 650, 670, and
690.
Grafting Antibody Fragments Into Alternative Frameworks or
Scaffolds
[0195] A wide variety of antibody/immunoglobulin frameworks or
scaffolds can be employed so long as the resulting polypeptide
includes at least one binding region which specifically binds to
HER3. Such frameworks or scaffolds include the 5 main idiotypes of
human immunoglobulins, or fragments thereof, and include
immunoglobulins of other animal species, preferably having
humanized aspects. Novel frameworks, scaffolds and fragments
continue to be discovered and developed by those skilled in the
art.
[0196] In one aspect, the invention pertains to generating
non-immunoglobulin based antibodies using non-immunoglobulin
scaffolds onto which CDRs of the invention can be grafted. Known or
future non-immunoglobulin frameworks and scaffolds may be employed,
as long as they comprise a binding region specific for the target
HER3 protein (e.g., human and/or cynomologus HER3). Known
non-immunoglobulin frameworks or scaffolds include, but are not
limited to, fibronectin (Compound Therapeutics, Inc., Waltham,
Mass.), ankyrin (Molecular Partners AG, Zurich, Switzerland),
domain antibodies (Domantis, Ltd., Cambridge, Mass., and Ablynx nv,
Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising,
Germany), small modular immuno-pharmaceuticals (Trubion
Pharmaceuticals Inc., Seattle, Wash.), maxybodies (Avidia, Inc.,
Mountain View, Calif.), Protein A (Affibody AG, Sweden), and
affilin (gamma-crystallin or ubiquitin) (Scil Proteins GmbH, Halle,
Germany).
[0197] The fibronectin scaffolds are based on fibronectin type III
domain (e.g., the tenth module of the fibronectin type III (.sup.10
Fn3 domain)). The fibronectin type III domain has 7 or 8 beta
strands which are distributed between two beta sheets, which
themselves pack against each other to form the core of the protein,
and further containing loops (analogous to CDRs) which connect the
beta strands to each other and are solvent exposed. There are at
least three such loops at each edge of the beta sheet sandwich,
where the edge is the boundary of the protein perpendicular to the
direction of the beta strands (see U.S. Pat. No. 6,818,418). These
fibronectin-based scaffolds are not an immunoglobulin, although the
overall fold is closely related to that of the smallest functional
antibody fragment, the variable region of the heavy chain, which
comprises the entire antigen recognition unit in camel and llama
IgG. Because of this structure, the non-immunoglobulin antibody
mimics antigen binding properties that are similar in nature and
affinity to those of antibodies. These scaffolds can be used in a
loop randomization and shuffling strategy in vitro that is similar
to the process of affinity maturation of antibodies in vivo. These
fibronectin-based molecules can be used as scaffolds where the loop
regions of the molecule can be replaced with CDRs of the invention
using standard cloning techniques.
[0198] The ankyrin technology is based on using proteins with
ankyrin derived repeat modules as scaffolds for bearing variable
regions which can be used for binding to different targets. The
ankyrin repeat module is a 33 amino acid polypeptide consisting of
two anti-parallel .alpha.-helices and a .beta.-turn. Binding of the
variable regions is mostly optimized by using ribosome display.
[0199] Avimers are derived from natural A-domain containing protein
such as HER3. These domains are used by nature for protein-protein
interactions and in human over 250 proteins are structurally based
on A-domains. Avimers consist of a number of different "A-domain"
monomers (2-10) linked via amino acid linkers. Avimers can be
created that can bind to the target antigen using the methodology
described in, for example, U.S. Patent Application Publication Nos.
20040175756; 20050053973; 20050048512; and 20060008844.
[0200] Affibody affinity ligands are small, simple proteins
composed of a three-helix bundle based on the scaffold of one of
the IgG-binding domains of Protein A. Protein A is a surface
protein from the bacterium Staphylococcus aureus. This scaffold
domain consists of 58 amino acids, 13 of which are randomized to
generate affibody libraries with a large number of ligand variants
(See e.g., U.S. Pat. No. 5,831,012). Affibody molecules mimic
antibodies, they have a molecular weight of 6 kDa, compared to the
molecular weight of antibodies, which is 150 kDa. In spite of its
small size, the binding site of affibody molecules is similar to
that of an antibody.
[0201] Anticalins are products developed by the company Pieris
ProteoLab AG. They are derived from lipocalins, a widespread group
of small and robust proteins that are usually involved in the
physiological transport or storage of chemically sensitive or
insoluble compounds. Several natural lipocalins occur in human
tissues or body liquids. The protein architecture is reminiscent of
immunoglobulins, with hypervariable loops on top of a rigid
framework. However, in contrast with antibodies or their
recombinant fragments, lipocalins are composed of a single
polypeptide chain with 160 to 180 amino acid residues, being just
marginally bigger than a single immunoglobulin domain. The set of
four loops, which makes up the binding pocket, shows pronounced
structural plasticity and tolerates a variety of side chains. The
binding site can thus be reshaped in a proprietary process in order
to recognize prescribed target molecules of different shape with
high affinity and specificity. One protein of lipocalin family, the
bilin-binding protein (BBP) of Pieris Brassicae has been used to
develop anticalins by mutagenizing the set of four loops. One
example of a patent application describing anticalins is in PCT
Publication No. WO 199916873.
[0202] Affilin molecules are small non-immunoglobulin proteins
which are designed for specific affinities towards proteins and
small molecules. New affilin molecules can be very quickly selected
from two libraries, each of which is based on a different human
derived scaffold protein. Affilin molecules do not show any
structural homology to immunoglobulin proteins. Currently, two
affilin scaffolds are employed, one of which is gamma crystalline,
a human structural eye lens protein and the other is "ubiquitin"
superfamily proteins. Both human scaffolds are very small, show
high temperature stability and are almost resistant to pH changes
and denaturing agents. This high stability is mainly due to the
expanded beta sheet structure of the proteins. Examples of gamma
crystalline derived proteins are described in WO200104144 and
examples of "ubiquitin-like" proteins are described in
WO2004106368.
[0203] Protein epitope mimetics (PEM) are medium-sized, cyclic,
peptide-like molecules (MW 1-2 kDa) mimicking beta-hairpin
secondary structures of proteins, the major secondary structure
involved in protein-protein interactions.
[0204] In some embodiments, the Fabs are converted to silent IgG1
format by changing the Fc region. For example, antibodies in Table
1 or Table 2 can be converted to IgG format.
Human or Humanized Antibodies
[0205] The present invention provides fully human antibodies that
specifically bind to a HER3 protein (e.g., human and/or
cynomologus/mouse/rat HER3). Compared to the chimeric or humanized
antibodies, the human HER3 antibodies or fragments thereof, have
further reduced antigenicity when administered to human
subjects.
[0206] Human HER3 antibodies or fragments thereof can be generated
using methods that are known in the art. For example, the
humaneering technology used to converting non-human antibodies into
engineered human antibodies. U.S. Patent Publication No.
20050008625 describes an in vivo method for replacing a nonhuman
antibody variable region with a human variable region in an
antibody while maintaining the same or providing better binding
characteristics relative to that of the nonhuman antibody. The
method relies on epitope guided replacement of variable regions of
a non-human reference antibody with a fully human antibody. The
resulting human antibody is generally unrelated structurally to the
reference nonhuman antibody, but binds to the same epitope on the
same antigen as the reference antibody. Briefly, the serial
epitope-guided complementarity replacement approach is enabled by
setting up a competition in cells between a "competitor" and a
library of diverse hybrids of the reference antibody ("test
antibodies") for binding to limiting amounts of antigen in the
presence of a reporter system which responds to the binding of test
antibody to antigen. The competitor can be the reference antibody
or derivative thereof such as a single-chain Fv fragment. The
competitor can also be a natural or artificial ligand of the
antigen which binds to the same epitope as the reference antibody.
The only requirements of the competitor are that it binds to the
same epitope as the reference antibody, and that it competes with
the reference antibody for antigen binding. The test antibodies
have one antigen-binding V-region in common from the nonhuman
reference antibody, and the other V-region selected at random from
a diverse source such as a repertoire library of human antibodies.
The common V-region from the reference antibody serves as a guide,
positioning the test antibodies on the same epitope on the antigen,
and in the same orientation, so that selection is biased toward the
highest antigen-binding fidelity to the reference antibody.
[0207] Many types of reporter system can be used to detect desired
interactions between test antibodies and antigen. For example,
complementing reporter fragments may be linked to antigen and test
antibody, respectively, so that reporter activation by fragment
complementation only occurs when the test antibody binds to the
antigen. When the test antibody- and antigen-reporter fragment
fusions are co-expressed with a competitor, reporter activation
becomes dependent on the ability of the test antibody to compete
with the competitor, which is proportional to the affinity of the
test antibody for the antigen. Other reporter systems that can be
used include the reactivator of an auto-inhibited reporter
reactivation system (RAIR) as disclosed in U.S. patent application
Ser. No. 10/208,730 (Publication No. 20030198971), or competitive
activation system disclosed in U.S. patent application Ser. No.
10/076,845 (Publication No. 20030157579).
[0208] With the serial epitope-guided complementarity replacement
system, selection is made to identify cells expresses a single test
antibody along with the competitor, antigen, and reporter
components. In these cells, each test antibody competes one-on-one
with the competitor for binding to a limiting amount of antigen.
Activity of the reporter is proportional to the amount of antigen
bound to the test antibody, which in turn is proportional to the
affinity of the test antibody for the antigen and the stability of
the test antibody. Test antibodies are initially selected on the
basis of their activity relative to that of the reference antibody
when expressed as the test antibody. The result of the first round
of selection is a set of "hybrid" antibodies, each of which is
comprised of the same non-human V-region from the reference
antibody and a human V-region from the library, and each of which
binds to the same epitope on the antigen as the reference antibody.
One of more of the hybrid antibodies selected in the first round
will have an affinity for the antigen comparable to or higher than
that of the reference antibody.
[0209] In the second V-region replacement step, the human V-regions
selected in the first step are used as guide for the selection of
human replacements for the remaining non-human reference antibody
V-region with a diverse library of cognate human V-regions. The
hybrid antibodies selected in the first round may also be used as
competitors for the second round of selection. The result of the
second round of selection is a set of fully human antibodies which
differ structurally from the reference antibody, but which compete
with the reference antibody for binding to the same antigen. Some
of the selected human antibodies bind to the same epitope on the
same antigen as the reference antibody. Among these selected human
antibodies, one or more binds to the same epitope with an affinity
which is comparable to or higher than that of the reference
antibody.
[0210] Using one of the mouse or chimeric HER3 antibodies or
fragments thereof described above as the reference antibody, this
method can be readily employed to generate human antibodies that
bind to human HER3 with the same binding specificity and the same
or better binding affinity. In addition, such human HER3 antibodies
or fragments thereof can also be commercially obtained from
companies which customarily produce human antibodies, e.g.,
KaloBios, Inc. (Mountain View, Calif.).
Camelid Antibodies
[0211] Antibody proteins obtained from members of the camel and
dromedary (Camelus bactrianus and Calelus dromaderius) family
including new world members such as llama species (Lama paccos,
Lama glama and Lama vicugna) have been characterized with respect
to size, structural complexity and antigenicity for human subjects.
Certain IgG antibodies from this family of mammals as found in
nature lack light chains, and are thus structurally distinct from
the typical four chain quaternary structure having two heavy and
two light chains, for antibodies from other animals. See
PCT/EP93/02214 (WO 94/04678 published 3 Mar. 1994).
[0212] A region of the camelid antibody which is the small single
variable domain identified as VHH can be obtained by genetic
engineering to yield a small protein having high affinity for a
target, resulting in a low molecular weight antibody-derived
protein known as a "camelid nanobody". See U.S. Pat. No. 5,759,808
issued Jun. 2, 1998; see also Stijlemans et al., (2004) J Biol Chem
279:1256-1261; Dumoulin et al., (2003) Nature 424:783-788;
Pleschberger et al., (2003) Bioconjugate Chem 14:440-448;
Cortez-Retamozo et al., (2002) Int J Cancer 89:456-62; and
Lauwereys et al., (1998) EMBO J. 17:3512-3520. Engineered libraries
of camelid antibodies and antibody fragments are commercially
available, for example, from Ablynx, Ghent, Belgium. (e.g.,
US20060115470; Domantis (US20070065440, US20090148434). As with
other antibodies of non-human origin, an amino acid sequence of a
camelid antibody can be altered recombinantly to obtain a sequence
that more closely resembles a human sequence, i.e., the nanobody
can be "humanized". Thus the natural low antigenicity of camelid
antibodies to humans can be further reduced.
[0213] The camelid nanobody has a molecular weight approximately
one-tenth that of a human IgG molecule, and the protein has a
physical diameter of only a few nanometers. One consequence of the
small size is the ability of camelid nanobodies to bind to
antigenic sites that are functionally invisible to larger antibody
proteins, i.e., camelid nanobodies are useful as reagents detect
antigens that are otherwise cryptic using classical immunological
techniques, and as possible therapeutic agents. Thus yet another
consequence of small size is that a camelid nanobody can inhibit as
a result of binding to a specific site in a groove or narrow cleft
of a target protein, and hence can serve in a capacity that more
closely resembles the function of a classical low molecular weight
drug than that of a classical antibody.
[0214] The low molecular weight and compact size further result in
camelid nanobodies being extremely thermostable, stable to extreme
pH and to proteolytic digestion, and poorly antigenic. Another
consequence is that camelid nanobodies readily move from the
circulatory system into tissues, and even cross the blood-brain
barrier and can treat disorders that affect nervous tissue.
Nanobodies can further facilitated drug transport across the blood
brain barrier. See U.S. patent application 20040161738 published
Aug. 19, 2004. These features combined with the low antigenicity to
humans indicate great therapeutic potential. Further, these
molecules can be fully expressed in prokaryotic cells such as E.
coli and are expressed as fusion proteins with bacteriophage and
are functional.
[0215] Accordingly, a feature of the present invention is a camelid
antibody or nanobody having high affinity for HER3. In certain
embodiments herein, the camelid antibody or nanobody is naturally
produced in the camelid animal, i.e., is produced by the camelid
following immunization with HER3 or a peptide fragment thereof,
using techniques described herein for other antibodies.
Alternatively, the HER3-binding camelid nanobody is engineered,
i.e., produced by selection for example from a library of phage
displaying appropriately mutagenized camelid nanobody proteins
using panning procedures with HER3 as a target as described in the
examples herein. Engineered nanobodies can further be customized by
genetic engineering to have a half life in a recipient subject of
from 45 minutes to two weeks. In a specific embodiment, the camelid
antibody or nanobody is obtained by grafting the CDRs sequences of
the heavy or light chain of the human antibodies of the invention
into nanobody or single domain antibody framework sequences, as
described for example in PCT/EP93/02214. In one embodiment, the
camelid antibody or nanobody binds to at least amino acids residue
in domain 3 of HER3 selected from amino acid residues: 335-342,
362-376, 398, 400, 424-428, 431, 433-434 and 455 (within domain 3),
or a subset thereof. In one embodiment, the camelid antibody or
nanobody binds to at least amino acids residue in domain 3 of HER3
selected from amino acid residues: 571, 582-584, 596-597, 600-602,
609-615 (of domain 4), or a subset thereof.
Bispecific Molecules and Multivalent Antibodies
[0216] In another aspect, the present invention features
biparatopic, bispecific or multispecific molecules comprising an
antibody or a fragment thereof that binds to a non-linear or
conformational epitope within domain 3 of HER3. In another aspect,
the biparatopic, bispecific or multispecific molecules comprise an
antibody or a fragment thereof that binds to an epitope within
domain 4 of HER3. The antibody or fragment thereof can be
derivatized or linked to another functional molecule, e.g., another
peptide or protein (e.g., another antibody or ligand for a
receptor) to generate a bispecific molecule that binds to at least
two different binding sites or target molecules. The antibody or
fragment thereof may in fact be derivatized or linked to more than
one other functional molecule to generate biparatopic or
multi-specific molecules that bind to more than two different
binding sites and/or target molecules; such biparatopic or
multi-specific molecules. To create a bispecific molecule, an
antibody or fragment thereof can be functionally linked (e.g., by
chemical coupling, genetic fusion, non-covalent association or
otherwise) to one or more other binding molecules, such as another
antibody, antibody fragment, peptide or binding mimetic, such that
a bispecific molecule results.
[0217] Further clinical benefits may be provided by the binding of
two or more antigens within one antibody (Coloma et al., (1997);
Merchant et al., (1998); Alt et al., (1999); Zuo et al., (2000); Lu
et al., (2004); Lu et al., (2005); Marvin et al., (2005); Marvin et
al., (2006); Shen et al., (2007); Wu et al., (2007); Dimasi et al.,
(2009); Michaelson et al., (2009)). (Morrison et al., (1997) Nature
Biotech. 15:159-163; Alt et al. (1999) FEBS Letters 454:90-94; Zuo
et al., (2000) Protein Engineering 13:361-367; Lu et al., (2004)
JBC 279:2856-2865; Lu et al., (2005) JBC 280:19665-19672; Marvin et
al., (2005) Acta Pharmacologica Sinica 26:649-658; Marvin et al.,
(2006) Curr Opin Drug Disc Develop 9:184-193; Shen et al., (2007) J
Immun Methods 218:65-74; Wu et al., (2007) Nat. Biotechnol.
11:1290-1297; Dimasi et al., (2009) J Mol. Biol. 393:672-692; and
Michaelson et al., (2009) mAbs 1:128-141.
[0218] The bispecific molecules can be prepared by conjugating the
constituent binding specificities, using methods known in the art.
For example, each binding specificity of the bispecific molecule
can be generated separately and then conjugated to one another, for
example, a variety of coupling or cross-linking agents can be used
for covalent conjugation. Examples of cross-linking agents include
protein A, carbodiimide, N-succinimidyl-5-acetyl-thioacetate
(SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB),
o-phenylenedimaleimide (oPDM),
N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and
sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohaxane-1-carboxylate
(sulfo-SMCC) (see e.g., Karpovsky et al., (1984) J. Exp. Med.
160:1686; Liu et al., (1985) Proc. Natl. Acad. Sci. USA 82:8648).
Other methods include those described in Paulus (1985) Behring Ins.
Mitt. No. 78:118-132; Brennan et al., (1985) Science 229:81-83),
and Glennie et al., (1987) J. Immunol. 139: 2367-2375). Conjugating
agents are SATA and sulfo-SMCC, both available from Pierce Chemical
Co. (Rockford, Ill.).
[0219] With antibodies, they can be conjugated by sulfhydryl
bonding of the C-terminus hinge regions of the two heavy chains. In
a particularly embodiment, the hinge region is modified to contain
an odd number of sulfhydryl residues, for example one, prior to
conjugation.
[0220] Alternatively, both binding specificities can be encoded in
the same vector and expressed and assembled in the same host cell.
This method is particularly useful where the bispecific molecule is
a mAb.times.mAb, mAb.times.Fab, Fab.times.F(ab').sub.2 or ligand x
Fab fusion protein. A bispecific molecule of the invention can be a
single chain molecule comprising one single chain antibody and a
binding determinant, or a single chain bispecific molecule
comprising two binding determinants. Bispecific molecules may
comprise at least two single chain molecules. Methods for preparing
bispecific molecules are described for example in U.S. Pat. No.
5,260,203; U.S. Pat. No. 5,455,030; U.S. Pat. No. 4,881,175; U.S.
Pat. No. 5,132,405; U.S. Pat. No. 5,091,513; U.S. Pat. No.
5,476,786; U.S. Pat. No. 5,013,653; U.S. Pat. No. 5,258,498; and
U.S. Pat. No. 5,482,858.
[0221] Binding of the bispecific molecules to their specific
targets can be confirmed by, for example, enzyme-linked
immunosorbent assay (ELISA), radioimmunoassay (REA), FACS analysis,
bioassay (e.g., growth inhibition), or Western Blot assay. Each of
these assays generally detects the presence of protein-antibody
complexes of particular interest by employing a labeled reagent
(e.g., an antibody) specific for the complex of interest.
[0222] In another aspect, the present invention provides
multivalent compounds comprising at least two identical or
different fragments of the antibodies binding to HER3. The antibody
fragments can be linked together via protein fusion or covalent or
non covalent linkage. Tetravalent compounds can be obtained for
example by cross-linking antibodies of the antibodies of the
invention with an antibody that binds to the constant regions of
the antibodies of the invention, for example the Fc or hinge
region. Trimerizing domain are described for example in Borean
patent EP 1012280B1. Pentamerizing modules are described for
example in PCT/EP97/05897.
[0223] In one embodiment, the biparatopic/bispecific antibody binds
to at least amino acids residue in domain 3 of HER3 selected from
amino acid residues: 335-342, 362-376, 398, 400, 424-428, 431,
433-434 and 455 (within domain 3), or a subset thereof. In one
embodiment, the biparatopic/bispecific antibody binds to at least
amino acids residue in domain 3 of HER3 selected from amino acid
residues: 571, 582-584, 596-597, 600-602, 609-615 (of domain 4), or
a subset thereof.
[0224] In another embodiment, the invention pertains to dual
function antibodies in which a single monoclonal antibody has been
modified such that the antigen binding site binds to more than one
antigen, such as a dual function antibody which binds both HER3 and
another antigen (e.g., HER1, HER2, and HER4). In another
embodiment, the invention pertains to a dual function antibody that
targets antigens having the same conformation, for example an
antigen that has the same conformation of HER3 in the "closed" or
"inactive" state. Examples of antigens with the same conformation
of HER3 in the "closed" or "inactive" state include, but are not
limited to, HER1 and HER4. Thus, a dual function antibody may bind
to both HER3 and HER1; HER3 and HER4, or HER1 and HER4. The dual
binding specificity of the dual function antibody may further
translate into dual activity, or inhibition of activity. (See e.g.,
Jenny Bostrom et al., (2009) Science: 323; 1610-1614).
Antibodies with Extended Half Life
[0225] The present invention provides for antibodies or fragments
thereof that specifically bind to a non-linear or conformational
epitope within domain 3 of HER3 which have an extended half-life in
vivo. The present invention also provides for antibodies that
specifically bind to an epitope within domain 4 of HER3 which have
an extended half-life in vivo.
[0226] Many factors may affect a protein's half life in vivo. For
examples, kidney filtration, metabolism in the liver, degradation
by proteolytic enzymes (proteases), and immunogenic responses
(e.g., protein neutralization by antibodies and uptake by
macrophages and dentritic cells). A variety of strategies can be
used to extend the half life of the antibodies of the present
invention. For example, by chemical linkage to polyethyleneglycol
(PEG), reCODE PEG, antibody scaffold, polysialic acid (PSA),
hydroxyethyl starch (HES), albumin-binding ligands, and
carbohydrate shields; by genetic fusion to proteins binding to
serum proteins, such as albumin, IgG, FcRn, and transferring; by
coupling (genetically or chemically) to other binding moieties that
bind to serum proteins, such as nanobodies, Fabs, DARPins, avimers,
affibodies, and anticalins; by genetic fusion to rPEG, albumin,
domain of albumin, albumin-binding proteins, and Fc; or by
incorporation into nanocarriers, slow release formulations, or
medical devices.
[0227] To prolong the serum circulation of antibodies in vivo,
inert polymer molecules such as high molecular weight PEG can be
attached to the antibodies or a fragment thereof with or without a
multifunctional linker either through site-specific conjugation of
the PEG to the N- or C-terminus of the antibodies or via
epsilon-amino groups present on lysine residues. To pegylate an
antibody, the antibody, or fragment thereof, typically is reacted
with polyethylene glycol (PEG), such as a reactive ester or
aldehyde derivative of PEG, under conditions in which one or more
PEG groups become attached to the antibody or antibody fragment.
The pegylation can be carried out by an acylation reaction or an
alkylation reaction with a reactive PEG molecule (or an analogous
reactive water-soluble polymer). As used herein, the term
"polyethylene glycol" is intended to encompass any of the forms of
PEG that have been used to derivatize other proteins, such as mono
(C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene
glycol-maleimide. In certain embodiments, the antibody to be
pegylated is an aglycosylated antibody. Linear or branched polymer
derivatization that results in minimal loss of biological activity
will be used. The degree of conjugation can be closely monitored by
SDS-PAGE and mass spectrometry to ensure proper conjugation of PEG
molecules to the antibodies. Unreacted PEG can be separated from
antibody-PEG conjugates by size-exclusion or by ion-exchange
chromatography. PEG-derivatized antibodies can be tested for
binding activity as well as for in vivo efficacy using methods
well-known to those of skill in the art, for example, by
immunoassays described herein. Methods for pegylating proteins are
known in the art and can be applied to the antibodies of the
invention. See for example, EP 0 154 316 by Nishimura et al. and EP
0 401 384 by Ishikawa et al.
[0228] Other modified pegylation technologies include
reconstituting chemically orthogonal directed engineering
technology (ReCODE PEG), which incorporates chemically specified
side chains into biosynthetic proteins via a reconstituted system
that includes tRNA synthetase and tRNA. This technology enables
incorporation of more than 30 new amino acids into biosynthetic
proteins in E. coli, yeast, and mammalian cells. The tRNA
incorporates a normative amino acid any place an amber codon is
positioned, converting the amber from a stop codon to one that
signals incorporation of the chemically specified amino acid.
[0229] Recombinant pegylation technology (rPEG) can also be used
for serum half-life extension. This technology involves genetically
fusing a 300-600 amino acid unstructured protein tail to an
existing pharmaceutical protein. Because the apparent molecular
weight of such an unstructured protein chain is about 15-fold
larger than its actual molecular weight, the serum half-life of the
protein is greatly increased. In contrast to traditional
PEGylation, which requires chemical conjugation and repurification,
the manufacturing process is greatly simplified and the product is
homogeneous.
[0230] Polysialytion is another technology, which uses the natural
polymer polysialic acid (PSA) to prolong the active life and
improve the stability of therapeutic peptides and proteins. PSA is
a polymer of sialic acid (a sugar). When used for protein and
therapeutic peptide drug delivery, polysialic acid provides a
protective microenvironment on conjugation. This increases the
active life of the therapeutic protein in the circulation and
prevents it from being recognized by the immune system. The PSA
polymer is naturally found in the human body. It was adopted by
certain bacteria which evolved over millions of years to coat their
walls with it. These naturally polysialylated bacteria were then
able, by virtue of molecular mimicry, to foil the body's defense
system. PSA, nature's ultimate stealth technology, can be easily
produced from such bacteria in large quantities and with
predetermined physical characteristics. Bacterial PSA is completely
non-immunogenic, even when coupled to proteins, as it is chemically
identical to PSA in the human body.
[0231] Another technology include the use of hydroxyethyl starch
("HES") derivatives linked to antibodies. HES is a modified natural
polymer derived from waxy maize starch and can be metabolized by
the body's enzymes. HES solutions are usually administered to
substitute deficient blood volume and to improve the rheological
properties of the blood. Hesylation of an antibody enables the
prolongation of the circulation half-life by increasing the
stability of the molecule, as well as by reducing renal clearance,
resulting in an increased biological activity. By varying different
parameters, such as the molecular weight of HES, a wide range of
HES antibody conjugates can be customized.
[0232] Antibodies having an increased half-life in vivo can also be
generated introducing one or more amino acid modifications (i.e.,
substitutions, insertions or deletions) into an IgG constant
domain, or FcRn binding fragment thereof (preferably a Fc or hinge
Fc domain fragment). See, e.g., International Publication No. WO
98/23289; International Publication No. WO 97/34631; and U.S. Pat.
No. 6,277,375.
[0233] Further, antibodies can be conjugated to albumin in order to
make the antibody or antibody fragment more stable in vivo or have
a longer half life in vivo. The techniques are well-known in the
art, see, e.g., International Publication Nos. WO 93/15199, WO
93/15200, and WO 01/77137; and European Patent No. EP 413,622.
[0234] The HER3 antibody or a fragment thereof may also be fused to
one or more human serum albumin (HSA) polypeptides, or a portion
thereof. HSA, a protein of 585 amino acids in its mature form, is
responsible for a significant proportion of the osmotic pressure of
serum and also functions as a carrier of endogenous and exogenous
ligands. The role of albumin as a carrier molecule and its inert
nature are desirable properties for use as a carrier and
transporter of polypeptides in vivo. The use of albumin as a
component of an albumin fusion protein as a carrier for various
proteins has been suggested in WO 93/15199, WO 93/15200, and EP 413
622. The use of N-terminal fragments of HSA for fusions to
polypeptides has also been proposed (EP 399 666). Accordingly, by
genetically or chemically fusing or conjugating the antibodies or
fragments thereof to albumin, can stabilize or extend the
shelf-life, and/or to retain the molecule's activity for extended
periods of time in solution, in vitro and/or in vivo.
[0235] Fusion of albumin to another protein may be achieved by
genetic manipulation, such that the DNA coding for HSA, or a
fragment thereof, is joined to the DNA coding for the protein. A
suitable host is then transformed or transfected with the fused
nucleotide sequences, so arranged on a suitable plasmid as to
express a fusion polypeptide. The expression may be effected in
vitro from, for example, prokaryotic or eukaryotic cells, or in
vivo e.g. from a transgenic organism. Additional methods pertaining
to HSA fusions can be found, for example, in WO 2001077137 and WO
200306007, incorporated herein by reference. In a specific
embodiment, the expression of the fusion protein is performed in
mammalian cell lines, for example, CHO cell lines. Altered
differential binding of an antibody to a receptor at low or high
pHs is also contemplated to be within the scope of the invention.
For example, the affinity of an antibody may be modified such that
it remains bound to it's receptor at a low pH, e.g., the low pH
within a lyzozome, by modifying the antibody to include additional
amino acids such as a histine in a CDR of the antibody (See e.g.,
Tomoyuki Igawa et al. (2010) Nature Biotechnology; 28,
1203-1207).
Antibody Conjugates
[0236] The present invention provides antibodies or fragments
thereof that specifically bind to HER3 recombinantly fused or
chemically conjugated (including both covalent and non-covalent
conjugations) to a heterologous protein or polypeptide (or fragment
thereof, preferably to a polypeptide of at least 10, at least 20,
at least 30, at least 40, at least 50, at least 60, at least 70, at
least 80, at least 90 or at least 100 amino acids) to generate
fusion proteins. In particular, the invention provides fusion
proteins comprising an antibody fragment described herein (e.g., a
Fab fragment, Fd fragment, Fv fragment, F(ab).sub.2 fragment, a VH
domain, a VH CDR, a VL domain or a VL CDR) and a heterologous
protein, polypeptide, or peptide. Methods for fusing or conjugating
proteins, polypeptides, or peptides to an antibody or an antibody
fragment are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603,
5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; European
Patent Nos. EP 307,434 and EP 367,166; International Publication
Nos. WO 96/04388 and WO 91/06570; Ashkenazi et al., (1991) Proc.
Natl. Acad. Sci. USA 88:10535-10539; Zheng et al., (1995) J.
Immunol. 154:5590-5600; and Vil et al., (1992) Proc. Natl. Acad.
Sci. USA 89:11337-11341.
[0237] Additional fusion proteins may be generated through the
techniques of gene-shuffling, motif-shuffling, exon-shuffling,
and/or codon-shuffling (collectively referred to as "DNA
shuffling"). DNA shuffling may be employed to alter the activities
of antibodies of the invention or fragments thereof (e.g.,
antibodies or fragments thereof with higher affinities and lower
dissociation rates). See, generally, U.S. Pat. Nos. 5,605,793,
5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten et al.,
(1997) Curr. Opinion Biotechnol. 8:724-33; Harayama, (1998) Trends
Biotechnol. 16(2):76-82; Hansson et al., (1999) J. Mol. Biol.
287:265-76; and Lorenzo and Blasco, (1998) Biotechniques
24(2):308-313 (each of these patents and publications are hereby
incorporated by reference in its entirety). Antibodies or fragments
thereof, or the encoded antibodies or fragments thereof, may be
altered by being subjected to random mutagenesis by error-prone
PCR, random nucleotide insertion or other methods prior to
recombination. A polynucleotide encoding an antibody or fragment
thereof that specifically binds to a HER3 protein may be recombined
with one or more components, motifs, sections, parts, domains,
fragments, etc. of one or more heterologous molecules.
[0238] Moreover, the antibodies or fragments thereof can be fused
to marker sequences, such as a peptide to facilitate purification.
In preferred embodiments, the marker amino acid sequence is a
hexa-histidine peptide (SEQ ID NO: 702), such as the tag provided
in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth,
Calif., 91311), among others, many of which are commercially
available. As described in Gentz et al., (1989) Proc. Natl. Acad.
Sci. USA 86:821-824, for instance, hexa-histidine (SEQ ID NO: 702)
provides for convenient purification of the fusion protein. Other
peptide tags useful for purification include, but are not limited
to, the hemagglutinin ("HA") tag, which corresponds to an epitope
derived from the influenza hemagglutinin protein (Wilson et al.,
(1984) Cell 37:767), and the "flag" tag.
[0239] In other embodiments, antibodies of the present invention or
fragments thereof conjugated to a diagnostic or detectable agent.
Such antibodies can be useful for monitoring or prognosing the
onset, development, progression and/or severity of a disease or
disorder as part of a clinical testing procedure, such as
determining the efficacy of a particular therapy. Such diagnosis
and detection can accomplished by coupling the antibody to
detectable substances including, but not limited to, various
enzymes, such as, but not limited to, horseradish peroxidase,
alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;
prosthetic groups, such as, but not limited to, streptavidin/biotin
and avidin/biotin; fluorescent materials, such as, but not limited
to, umbelliferone, fluorescein, fluorescein isothiocynate,
rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or
phycoerythrin; luminescent materials, such as, but not limited to,
luminol; bioluminescent materials, such as but not limited to,
luciferase, luciferin, and aequorin; radioactive materials, such
as, but not limited to, iodine (.sup.131I, .sup.125I, .sup.123I,
and .sup.121I), carbon (.sup.14C), sulfur (.sup.35S), tritium
(.sup.3H), indium (.sup.115In, .sup.113In, .sup.112In, and
.sup.111In), technetium (.sup.99Tc), thallium (.sup.201Ti), gallium
(.sup.68Ga, .sup.67Ga), palladium (.sup.103Pd), molybdenum
(.sup.99Mo), xenon (.sup.133Xe), fluorine (.sup.18F), .sup.153Sm,
.sup.177Lu, .sup.159Gd, .sup.149Pm, .sup.140La, .sup.175Yb,
.sup.166Ho, .sup.190Y, 47Sc, .sup.186Re, .sup.188Re, .sup.142 Pr,
.sup.105Rh, .sup.97Ru, .sup.68Ge, .sup.57Co, .sup.65Zn, .sup.85Sr,
.sup.32P, .sup.153Gd, .sup.169Yb, .sup.51Cr, .sup.54Mn, .sup.75Se,
.sup.113Sn, and .sup.117Tin; and positron emitting metals using
various positron emission tomographies, and noradioactive
paramagnetic metal ions.
[0240] The present invention further encompasses uses of antibodies
or fragments thereof conjugated to a therapeutic moiety. An
antibody or fragment thereof may be conjugated to a therapeutic
moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent,
a therapeutic agent or a radioactive metal ion, e.g.,
alpha-emitters. A cytotoxin or cytotoxic agent includes any agent
that is detrimental to cells.
[0241] Further, an antibody or fragment thereof may be conjugated
to a therapeutic moiety or drug moiety that modifies a given
biological response. Therapeutic moieties or drug moieties are not
to be construed as limited to classical chemical therapeutic
agents. For example, the drug moiety may be a protein, peptide, or
polypeptide possessing a desired biological activity. Such proteins
may include, for example, a toxin such as abrin, ricin A,
pseudomonas exotoxin, cholera toxin, or diphtheria toxin; a protein
such as tumor necrosis factor, .alpha.-interferon,
.beta.-interferon, nerve growth factor, platelet derived growth
factor, tissue plasminogen activator, an apoptotic agent, an
anti-angiogenic agent; or, a biological response modifier such as,
for example, a lymphokine. In one embodiment, the HER3 antibody, or
a fragment thereof is conjugated to a therapeutic moiety, such as a
cytotoxin, a drug (e.g., an immunosuppressant) or a radiotoxin.
Such conjugates are referred to herein as "immunoconjugates".
Immunoconjugates that include one or more cytotoxins are referred
to as "immunotoxins." A cytotoxin or cytotoxic agent includes any
agent that is detrimental to (e.g., kills) cells. Examples include
taxon, cytochalasin B, gramicidin D, ethidium bromide, emetine,
mitomycin, etoposide, tenoposide, vincristine, vinblastine, t.
colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione,
mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone,
glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and
puromycin and analogs or homologs thereof. Therapeutic agents also
include, for example, antimetabolites (e.g., methotrexate,
6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil
decarbazine), ablating agents (e.g., mechlorethamine, thioepa
chloraxnbucil, meiphalan, carmustine (BSNU) and lomustine (CCNU),
cyclothosphamide, busulfan, dibromomannitol, streptozotocin,
mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin,
anthracyclines (e.g., daunorubicin (formerly daunomycin) and
doxorubicin), antibiotics (e.g., dactinomycin (formerly
actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and
anti-mitotic agents (e.g., vincristine and vinblastine). (See e.g.,
Seattle Genetics US20090304721).
[0242] Other examples of therapeutic cytotoxins that can be
conjugated to an antibody or fragment thereof of the invention
include duocarmycins, calicheamicins, maytansines and auristatins,
and derivatives thereof. An example of a calicheamicin antibody
conjugate is commercially available (Mylotarg.TM.;
Wyeth-Ayerst).
[0243] Cytoxins can be conjugated to antibodies or fragments
thereof of the invention using linker technology available in the
art. Examples of linker types that have been used to conjugate a
cytotoxin to an antibody include, but are not limited to,
hydrazones, thioethers, esters, disulfides and peptide-containing
linkers. A linker can be chosen that is, for example, susceptible
to cleavage by low pH within the lysosomal compartment or
susceptible to cleavage by proteases, such as proteases
preferentially expressed in tumor tissue such as cathepsins (e.g.,
cathepsins B, C, D).
[0244] For further discussion of types of cytotoxins, linkers and
methods for conjugating therapeutic agents to antibodies, see also
Saito et al., (2003) Adv. Drug Deliv. Rev. 55:199-215; Trail et
al., (2003) Cancer Immunol. Immunother. 52:328-337; Payne, (2003)
Cancer Cell 3:207-212; Allen, (2002) Nat. Rev. Cancer 2:750-763;
Pastan and Kreitman, (2002) Curr. Opin. Investig. Drugs
3:1089-1091; Senter and Springer, (2001) Adv. Drug Deliv. Rev.
53:247-264.
[0245] Antibodies or fragments thereof of the present invention
also can be conjugated to a radioactive isotope to generate
cytotoxic radiopharmaceuticals, also referred to as
radioimmunoconjugates. Examples of radioactive isotopes that can be
conjugated to antibodies for use diagnostically or therapeutically
include, but are not limited to, iodine.sup.111, indium.sup.111,
yttrium.sup.90, and lutetium.sup.177. Method for preparing
radioimmunconjugates are established in the art. Examples of
radioimmunoconjugates are commercially available, including
Zevalin.TM. (DEC Pharmaceuticals) and Bexxar.TM. (Corixa
Pharmaceuticals), and similar methods can be used to prepare
radioimmunoconjugates using the antibodies of the invention. In
certain embodiments, the macrocyclic chelator is
1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid
(DOTA) which can be attached to the antibody via a linker molecule.
Such linker molecules are commonly known in the art and described
in Denardo et al., (1998) Clin Cancer Res. 4(10):2483-90; Peterson
et al., (1999) Bioconjug. Chem. 10(4):553-7; and Zimmerman et al.,
(1999) Nucl. Med. Biol. 26(8):943-50, each incorporated by
reference in their entireties.
[0246] Techniques for conjugating therapeutic moieties to
antibodies are well known, see, e.g., Amon et al., "Monoclonal
Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in
Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.),
pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies
For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson
et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe,
"Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A
Review", in Monoclonal Antibodies 84: Biological And Clinical
Applications, Pinchera et al. (eds.), pp. 475-506 (1985);
"Analysis, Results, And Future Prospective Of The Therapeutic Use
Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal
Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.),
pp. 303-16 (Academic Press 1985), and Thorpe et al., (1982)
Immunol. Rev. 62:119-58.
[0247] Antibodies may also be attached to solid supports, which are
particularly useful for immunoassays or purification of the target
antigen. Such solid supports include, but are not limited to,
glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl
chloride or polypropylene.
Antibody Combinations
[0248] An another aspect, the invention pertains to HER3
antibodies, or fragments thereof of the invention used with other
therapeutic agents such as another antibodies, small molecule
inhibitors, mTOR inhibitors or PI3Kinase inhibitors. Examples
include, but are not limited to, the following:
[0249] HER1 inhibitors: The HER3 antibodies or fragments thereof
can be used with HER1 inhibitors which include, but are not limited
to, Matuzumab (EMD72000), Erbitux.RTM./Cetuximab (Imclone),
Vectibix.RTM./Panitumumab (Amgen), mAb 806, and Nimotuzumab
(TheraCIM), Iressa.RTM./Gefitinib (Astrazeneca); CI-1033 (PD183805)
(Pfizer), Lapatinib (GW-572016) (GlaxoSmithKline),
Tykerb.RTM./Lapatinib Ditosylate (SmithKlineBeecham),
Tarceva.RTM./Erlotinib HCL (OSI-774) (OSI Pharma), and PKI-166
(Novartis), and N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3
"S")-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenam-
ide, sold under the tradename Tovok.RTM. by Boehringer
Ingelheim).
[0250] HER2 inhibitors: The HER3 antibodies or fragments thereof
can be used with HER2 inhibitors which include, but are not limited
to, Pertuzumab (sold under the trademark Omnitarg.RTM., by
Genentech), Trastuzumab (sold under the trademark Herceptin.RTM. by
Genentech/Roche), MM-111, neratinib (also known as HKI-272,
(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-eth-
oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT
Publication No. WO 05/028443), lapatinib or lapatinib ditosylate
(sold under the trademark Tykerb.RTM. by GlaxoSmithKline.
[0251] HER3 inhibitors: The HER3 antibodies or fragments thereof
can be used with HER3 inhibitors which include, but are not limited
to, MM-121, MM-111, IB4C3, 2DID12 (U3 Pharma AG), AMG888 (Amgen),
AV-203 (Aveo), MEHD7945A (Genentech), and small molecules that
inhibit HER3.
[0252] HER4 inhibitors: The HER3 antibodies or fragments thereof
can be used with HER4 inhibitors.
[0253] PI3K inhibitors: The HER3 antibodies or fragments thereof
can be used with PI3 kinase inhibitors which include, but are not
limited to,
4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno-
[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and
described in PCT Publication Nos. WO 09/036,082 and WO 09/055,730),
2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]-
quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or
NVP-BEZ 235, and described in PCT Publication No. WO 06/122806),
BKM120 and BYL719.
[0254] mTOR inhibitors: The HER3 antibodies or fragments thereof
can be used with mTOR inhibitors which include, but are not limited
to, Temsirolimus (sold under the tradename Torisel.RTM. by Pfizer),
ridaforolimus (formally known as deferolimus,
(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,3-
2S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10-
,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,-
26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl
dimethylphosphinate, also known as Deforolimus, AP23573 and MK8669
(Ariad Pharm.), and described in PCT Publication No. WO 03/064383),
everolimus (RAD001) (sold under the tradename Afinitor.RTM. by
Novartis), One or more therapeutic agents may be administered
either simultaneously or before or after administration of a HER3
antibody or fragment thereof of the present invention.
Methods of Producing Antibodies of the Invention
(i) Nucleic Acids Encoding the Antibodies
[0255] The invention provides substantially purified nucleic acid
molecules which encode polypeptides comprising segments or domains
of the HER3 antibody chains described above.
[0256] Some of the nucleic acids of the invention comprise the
nucleotide sequence encoding the HER3 antibody heavy chain variable
region, and/or the nucleotide sequence encoding the light chain
variable region. In a specific embodiment, the nucleic acid
molecules are those identified in Table 1 or Table 2. Some other
nucleic acid molecules of the invention comprise nucleotide
sequences that are substantially identical (e.g., at least 80%,
90%, 95%, 96%, 97%, 98%, or 99%) to the nucleotide sequences of
those identified in Table 1 or Table 2. When expressed from
appropriate expression vectors, polypeptides encoded by these
polynucleotides are capable of exhibiting HER3 antigen binding
capacity.
[0257] Also provided in the invention are polynucleotides which
encode at least one CDR region and usually all three CDR regions
from the heavy or light chain of the antibody or fragment thereof
set forth above. Some other polynucleotides encode all or
substantially all of the variable region sequence of the heavy
chain and/or the light chain of the antibody or fragment thereof
set forth above. Because of the degeneracy of the code, a variety
of nucleic acid sequences will encode each of the immunoglobulin
amino acid sequences.
[0258] The nucleic acid molecules of the invention can encode both
a variable region and a constant region of the antibody. Some of
nucleic acid sequences of the invention comprise nucleotides
encoding a mature heavy chain variable region sequence that is
substantially identical (e.g., at least 80%, 90%, 95%, 96%, 97%,
98%, or 99%) to the mature heavy chain variable region sequence of
a HER3 antibody set forth in Table 1 or Table 2. Some other nucleic
acid sequences comprising nucleotide encoding a mature light chain
variable region sequence that is substantially identical (e.g., at
least 80%, 90%, 95%, 96%, 97%, 98%, or 99%) to the mature light
chain variable region sequence of a HER3 antibody set forth in
Table 1 or Table 2.
[0259] The polynucleotide sequences can be produced by de novo
solid-phase DNA synthesis or by PCR mutagenesis of an existing
sequence encoding the antibody or fragment thereof. Direct chemical
synthesis of nucleic acids can be accomplished by methods known in
the art, such as the phosphotriester method of Narang et al.,
(1979) Meth. Enzymol. 68:90; the phosphodiester method of Brown et
al., (1979) Meth. Enzymol. 68:109; the diethylphosphoramidite
method of Beaucage et al., (1981) Tetra. Lett., 22:1859; and the
solid support method of U.S. Pat. No. 4,458,066. Introducing
mutations to a polynucleotide sequence by PCR can be performed as
described in, e.g., PCR Technology: Principles and Applications for
DNA Amplification, H. A. Erlich (Ed.), Freeman Press, NY, N.Y.,
1992; PCR Protocols: A Guide to Methods and Applications, Innis et
al. (Ed.), Academic Press, San Diego, Calif., 1990; Mattila et al.,
(1991) Nucleic Acids Res. 19:967; and Eckert et al., (1991) PCR
Methods and Applications 1:17.
[0260] Also provided in the invention are expression vectors and
host cells for producing the antibodies or fragments thereof.
Various expression vectors can be employed to express the
polynucleotides encoding the HER3 antibody chains or fragments
thereof. Both viral-based and nonviral expression vectors can be
used to produce the antibodies in a mammalian host cell. Nonviral
vectors and systems include plasmids, episomal vectors, typically
with an expression cassette for expressing a protein or RNA, and
human artificial chromosomes (see, e.g., Harrington et al., (1997)
Nat Genet. 15:345). For example, nonviral vectors useful for
expression of the HER3 polynucleotides and polypeptides in
mammalian (e.g., human) cells include pThioHis A, B & C,
pcDNA3.1/His, pEBVHis A, B & C, (Invitrogen, San Diego,
Calif.), MPSV vectors, and numerous other vectors known in the art
for expressing other proteins. Useful viral vectors include vectors
based on retroviruses, adenoviruses, adenoassociated viruses,
herpes viruses, vectors based on SV40, papilloma virus, HBP Epstein
Barr virus, vaccinia virus vectors and Semliki Forest virus (SFV).
See, Brent et al., (1995) supra; Smith, Annu. Rev. Microbiol.
49:807; and Rosenfeld et al., (1992) Cell 68:143.
[0261] The choice of expression vector depends on the intended host
cells in which the vector is to be expressed. Typically, the
expression vectors contain a promoter and other regulatory
sequences (e.g., enhancers) that are operably linked to the
polynucleotides encoding an antibody chain or fragment thereof. In
some embodiments, an inducible promoter is employed to prevent
expression of inserted sequences except under inducing conditions.
Inducible promoters include, e.g., arabinose, lacZ, metallothionein
promoter or a heat shock promoter. Cultures of transformed
organisms can be expanded under noninducing conditions without
biasing the population for coding sequences whose expression
products are better tolerated by the host cells. In addition to
promoters, other regulatory elements may also be required or
desired for efficient expression of antibody chain or fragment
thereof. These elements typically include an ATG initiation codon
and adjacent ribosome binding site or other sequences. In addition,
the efficiency of expression may be enhanced by the inclusion of
enhancers appropriate to the cell system in use (see, e.g., Scharf
et al., (1994) Results Probl. Cell Differ. 20:125; and Bittner et
al., (1987) Meth. Enzymol., 153:516). For example, the SV40
enhancer or CMV enhancer may be used to increase expression in
mammalian host cells.
[0262] The expression vectors may also provide a secretion signal
sequence position to form a fusion protein with polypeptides
encoded by inserted antibody or fragment sequences. More often, the
inserted antibody or fragment sequences are linked to a signal
sequences before inclusion in the vector. Vectors to be used to
receive sequences encoding the antibody or fragment light and heavy
chain variable domains sometimes also encode constant regions or
parts thereof. Such vectors allow expression of the variable
regions as fusion proteins with the constant regions thereby
leading to production of intact antibodies or fragments thereof.
Typically, such constant regions are human.
[0263] The host cells for harboring and expressing the antibody or
fragment chains can be either prokaryotic or eukaryotic. E. coli is
one prokaryotic host useful for cloning and expressing the
polynucleotides of the present invention. Other microbial hosts
suitable for use include bacilli, such as Bacillus subtilis, and
other enterobacteriaceae, such as Salmonella, Serratia, and various
Pseudomonas species. In these prokaryotic hosts, one can also make
expression vectors, which typically contain expression control
sequences compatible with the host cell (e.g., an origin of
replication). In addition, any number of a variety of well-known
promoters will be present, such as the lactose promoter system, a
tryptophan (trp) promoter system, a beta-lactamase promoter system,
or a promoter system from phage lambda. The promoters typically
control expression, optionally with an operator sequence, and have
ribosome binding site sequences and the like, for initiating and
completing transcription and translation. Other microbes, such as
yeast, can also be employed to express antibodies or fragments
thereof. Insect cells in combination with baculovirus vectors can
also be used.
[0264] In some preferred embodiments, mammalian host cells are used
to express and produce the antibodies or fragments thereof. For
example, they can be either a hybridoma cell line expressing
endogenous immunoglobulin genes or a mammalian cell line harboring
an exogenous expression vector. These include any normal mortal or
normal or abnormal immortal animal or human cell. For example, a
number of suitable host cell lines capable of secreting intact
immunoglobulins have been developed including the CHO cell lines,
various Cos cell lines, HeLa cells, myeloma cell lines, transformed
B-cells and hybridomas. The use of mammalian tissue cell culture to
express polypeptides is discussed generally in, e.g., Winnacker,
FROM GENES TO CLONES, VCH Publishers, N.Y., N.Y., 1987. Expression
vectors for mammalian host cells can include expression control
sequences, such as an origin of replication, a promoter, and an
enhancer (see, e.g., Queen et al., (1986) Immunol. Rev. 89:49-68),
and necessary processing information sites, such as ribosome
binding sites, RNA splice sites, polyadenylation sites, and
transcriptional terminator sequences. These expression vectors
usually contain promoters derived from mammalian genes or from
mammalian viruses. Suitable promoters may be constitutive, cell
type-specific, stage-specific, and/or modulatable or regulatable.
Useful promoters include, but are not limited to, the
metallothionein promoter, the constitutive adenovirus major late
promoter, the dexamethasone-inducible MMTV promoter, the SV40
promoter, the MRP polIII promoter, the constitutive MPSV promoter,
the tetracycline-inducible CMV promoter (such as the human
immediate-early CMV promoter), the constitutive CMV promoter, and
promoter-enhancer combinations known in the art.
[0265] Methods for introducing expression vectors containing the
polynucleotide sequences of interest vary depending on the type of
cellular host. For example, calcium chloride transfection is
commonly utilized for prokaryotic cells, whereas calcium phosphate
treatment or electroporation may be used for other cellular hosts.
(See generally Sambrook, et al., supra). Other methods include,
e.g., electroporation, calcium phosphate treatment,
liposome-mediated transformation, injection and microinjection,
ballistic methods, virosomes, immunoliposomes, polycation:nucleic
acid conjugates, naked DNA, artificial virions, fusion to the
herpes virus structural protein VP22 (Elliot and O'Hare, (1997)
Cell 88:223), agent-enhanced uptake of DNA, and ex vivo
transduction. For long-term, high-yield production of recombinant
proteins, stable expression will often be desired. For example,
cell lines which stably express antibody chains or fragments can be
prepared using expression vectors of the invention which contain
viral origins of replication or endogenous expression elements and
a selectable marker gene. Following the introduction of the vector,
cells may be allowed to grow for 1-2 days in an enriched media
before they are switched to selective media. The purpose of the
selectable marker is to confer resistance to selection, and its
presence allows growth of cells which successfully express the
introduced sequences in selective media. Resistant, stably
transfected cells can be proliferated using tissue culture
techniques appropriate to the cell type.
(ii) Generation of Monoclonal Antibodies of the Invention
[0266] Monoclonal antibodies (mAbs) can be produced by a variety of
techniques, including conventional monoclonal antibody methodology
e.g., the standard somatic cell hybridization technique of Kohler
and Milstein, (1975) Nature 256:495. Many techniques for producing
monoclonal antibody can be employed e.g., viral or oncogenic
transformation of B lymphocytes.
[0267] An animal system for preparing hybridomas is the murine
system. Hybridoma production in the mouse is a well established
procedure. Immunization protocols and techniques for isolation of
immunized splenocytes for fusion are known in the art. Fusion
partners (e.g., murine myeloma cells) and fusion procedures are
also known.
[0268] Chimeric or humanized antibodies of the present invention
can be prepared based on the sequence of a murine monoclonal
antibody prepared as described above. DNA encoding the heavy and
light chain immunoglobulins can be obtained from the murine
hybridoma of interest and engineered to contain non-murine (e.g.,
human) immunoglobulin sequences using standard molecular biology
techniques. For example, to create a chimeric antibody, the murine
variable regions can be linked to human constant regions using
methods known in the art (see e.g., U.S. Pat. No. 4,816,567 to
Cabilly et al.). To create a humanized antibody, the murine CDR
regions can be inserted into a human framework using methods known
in the art. See e.g., U.S. Pat. No. 5,225,539 to Winter, and U.S.
Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6180370 to Queen et
al.
[0269] In a certain embodiment, the antibodies of the invention are
human monoclonal antibodies. Such human monoclonal antibodies
directed against HER3 can be generated using transgenic or
transchromosomic mice carrying parts of the human immune system
rather than the mouse system. These transgenic and transchromosomic
mice include mice referred to herein as HuMAb mice and KM mice,
respectively, and are collectively referred to herein as "human Ig
mice."
[0270] The HuMAb Mouse.RTM. (Medarex, Inc.) contains human
immunoglobulin gene miniloci that encode un-rearranged human heavy
(.mu. and .gamma.) and .kappa. light chain immunoglobulin
sequences, together with targeted mutations that inactivate the
endogenous .mu. and .kappa. chain loci (see e.g., Lonberg et al.,
(1994) Nature 368(6474): 856-859). Accordingly, the mice exhibit
reduced expression of mouse IgM or .kappa., and in response to
immunization, the introduced human heavy and light chain transgenes
undergo class switching and somatic mutation to generate high
affinity human IgG.kappa. monoclonal (Lonberg et al., (1994) supra;
reviewed in Lonberg, (1994) Handbook of Experimental Pharmacology
113:49-101; Lonberg and Huszar, (1995) Intern. Rev. Immunol.
13:65-93, and Harding and Lonberg, (1995) Ann. N.Y. Acad. Sci.
764:536-546). The preparation and use of HuMAb mice, and the
genomic modifications carried by such mice, is further described in
Taylor et al., (1992) Nucleic Acids Research 20:6287-6295; Chen et
al., (1993) International Immunology 5:647-656; Tuaillon et al.,
(1993) Proc. Natl. Acad. Sci. USA 94:3720-3724; Choi et al., (1993)
Nature Genetics 4:117-123; Chen et al., (1993) EMBO J. 12:821-830;
Tuaillon et al., (1994) J. Immunol. 152:2912-2920; Taylor et al.,
(1994) International Immunology 579-591; and Fishwild et al.,
(1996) Nature Biotechnology 14:845-851, the contents of all of
which are hereby specifically incorporated by reference in their
entirety. See further, U.S. Pat. Nos. 5,545,806; 5,569,825;
5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318;
5,874,299; and 5,770,429; all to Lonberg and Kay; U.S. Pat. No.
5,545,807 to Surani et al.; PCT Publication Nos. WO 92103918, WO
93/12227, WO 94/25585, WO 97113852, WO 98/24884 and WO 99/45962,
all to Lonberg and Kay; and PCT Publication No. WO 01/14424 to
Korman et al.
[0271] In another embodiment, human antibodies of the invention can
be raised using a mouse that carries human immunoglobulin sequences
on transgenes and transchomosomes such as a mouse that carries a
human heavy chain transgene and a human light chain
transchromosome. Such mice, referred to herein as "KM mice", are
described in detail in PCT Publication WO 02/43478 to Ishida et
al.
[0272] Still further, alternative transgenic animal systems
expressing human immunoglobulin genes are available in the art and
can be used to raise HER3 antibodies of the invention. For example,
an alternative transgenic system referred to as the Xenomouse
(Abgenix, Inc.) can be used. Such mice are described in, e.g., U.S.
Pat. Nos. 5,939,598; 6,075,181; 6,114,598; 6,150,584 and 6,162,963
to Kucherlapati et al.
[0273] Moreover, alternative transchromosomic animal systems
expressing human immunoglobulin genes are available in the art and
can be used to raise HER3 antibodies of the invention. For example,
mice carrying both a human heavy chain transchromosome and a human
light chain tranchromosome, referred to as "TC mice" can be used;
such mice are described in Tomizuka et al., (2000) Proc. Natl.
Acad. Sci. USA 97:722-727. Furthermore, cows carrying human heavy
and light chain transchromosomes have been described in the art
(Kuroiwa et al., (2002) Nature Biotechnology 20:889-894) and can be
used to raise HER3 antibodies of the invention.
[0274] Human monoclonal antibodies of the invention can also be
prepared using phage display methods for screening libraries of
human immunoglobulin genes. Such phage display methods for
isolating human antibodies are established in the art or described
in the examples below. See for example: U.S. Pat. Nos. 5,223,409;
5,403,484; and 5,571,698 to Ladner et al.; U.S. Pat. Nos. 5,427,908
and 5,580,717 to Dower et al.; U.S. Pat. Nos. 5,969,108 and
6,172,197 to McCafferty et al.; and U.S. Pat. Nos. 5,885,793;
6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081 to
Griffiths et al.
[0275] Human monoclonal antibodies of the invention can also be
prepared using SCID mice into which human immune cells have been
reconstituted such that a human antibody response can be generated
upon immunization. Such mice are described in, for example, U.S.
Pat. Nos. 5,476,996 and 5,698,767 to Wilson et al.
(Iii) Framework or Fc Engineering
[0276] Engineered antibodies of the invention include those in
which modifications have been made to framework residues within VH
and/or VL, e.g. to improve the properties of the antibody.
Typically such framework modifications are made to decrease the
immunogenicity of the antibody. For example, one approach is to
"backmutate" one or more framework residues to the corresponding
germline sequence. More specifically, an antibody that has
undergone somatic mutation may contain framework residues that
differ from the germline sequence from which the antibody is
derived. Such residues can be identified by comparing the antibody
framework sequences to the germline sequences from which the
antibody is derived. To return the framework region sequences to
their germline configuration, the somatic mutations can be
"backmutated" to the germline sequence by, for example,
site-directed mutagenesis. Such "backmutated" antibodies are also
intended to be encompassed by the invention.
[0277] Another type of framework modification involves mutating one
or more residues within the framework region, or even within one or
more CDR regions, to remove T cell-epitopes to thereby reduce the
potential immunogenicity of the antibody. This approach is also
referred to as "deimmunization" and is described in further detail
in U.S. Patent Publication No. 20030153043 by Carr et al.
[0278] In addition or alternative to modifications made within the
framework or CDR regions, antibodies of the invention may be
engineered to include modifications within the Fc region, typically
to alter one or more functional properties of the antibody, such as
serum half-life, complement fixation, Fc receptor binding, and/or
antigen-dependent cellular cytotoxicity.
[0279] Furthermore, an antibody of the invention may be chemically
modified (e.g., one or more chemical moieties can be attached to
the antibody) or be modified to alter its glycosylation, again to
alter one or more functional properties of the antibody. Each of
these embodiments is described in further detail below. The
numbering of residues in the Fc region is that of the EU index of
Kabat.
[0280] In one embodiment, the hinge region of CH1 is modified such
that the number of cysteine residues in the hinge region is
altered, e.g., increased or decreased. This approach is described
further in U.S. Pat. No. 5,677,425 by Bodmer et al. The number of
cysteine residues in the hinge region of CH1 is altered to, for
example, facilitate assembly of the light and heavy chains or to
increase or decrease the stability of the antibody.
[0281] In another embodiment, the Fc hinge region of an antibody is
mutated to decrease the biological half-life of the antibody. More
specifically, one or more amino acid mutations are introduced into
the CH2-CH3 domain interface region of the Fc-hinge fragment such
that the antibody has impaired Staphylococcyl protein A (SpA)
binding relative to native Fc-hinge domain SpA binding. This
approach is described in further detail in U.S. Pat. No. 6,165,745
by Ward et al.
[0282] In yet other embodiments, the Fc region is altered by
replacing at least one amino acid residue with a different amino
acid residue to alter the effector functions of the antibody. For
example, one or more amino acids can be replaced with a different
amino acid residue such that the antibody has an altered affinity
for an effector ligand but retains the antigen-binding ability of
the parent antibody. The effector ligand to which affinity is
altered can be, for example, an Fc receptor or the Cl component of
complement. This approach is described in further detail in U.S.
Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.
[0283] In another embodiment, one or more amino acids selected from
amino acid residues can be replaced with a different amino acid
residue such that the antibody has altered C1q binding and/or
reduced or abolished complement dependent cytotoxicity (CDC). This
approach is described in further detail in U.S. Pat. No. 6,194,551
by Idusogie et al.
[0284] In another embodiment, one or more amino acid residues are
altered to thereby alter the ability of the antibody to fix
complement. This approach is described further in PCT Publication
WO 94/29351 by Bodmer et al.
[0285] In yet another embodiment, the Fc region is modified to
increase the ability of the antibody to mediate antibody dependent
cellular cytotoxicity (ADCC) and/or to increase the affinity of the
antibody for an Fc.gamma. receptor by modifying one or more amino
acids. This approach is described further in PCT Publication WO
00/42072 by Presta. Moreover, the binding sites on human IgG1 for
Fc.gamma.R1, Fc.gamma.RII, Fc.gamma.RIII and FcRn have been mapped
and variants with improved binding have been described (see Shields
et al., (2001) J. Biol. Chen. 276:6591-6604).
[0286] In still another embodiment, the glycosylation of an
antibody is modified. For example, an aglycoslated antibody can be
made (i.e., the antibody lacks glycosylation). Glycosylation can be
altered to, for example, increase the affinity of the antibody for
"antigen". Such carbohydrate modifications can be accomplished by,
for example, altering one or more sites of glycosylation within the
antibody sequence. For example, one or more amino acid
substitutions can be made that result in elimination of one or more
variable region framework glycosylation sites to thereby eliminate
glycosylation at that site. Such aglycosylation may increase the
affinity of the antibody for antigen. Such an approach is described
in further detail in U.S. Pat. Nos. 5,714,350 and 6,350,861 by Co
et al.
[0287] Additionally or alternatively, an antibody can be made that
has an altered type of glycosylation, such as a hypofucosylated
antibody having reduced amounts of fucosyl residues or an antibody
having increased bisecting GlcNac structures. Such altered
glycosylation patterns have been demonstrated to increase the ADCC
ability of antibodies. Such carbohydrate modifications can be
accomplished by, for example, expressing the antibody in a host
cell with altered glycosylation machinery. Cells with altered
glycosylation machinery have been described in the art and can be
used as host cells in which to express recombinant antibodies of
the invention to thereby produce an antibody with altered
glycosylation. For example, EP 1,176,195 by Hang et al. describes a
cell line with a functionally disrupted FUT8 gene, which encodes a
fucosyl transferase, such that antibodies expressed in such a cell
line exhibit hypofucosylation. PCT Publication WO 03/035835 by
Presta describes a variant CHO cell line, Lec13 cells, with reduced
ability to attach fucose to Asn(297)-linked carbohydrates, also
resulting in hypofucosylation of antibodies expressed in that host
cell (see also Shields et al., (2002) J. Biol. Chem.
277:26733-26740). PCT Publication WO 99/54342 by Umana et al.
describes cell lines engineered to express glycoprotein-modifying
glycosyl transferases (e.g., beta(1,4)--N
acetylglucosaminyltransferase III (GnTIII)) such that antibodies
expressed in the engineered cell lines exhibit increased bisecting
GlcNac structures which results in increased ADCC activity of the
antibodies (see also Umana et al., (1999) Nat. Biotech.
17:176-180).
[0288] In another embodiment, the antibody is modified to increase
its biological half-life. Various approaches are possible. For
example, one or more of the following mutations can be introduced:
T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375 to
Ward. Alternatively, to increase the biological half life, the
antibody can be altered within the CH1 or CL region to contain a
salvage receptor binding epitope taken from two loops of a CH2
domain of an Fc region of an IgG, as described in U.S. Pat. Nos.
5,869,046 and 6,121,022 by Presta et al.
(iv) Methods of Engineering Altered Antibodies
[0289] The HER3 antibodies or fragments thereof of the invention
having VH and VL sequences or full length heavy and light chain
sequences shown herein can be used to create new HER3 antibodies by
modifying full length heavy chain and/or light chain sequences, VH
and/or VL sequences, or the constant region(s) attached thereto.
Thus, in another aspect of the invention, the structural features
of a HER3 antibody or fragment thereof are used to create
structurally related HER3 antibodies that retain at least one
functional property of the antibodies of the invention, such as
binding to human HER3 and also inhibiting one or more functional
properties of HER3. For example, one or more CDR regions of the
antibodies of the present invention, or mutations thereof, can be
combined recombinantly with known framework regions and/or other
CDRs to create additional, recombinantly-engineered, HER3
antibodies as discussed above. Other types of modifications include
those described in the previous section. The starting material for
the engineering method is one or more of the VH and/or VL sequences
provided herein, or one or more CDR regions thereof. To create the
engineered antibody, it is not necessary to actually prepare (i.e.,
express as a protein) an antibody having one or more of the VH
and/or VL sequences provided herein, or one or more CDR regions
thereof. Rather, the information contained in the sequence(s) is
used as the starting material to create a "second generation"
sequence(s) derived from the original sequence(s) and then the
"second generation" sequence(s) is prepared and expressed as a
protein.
[0290] Accordingly, in another embodiment, the invention provides a
method for preparing a antibody that binds to domain 3 of HER3
consisting of: a heavy chain variable region antibody sequence
having a CDR1 sequence selected from the group consisting of SEQ ID
NOs: 2, 22, 42, 62, 82, 102, 122, 142, and 162; a CDR2 sequence
selected from the group consisting of SEQ ID NOs: 3, 23, 43, 63,
83, 103, 123, 143, and 163; and/or a CDR3 sequence selected from
the group consisting of SEQ ID NOs: 4, 24, 44, 64, 84, 104, 124,
144, and 164; and a light chain variable region antibody sequence
having a CDR1 sequence selected from the group consisting of SEQ ID
NOs: 8, 28, 48, 68, 88, 108, 128, 148, and 168; a CDR2 sequence
selected from the group consisting of SEQ ID NOs: 9, 29, 49, 69,
89, 109, 129, 149, and 169; and/or a CDR3 sequence selected from
the group consisting of SEQ ID NOs: 10, 30, 50, 70, 90, 110, 130,
150, and 170; altering at least one amino acid residue within the
heavy chain variable region antibody sequence and/or the light
chain variable region antibody sequence to create at least one
altered antibody sequence; and expressing the altered antibody
sequence as a protein. The altered antibody sequence can also be
prepared by screening antibody libraries having fixed CDR3
sequences or minimal essential binding determinants as described in
US20050255552 and diversity on CDR1 and CDR2 sequences. The
screening can be performed according to any screening technology
appropriate for screening antibodies from antibody libraries, such
as phage display technology.
[0291] Accordingly, in another embodiment, the invention provides a
method for preparing a antibody that binds to domains 3-4 of HER3
consisting of: a heavy chain variable region antibody sequence
having a CDR1 sequence selected from the group consisting of SEQ ID
NOs: 182, 202, 222, 242, 262, 282, 302, 322, 342, 362, 382, 402,
422, 442, 462, 482, 502, 522, 542, 562, 582, 602, 622, 642, 662,
and 682; a CDR2 sequence selected from the group consisting of SEQ
ID NOs: 183, 203, 223, 243, 263, 283, 303, 323, 343, 363, 383, 403,
423, 443, 463, 483, 503, 523, 543, 563, 583, 603, 623, 643, 663,
and 683; and/or a CDR3 sequence selected from the group consisting
of SEQ ID NOs: 184, 204, 224, 244, 264, 284, 304, 324, 344, 364,
384, 404, 424, 444, 464, 484, 504, 524, 544, 564, 584, 604, 624,
644, 664, and 684; and a light chain variable region antibody
sequence having a CDR1 sequence selected from the group consisting
of SEQ ID NOs: 188, 208, 228, 248, 268, 288, 308, 328, 348, 368,
388, 408, 428, 448, 468, 488, 508, 528, 548, 568, 588, 608, 628,
648, 668, and 688; a CDR2 sequence selected from the group
consisting of SEQ ID NOs: 189, 209, 229, 249, 269, 289, 309, 329,
349, 369, 389, 409, 429, 449, 469, 489, 509, 529, 549, 569, 589,
609, 629, 649, 669, and 689; and/or a CDR3 sequence selected from
the group consisting of SEQ ID NOs: 190, 210, 230, 250, 270, 290,
310, 330, 350, 370, 390, 410, 430, 450, 470, 490, 510, 530, 550,
570, 590, 610, 630, 650, 670, and 690; altering at least one amino
acid residue within the heavy chain variable region antibody
sequence and/or the light chain variable region antibody sequence
to create at least one altered antibody sequence; and expressing
the altered antibody sequence as a protein. The altered antibody
sequence can also be prepared by screening antibody libraries
having fixed CDR3 sequences or minimal essential binding
determinants as described in US20050255552 and diversity on CDR1
and CDR2 sequences. The screening can be performed according to any
screening technology appropriate for screening antibodies from
antibody libraries, such as phage display technology.
[0292] Standard molecular biology techniques can be used to prepare
and express the altered antibody sequence. The antibody encoded by
the altered antibody sequence(s) is one that retains one, some or
all of the functional properties of the antibodies or fragments
thereof described herein, which functional properties include, but
are not limited to, specifically binding to human and/or
cynomologus HER3; the antibody binds to HER3 and inhibits HER3
biological activity by inhibiting the HER signaling activity in a
phospho-HER assay.
[0293] The functional properties of the altered antibodies can be
assessed using standard assays available in the art and/or
described herein, such as those set forth in the Examples (e.g.,
ELISAs).
[0294] In certain embodiments of the methods of engineering
antibodies of the invention, mutations can be introduced randomly
or selectively along all or part of an antibody or fragment coding
sequence and the resulting modified HER3 antibodies can be screened
for binding activity and/or other functional properties as
described herein. Mutational methods have been described in the
art. For example, PCT Publication WO 02/092780 by Short describes
methods for creating and screening antibody mutations using
saturation mutagenesis, synthetic ligation assembly, or a
combination thereof. Alternatively, PCT Publication WO 03/074679 by
Lazar et al. describes methods of using computational screening
methods to optimize physiochemical properties of antibodies.
Characterization of the Antibodies of the Invention
[0295] The antibodies of the invention can be characterized by
various functional assays. For example, they can be characterized
by their ability to inhibit biological activity by inhibiting HER
signaling in a phospho-HER assay as described herein, their
affinity to a HER3 protein (e.g., human and/or cynomologus HER3),
the epitope binning, their resistance to proteolysis, and their
ability to block HER3 downstream signaling. Various methods can be
used to measure HER3-mediated signaling. For example, the HER
signaling pathway can be monitored by (i) measurement of
phospho-HER3; (ii) measurement of phosphorylation of HER3 or other
downstream signaling proteins (e.g. Akt), (iii) ligand blocking
assays as described herein, (iv) heterodimer formation, (v) HER3
dependent gene expression signature, (vi) receptor internalization,
and (vii) HER3 driven cell phenotypes (e.g. proliferation).
[0296] The ability of an antibody to bind to HER3 can be detected
by labelling the antibody of interest directly, or the antibody may
be unlabelled and binding detected indirectly using various
sandwich assay formats known in the art.
[0297] In some embodiments, the HER3 antibodies block or compete
with binding of a reference HER3 antibody to a HER3. These can be
fully human HER3 antibodies described above. They can also be other
mouse, chimeric or humanized HER3 antibodies which bind to the same
epitope as the reference antibody. The capacity to block or compete
with the reference antibody binding indicates that a HER3 antibody
under test binds to the same or similar epitope as that defined by
the reference antibody, or to an epitope which is sufficiently
proximal to the epitope bound by the reference HER3 antibody. Such
antibodies are especially likely to share the advantageous
properties identified for the reference antibody. The capacity to
block or compete with the reference antibody may be determined by,
e.g., a competition binding assay. With a competition binding
assay, the antibody under test is examined for ability to inhibit
specific binding of the reference antibody to a common antigen,
such as a HER3 polypeptide or protein. A test antibody competes
with the reference antibody for specific binding to the antigen if
an excess of the test antibody substantially inhibits binding of
the reference antibody. Substantial inhibition means that the test
antibody reduces specific binding of the reference antibody usually
by at least 10%, 25%, 50%, 75%, or 90%.
[0298] There are a number of known competition binding assays that
can be used to assess competition of a HER3 antibody with the
reference HER3 antibody for binding to a HER3. These include, e.g.,
solid phase direct or indirect radioimmunoassay (RIA), solid phase
direct or indirect enzyme immunoassay (EIA), sandwich competition
assay (see Stahli et al., (1983) Methods in Enzymology 9:242-253);
solid phase direct biotin-avidin EIA (see Kirkland et al., (1986)
J. Immunol. 137:3614-3619); solid phase direct labeled assay, solid
phase direct labeled sandwich assay (see Harlow & Lane, supra);
solid phase direct label RIA using 1-125 label (see Morel et al.,
(1988) Molec. Immunol. 25:7-15); solid phase direct biotin-avidin
EIA (Cheung et al., (1990) Virology 176:546-552); and direct
labeled RIA (Moldenhauer et al., (1990) Scand. J. Immunol.
32:77-82). Typically, such an assay involves the use of purified
antigen bound to a solid surface or cells bearing either of these,
an unlabelled test HER3-binding antibody and a labelled reference
antibody. Competitive inhibition is measured by determining the
amount of label bound to the solid surface or cells in the presence
of the test antibody. Usually the test antibody is present in
excess. Antibodies identified by competition assay (competing
antibodies) include antibodies binding to the same epitope as the
reference antibody and antibodies binding to an adjacent epitope
sufficiently proximal to the epitope bound by the reference
antibody for steric hindrance to occur.
[0299] To determine if the selected HER3 monoclonal antibodies bind
to unique epitopes, each antibody can be biotinylated using
commercially available reagents (e.g., reagents from Pierce,
Rockford, Ill.). Competition studies using unlabeled monoclonal
antibodies and biotinylated monoclonal antibodies can be performed
using a HER3 polypeptide coated-ELISA plates. Biotinylated MAb
binding can be detected with a strep-avidin-alkaline phosphatase
probe. To determine the isotype of a purified HER3-binding
antibody, isotype ELISAs can be performed. For example, wells of
microtiter plates can be coated with 1 .mu.g/ml of anti-human IgG
overnight at 4.degree. C. After blocking with 1% BSA, the plates
are reacted with 1 .mu.g/ml or less of the monoclonal HER3 antibody
or purified isotype controls, at ambient temperature for one to two
hours. The wells can then be reacted with either human IgG1 or
human IgM-specific alkaline phosphatase-conjugated probes. Plates
are then developed and analyzed so that the isotype of the purified
antibody can be determined.
[0300] To demonstrate binding of monoclonal HER3 antibodies to live
cells expressing a HER3 polypeptide, flow cytometry can be used.
Briefly, cell lines expressing HER3 (grown under standard growth
conditions) can be mixed with various concentrations of a
HER3-binding antibody in PBS containing 0.1% BSA and 10% fetal calf
serum, and incubated at 4.degree. C. for 1 hour. After washing, the
cells are reacted with Fluorescein-labeled anti-human IgG antibody
under the same conditions as the primary antibody staining. The
samples can be analyzed by FACScan instrument using light and side
scatter properties to gate on single cells. An alternative assay
using fluorescence microscopy may be used (in addition to or
instead of) the flow cytometry assay. Cells can be stained exactly
as described above and examined by fluorescence microscopy. This
method allows visualization of individual cells, but may have
diminished sensitivity depending on the density of the antigen.
[0301] The antibodies or fragments thereof of the invention can be
further tested for reactivity with a HER3 polypeptide or antigenic
fragment by Western blotting. Briefly, purified HER3 polypeptides
or fusion proteins, or cell extracts from cells expressing HER3 can
be prepared and subjected to sodium dodecyl sulfate polyacrylamide
gel electrophoresis. After electrophoresis, the separated antigens
are transferred to nitrocellulose membranes, blocked with 10% fetal
calf serum, and probed with the monoclonal antibodies to be tested.
Human IgG binding can be detected using anti-human IgG alkaline
phosphatase and developed with BCIP/NBT substrate tablets (Sigma
Chem. Co., St. Louis, Mo.).
[0302] A number of readouts can be used to assess the efficacy, and
specificity, of HER3 antibodies in cell-based assays of
ligand-induced heterodimer formation. Activity can be assessed by
one or more of the following:
[0303] (i) Inhibition of ligand-induced heterodimerisation of HER2
with other EGF family members in a target cell line, for example
MCF-7 breast cancer cells. Immunoprecipitation of HER2 complexes
from cell lysates can be performed with a receptor-specific
antibody, and the absence/presence of other EGF receptors and their
biologically relevant ligands within the complex can be analysed
following electrophoresis/Western transfer by probing with
antibodies to other EGF receptors.
[0304] (ii) Inhibition of the activation of signaling pathways by
ligand-activated heterodimers.
[0305] Association with HER3 appears key for other members of the
EGF family of receptors to elicit maximal cellular response
following ligand binding. In the case of the kinase-defective HER3,
HER2 provides a functional tyrosine kinase domain to enable
signaling to occur following binding of growth factor ligands.
Thus, cells co-expressing HER2 and HER3 can be treated with ligand,
for example heregulin, in the absence and presence of inhibitor and
the effect on HER3 tyrosine phosphorylation monitored by a number
of ways including immunoprecipitation of HER3 from treated cell
lysates and subsequent Western blotting using anti-phosphotyrosine
antibodies (see Agus op. cit. for details). Alternatively, a
high-throughput assay can be developed by trapping HER3 from
solubilized lysates onto the wells of a 96-well plate coated with
an anti-HER3 receptor antibody, and the level of tyrosine
phosphorylation measured using, for example, europium-labelled
anti-phosphotyrosine antibodies, as embodied by Waddleton et al.,
(2002) Anal. Biochem. 309:150-157.
[0306] In a broader extension of this approach, effector molecules
known to be activated downstream of activated receptor
heterodimers, such as mitogen-activated protein kinases (MAPK) and
Akt, may be analysed directly, by immunoprecipitation from treated
lysates and blotting with antibodies that detect the activated
forms of these proteins, or by analysing the ability of these
proteins to modify/activate specific substrates.
[0307] (iii) Inhibition of ligand-induced cellular proliferation. A
variety of cell lines are known to co-express combinations of ErbB
receptors, for example many breast and prostate cancer cell lines.
Assays may be performed in 24/48/96-well formats with the readout
based around DNA synthesis (tritiated thymidine incorporation),
increase in cell number (crystal violet staining) etc.
[0308] A number of readouts can be used to assess the efficacy, and
specificity, of HER3 antibodies in cell-based assays of
ligand-independent homo- and heterodimer formation. For example,
HER2 overexpression triggers ligand-independent activation of the
kinase domain as a result of spontaneous dimer formation. Over
expressed HER2 generates either homo- or heterodimers with other
HER molecules such as HER1, HER3 and HER4.
[0309] Ability of antibodies or fragments thereof to block in vivo
growth of tumour xenografts of human tumour cell lines whose
tumorigenic phenotype is known to be at least partly dependent on
ligand activation of HER3 heterodimer cell signaling e.g. BxPC3
pancreatic cancer cells etc. This can be assessed in
immunocompromised mice either alone or in combination with an
appropriate cytotoxic agent for the cell line in question. Examples
of functional assays are also described in the Example section
below.
Prophylactic and Therapeutic Uses
[0310] The present invention provides methods of treating a disease
or disorder associated with the HER3 signaling pathway by
administering to a subject in need thereof an effective amount of
the antibody or fragment thereof of the invention. In a specific
embodiment, the present invention provides a method of treating or
preventing cancers (e.g., breast cancer, colorectal cancer, lung
cancer, multiple myeloma, ovarian cancer, liver cancer, gastric
cancer, pancreatic cancer, acute myeloid leukemia, chronic myeloid
leukemia, osteosarcoma, squamous cell carcinoma, peripheral nerve
sheath tumors, schwannoma, head and neck cancer, bladder cancer,
esophageal cancer, Barretts esophageal cancer, glioblastoma, clear
cell sarcoma of soft tissue, malignant mesothelioma,
neurofibromatosis, renal cancer, melanoma, prostate cancer, benign
prostatic hyperplasia (BPH), gynacomastica, and endometriosis) by
administering to a subject in need thereof an effective amount of
the antibodies or fragments thereof of the invention. In some
embodiments, the present invention provides methods of treating or
preventing cancers associated with a HER3 signaling pathway by
administering to a subject in need thereof an effective amount of
the antibodies of the invention.
[0311] In a specific embodiment, the present invention provides
methods of treating cancers associated with a HER3 signaling
pathway that include, but are not limited to breast cancer,
colorectal cancer, lung cancer, multiple myeloma, ovarian cancer,
liver cancer, gastric cancer, pancreatic cancer, acute myeloid
leukemia, chronic myeloid leukemia, osteosarcoma, squamous cell
carcinoma, peripheral nerve sheath tumors schwannoma, head and neck
cancer, bladder cancer, esophageal cancer, Barretts esophageal
cancer, glioblastoma, clear cell sarcoma of soft tissue, malignant
mesothelioma, neurofibromatosis, renal cancer, melanoma, prostate
cancer, benign prostatic hyperplasia (BPH), gynacomastica, and
endometriosis.
[0312] The antibodies or fragments thereof of the invention can
also be used to treat or prevent other disorders associated with
aberrant or defective HER3 signaling, including but are not limited
to respiratory diseases, osteoporosis, osteoarthritis, polycystic
kidney disease, diabetes, schizophrenia, vascular disease, cardiac
disease, non-oncogenic proliferative diseases, fibrosis, and
neurodegenerative diseases such as Alzheimer's disease.
[0313] Suitable agents for combination treatment with HER3
antibodies include standard of care agents known in the art that
are able to modulate the ErbB signaling pathway. Suitable examples
of standard of care agents for HER2 include, but are not limited to
Herceptin and Tykerb. Suitable examples of standard of care agents
for EGFR include, but are not limited to Iressa, Tarceva, Erbitux
and Vectibix as described above. Other agents that may be suitable
for combination treatment with HER3 antibodies include, but are not
limited to those that modulate receptor tyrosine kinases, G-protein
coupled receptors, growth/survival signal transduction pathways,
nuclear hormone receptors, apoptotic pathways, cell cycle and
angiogenesis.
Diagnostic Uses
[0314] In one aspect, the invention encompasses diagnostic assays
for determining HER3 and/or nucleic acid expression as well as HER3
protein function, in the context of a biological sample (e.g.,
blood, serum, cells, tissue) or from individual afflicted with
cancer, or is at risk of developing cancer.
[0315] Diagnostic assays, such as competitive assays rely on the
ability of a labelled analogue (the "tracer") to compete with the
test sample analyte for a limited number of binding sites on a
common binding partner. The binding partner generally is
insolubilized before or after the competition and then the tracer
and analyte bound to the binding partner are separated from the
unbound tracer and analyte. This separation is accomplished by
decanting (where the binding partner was preinsolubilized) or by
centrifuging (where the binding partner was precipitated after the
competitive reaction). The amount of test sample analyte is
inversely proportional to the amount of bound tracer as measured by
the amount of marker substance. Dose-response curves with known
amounts of analyte are prepared and compared with the test results
in order to quantitatively determine the amount of analyte present
in the test sample. These assays are called ELISA systems when
enzymes are used as the detectable markers. In an assay of this
form, competitive binding between antibodies and HER3 antibodies
results in the bound HER3, preferably the HER3 epitopes of the
invention, being a measure of antibodies in the serum sample, most
particularly, inhibiting antibodies in the serum sample.
[0316] A significant advantage of the assay is that measurement is
made of inhibiting antibodies directly (i.e., those which interfere
with binding of HER3, specifically, epitopes). Such an assay,
particularly in the form of an ELISA test has considerable
applications in the clinical environment and in routine blood
screening.
[0317] Another aspect of the invention provides methods for
determining HER3 nucleic acid expression or HER3 activity in an
individual to thereby select appropriate therapeutic or
prophylactic agents for that individual (referred to herein as
"pharmacogenomics"). Pharmacogenomics allows for the selection of
agents (e.g., drugs) for therapeutic or prophylactic treatment of
an individual based on the genotype of the individual (e.g., the
genotype of the individual examined to determine the ability of the
individual to respond to a particular agent.)
[0318] Yet another aspect of the invention pertains to monitoring
the influence of agents (e.g., drugs) on the expression or activity
of HER3 in clinical trials.
Pharmaceutical Compositions
[0319] To prepare pharmaceutical or sterile compositions including
antibodies or fragments thereof, the antibodies or fragments
thereof are mixed with a pharmaceutically acceptable carrier or
excipient. The compositions can additionally contain one or more
other therapeutic agents that are suitable for treating or
preventing cancer (breast cancer, colorectal cancer, lung cancer,
multiple myeloma, ovarian cancer, liver cancer, gastric cancer,
pancreatic cancer, acute myeloid leukemia, chronic myeloid
leukemia, osteosarcoma, squamous cell carcinoma, peripheral nerve
sheath tumors schwannoma, head and neck cancer, bladder cancer,
esophageal cancer, glioblastoma, clear cell sarcoma of soft tissue,
malignant mesothelioma, neurofibromatosis, renal cancer, and
melanoma, Barretts esophageal cancer, prostate cancer, benign
prostatic hyperplasia (BPH), gynacomastica, and endometriosis).
[0320] Formulations of therapeutic and diagnostic agents can be
prepared by mixing with physiologically acceptable carriers,
excipients, or stabilizers in the form of, e.g., lyophilized
powders, slurries, aqueous solutions, lotions, or suspensions (see,
e.g., Hardman et al., (2001) Goodman and Gilman's The
Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.;
Gennaro (2000) Remington: The Science and Practice of Pharmacy,
Lippincott, Williams, and Wilkins, New York, N.Y.; Avis, et al.
(eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications,
Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical
Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.)
(1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel
Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and
Safety, Marcel Dekker, Inc., New York, N.Y.).
[0321] Selecting an administration regimen for a therapeutic
depends on several factors, including the serum or tissue turnover
rate of the entity, the level of symptoms, the immunogenicity of
the entity, and the accessibility of the target cells in the
biological matrix. In certain embodiments, an administration
regimen maximizes the amount of therapeutic delivered to the
patient consistent with an acceptable level of side effects.
Accordingly, the amount of biologic delivered depends in part on
the particular entity and the severity of the condition being
treated. Guidance in selecting appropriate doses of antibodies,
cytokines, and small molecules are available (see, e.g.,
Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd,
Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies,
Cytokines and Arthritis, Marcel Dekker, New York, N.Y.; Bach (ed.)
(1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune
Diseases, Marcel Dekker, New York, N.Y.; Baert et al., (2003) New
Engl. J. Med. 348:601-608; Milgrom et al., (1999) New Engl. J. Med.
341:1966-1973; Slamon et al., (2001) New Engl. J. Med. 344:783-792;
Beniaminovitz et al., (2000) New Engl. J. Med. 342:613-619; Ghosh
et al., (2003) New Engl. J. Med. 348:24-32; Lipsky et al., (2000)
New Engl. J. Med. 343:1594-1602).
[0322] Determination of the appropriate dose is made by the
clinician, e.g., using parameters or factors known or suspected in
the art to affect treatment or predicted to affect treatment.
Generally, the dose begins with an amount somewhat less than the
optimum dose and it is increased by small increments thereafter
until the desired or optimum effect is achieved relative to any
negative side effects. Important diagnostic measures include those
of symptoms of, e.g., the inflammation or level of inflammatory
cytokines produced.
[0323] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of the present invention may be varied
so as to obtain an amount of the active ingredient which is
effective to achieve the desired therapeutic response for a
particular patient, composition, and mode of administration,
without being toxic to the patient. The selected dosage level will
depend upon a variety of pharmacokinetic factors including the
activity of the particular compositions of the present invention
employed, or the ester, salt or amide thereof, the route of
administration, the time of administration, the rate of excretion
of the particular compound being employed, the duration of the
treatment, other drugs, compounds and/or materials used in
combination with the particular compositions employed, the age,
sex, weight, condition, general health and prior medical history of
the patient being treated, and like factors known in the medical
arts.
[0324] Compositions comprising antibodies or fragments thereof of
the invention can be provided by continuous infusion, or by doses
at intervals of, e.g., one day, one week, or 1-7 times per week.
Doses may be provided intravenously, subcutaneously, topically,
orally, nasally, rectally, intramuscular, intracerebrally, or by
inhalation. A specific dose protocol is one involving the maximal
dose or dose frequency that avoids significant undesirable side
effects.
[0325] A total weekly dose may be at least 0.05 .mu.g/kg body
weight, at least 0.2 .mu.g/kg, at least 0.5 .mu.g/kg, at least 1
.mu.g/kg, at least 10 .mu.g/kg, at least 100 .mu.g/kg, at least 0.2
mg/kg, at least 1.0 mg/kg, at least 2.0 mg/kg, at least 10 mg/kg,
at least 25 mg/kg, or at least 50 mg/kg (see, e.g., Yang et al.,
(2003) New Engl. J. Med. 349:427-434; Herold et al., (2002) New
Engl. J. Med. 346:1692-1698; Liu et al., (1999) J. Neurol.
Neurosurg. Psych. 67:451-456; Portielji et al., (2003) Cancer
Immunol. Immunother. 52:133-144). The desired dose of antibodies or
fragments thereof is about the same as for an antibody or
polypeptide, on a moles/kg body weight basis. The desired plasma
concentration of the antibodies or fragments thereof is about, on a
moles/kg body weight basis. The dose may be at least 15 .mu.g at
least 20 .mu.g, at least 25 .mu.g, at least 30 .mu.g, at least 35
.mu.g, at least 40 .mu.g, at least 45 .mu.g, at least 50 .mu.g, at
least 55 .mu.g, at least 60 .mu.g, at least 65 .mu.g, at least 70
.mu.g, at least 75 .mu.g, at least 80 .mu.g, at least 85 .mu.g, at
least 90 .mu.g, at least 95 .mu.g, or at least 100 .mu.g. The doses
administered to a subject may number at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12, or more.
[0326] For antibodies or fragments thereof the invention, the
dosage administered to a patient may be 0.0001 mg/kg to 100 mg/kg
of the patient's body weight. The dosage may be between 0.0001
mg/kg and 20 mg/kg, 0.0001 mg/kg and 10 mg/kg, 0.0001 mg/kg and 5
mg/kg, 0.0001 and 2 mg/kg, 0.0001 and 1 mg/kg, 0.0001 mg/kg and
0.75 mg/kg, 0.0001 mg/kg and 0.5 mg/kg, 0.0001 mg/kg to 0.25 mg/kg,
0.0001 to 0.15 mg/kg, 0.0001 to 0.10 mg/kg, 0.001 to 0.5 mg/kg,
0.01 to 0.25 mg/kg or 0.01 to 0.10 mg/kg of the patient's body
weight.
[0327] The dosage of the antibodies or fragments thereof of the
invention may be calculated using the patient's weight in kilograms
(kg) multiplied by the dose to be administered in mg/kg. The dosage
of the antibodies or fragments thereof the invention may be 150
.mu.g/kg or less, 125 .mu.g/kg or less, 100 .mu.g/kg or less, 95
.mu.g/kg or less, 90 .mu.g/kg or less, 85 .mu.g/kg or less, 80
.mu.g/kg or less, 75 .mu.g/kg or less, 70 .mu.g/kg or less, 65
.mu.g/kg or less, 60 .mu.g/kg or less, 55 .mu.g/kg or less, 50
.mu.g/kg or less, 45 .mu.g/kg or less, 40 .mu.g/kg or less, 35
.mu.g/kg or less, 30 .mu.g/kg or less, 25 .mu.g/kg or less, 20
.mu.g/kg or less, 15 .mu.g/kg or less, 10 .mu.g/kg or less, 5
.mu.g/kg or less, 2.5 .mu.g/kg or less, 2 .mu.g/kg or less, 1.5
.mu.g/kg or less, 1 .mu.g/kg or less, 0.5 .mu.g/kg or less, or 0.5
.mu.g/kg or less of a patient's body weight.
[0328] Unit dose of the antibodies or fragments thereof the
invention may be 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg,
0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg,
0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25
to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg, 0.5 mg to
2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg,
1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
[0329] The dosage of the antibodies or fragments thereof the
invention may achieve a serum titer of at least 0.1 .mu.g/ml, at
least 0.5 .mu.g/ml, at least 1 .mu.g/ml, at least 2 .mu.g/ml, at
least 5 .mu.g/ml, at least 6 .mu.g/ml, at least 10 .mu.g/ml, at
least 15 .mu.g/ml, at least 20 .mu.g/ml, at least 25 .mu.g/ml, at
least 50 .mu.g/ml, at least 100 .mu.g/ml, at least 125 .mu.g/ml, at
least 150 .mu.g/ml, at least 175 .mu.g/ml, at least 200 .mu.g/ml,
at least 225 .mu.g/ml, at least 250 .mu.g/ml, at least 275
.mu.g/ml, at least 300 .mu.g/ml, at least 325 .mu.g/ml, at least
350 .mu.g/ml, at least 375 .mu.g/ml, or at least 400 .mu.g/ml in a
subject.
[0330] Alternatively, the dosage of the antibodies or fragments
thereof the invention may achieve a serum titer of at least 0.1
.mu.g/ml, at least 0.5 .mu.g/ml, at least 1 .mu.g/ml, at least, 2
.mu.g/ml, at least 5 .mu.g/ml, at least 6 .mu.g/ml, at least 10
.mu.g/ml, at least 15 .mu.g/ml, at least 20 .mu.g/ml, at least 25
.mu.g/ml, at least 50 .mu.g/ml, at least 100 .mu.g/ml, at least 125
.mu.g/ml, at least 150 .mu.g/m.mu., at least 175 .mu.g/ml, at least
200 .mu.g/ml, at least 225 .mu.g/ml, at least 250 .mu.g/ml, at
least 275 .mu.g/ml, at least 300 .mu.g/ml, at least 325 .mu.g/ml,
at least 350 .mu.g/ml, at least 375 .mu.g/ml, or at least 400
.mu.g/ml in the subject.
[0331] Doses of antibodies or fragments thereof the invention may
be repeated and the administrations may be separated by at least 1
day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2
months, 75 days, 3 months, or at least 6 months.
[0332] An effective amount for a particular patient may vary
depending on factors such as the condition being treated, the
overall health of the patient, the method route and dose of
administration and the severity of side affects (see, e.g., Maynard
et al., (1996) A Handbook of SOPs for Good Clinical Practice,
Interpharm Press, Boca Raton, Fla.; Dent (2001) Good Laboratory and
Good Clinical Practice, Urch Publ., London, UK).
[0333] The route of administration may be by, e.g., topical or
cutaneous application, injection or infusion by intravenous,
intraperitoneal, intracerebral, intramuscular, intraocular,
intraarterial, intracerebrospinal, intralesional, or by sustained
release systems or an implant (see, e.g., Sidman et al., (1983)
Biopolymers 22:547-556; Langer et al., (1981) J. Biomed. Mater.
Res. 15:167-277; Langer (1982) Chem. Tech. 12:98-105; Epstein et
al., (1985) Proc. Natl. Acad. Sci. USA 82:3688-3692; Hwang et al.,
(1980) Proc. Natl. Acad. Sci. USA 77:4030-4034; U.S. Pat. Nos.
6,350,466 and 6,316,024). Where necessary, the composition may also
include a solubilizing agent and a local anesthetic such as
lidocaine to ease pain at the site of the injection. In addition,
pulmonary administration can also be employed, e.g., by use of an
inhaler or nebulizer, and formulation with an aerosolizing agent.
See, e.g., U.S. Pat. Nos. 6,019,968, 5,985,320, 5,985,309,
5,934,272, 5,874,064, 5,855,913, 5,290,540, and 4,880,078; and PCT
Publication Nos. WO 92/19244, WO 97/32572, WO 97/44013, WO
98/31346, and WO 99/66903, each of which is incorporated herein by
reference their entirety.
[0334] A composition of the present invention may also be
administered via one or more routes of administration using one or
more of a variety of methods known in the art. As will be
appreciated by the skilled artisan, the route and/or mode of
administration will vary depending upon the desired results.
Selected routes of administration for antibodies or fragments
thereof the invention include intravenous, intramuscular,
intradermal, intraperitoneal, subcutaneous, spinal or other
parenteral routes of administration, for example by injection or
infusion. Parenteral administration may represent modes of
administration other than enteral and topical administration,
usually by injection, and includes, without limitation,
intravenous, intramuscular, intraarterial, intrathecal,
intracapsular, intraorbital, intracardiac, intradermal,
intraperitoneal, transtracheal, subcutaneous, subcuticular,
intraarticular, subcapsular, subarachnoid, intraspinal, epidural
and intrasternal injection and infusion. Alternatively, a
composition of the invention can be administered via a
non-parenteral route, such as a topical, epidermal or mucosal route
of administration, for example, intranasally, orally, vaginally,
rectally, sublingually or topically. In one embodiment, the
antibodies or fragments thereof of the invention is administered by
infusion. In another embodiment, the multispecific epitope binding
protein of the invention is administered subcutaneously.
[0335] If the antibodies or fragments thereof of the invention are
administered in a controlled release or sustained release system, a
pump may be used to achieve controlled or sustained release (see
Langer, supra; Sefton, (1987) CRC Crit. Ref Biomed. Eng. 14:20;
Buchwald et al., (1980), Surgery 88:507; Saudek et al., (1989) N.
Engl. J. Med. 321:574). Polymeric materials can be used to achieve
controlled or sustained release of the therapies of the invention
(see e.g., Medical Applications of Controlled Release, Langer and
Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug
Bioavailability, Drug Product Design and Performance, Smolen and
Ball (eds.), Wiley, New York (1984); Ranger and Peppas, (1983) J.
Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al.,
(1985) Science 228:190; During et al., (1989) Ann. Neurol. 25:351;
Howard et al., (1989) J. Neurosurg. 7 1:105); U.S. Pat. No.
5,679,377; U.S. Pat. No. 5,916,597; U.S. Pat. No. 5,912,015; U.S.
Pat. No. 5,989,463; U.S. Pat. No. 5,128,326; PCT Publication No. WO
99/15154; and PCT Publication No. WO 99/20253. Examples of polymers
used in sustained release formulations include, but are not limited
to, poly(2-hydroxy ethyl methacrylate), poly(methyl methacrylate),
poly(acrylic acid), poly(ethylene-co-vinyl acetate),
poly(methacrylic acid), polyglycolides (PLG), polyanhydrides,
poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide,
poly(ethylene glycol), polylactides (PLA),
poly(lactide-co-glycolides) (PLGA), and polyorthoesters. In one
embodiment, the polymer used in a sustained release formulation is
inert, free of leachable impurities, stable on storage, sterile,
and biodegradable. A controlled or sustained release system can be
placed in proximity of the prophylactic or therapeutic target, thus
requiring only a fraction of the systemic dose (see, e.g., Goodson,
in Medical Applications of Controlled Release, supra, vol. 2, pp.
115-138 (1984)).
[0336] Controlled release systems are discussed in the review by
Langer, (1990), Science 249:1527-1533). Any technique known to one
of skill in the art can be used to produce sustained release
formulations comprising one or more antibodies or fragments thereof
the invention. See, e.g., U.S. Pat. No. 4,526,938, PCT publication
WO 91/05548, PCT publication WO 96/20698, Ning et al., (1996),
Radiotherapy & Oncology 39:179-189, Song et al., (1995) PDA
Journal of Pharmaceutical Science & Technology 50:372-397,
Cleek et al., (1997) Pro. Int'l. Symp. Control. Rel. Bioact. Mater.
24:853-854, and Lam et al., (1997) Proc. Int'l. Symp. Control Rel.
Bioact. Mater. 24:759-760, each of which is incorporated herein by
reference in their entirety.
[0337] If the antibodies or fragments thereof of the invention are
administered topically, they can be formulated in the form of an
ointment, cream, transdermal patch, lotion, gel, shampoo, spray,
aerosol, solution, emulsion, or other form well-known to one of
skill in the art. See, e.g., Remington's Pharmaceutical Sciences
and Introduction to Pharmaceutical Dosage Forms, 19th ed., Mack
Pub. Co., Easton, Pa. (1995). For non-sprayable topical dosage
forms, viscous to semi-solid or solid forms comprising a carrier or
one or more excipients compatible with topical application and
having a dynamic viscosity, in some instances, greater than water
are typically employed. Suitable formulations include, without
limitation, solutions, suspensions, emulsions, creams, ointments,
powders, liniments, salves, and the like, which are, if desired,
sterilized or mixed with auxiliary agents (e.g., preservatives,
stabilizers, wetting agents, buffers, or salts) for influencing
various properties, such as, for example, osmotic pressure. Other
suitable topical dosage forms include sprayable aerosol
preparations wherein the active ingredient, in some instances, in
combination with a solid or liquid inert carrier, is packaged in a
mixture with a pressurized volatile (e.g., a gaseous propellant,
such as freon) or in a squeeze bottle. Moisturizers or humectants
can also be added to pharmaceutical compositions and dosage forms
if desired. Examples of such additional ingredients are well-known
in the art.
[0338] If the compositions comprising antibodies or fragments
thereof are administered intranasally, it can be formulated in an
aerosol form, spray, mist or in the form of drops. In particular,
prophylactic or therapeutic agents for use according to the present
invention can be conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebuliser, with the
use of a suitable propellant (e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas). In the case of a pressurized aerosol the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges (composed of, e.g.,
gelatin) for use in an inhaler or insufflator may be formulated
containing a powder mix of the compound and a suitable powder base
such as lactose or starch.
[0339] Methods for co-administration or treatment with a second
therapeutic agent, e.g., a cytokine, steroid, chemotherapeutic
agent, antibiotic, or radiation, are known in the art (see, e.g.,
Hardman et al., (eds.) (2001) Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 10.sup.th ed., McGraw-Hill,
New York, N.Y.; Poole and Peterson (eds.) (2001)
Pharmacotherapeutics for Advanced Practice: A Practical Approach,
Lippincott, Williams & Wilkins, Phila., Pa.; Chabner and Longo
(eds.) (2001) Cancer Chemotherapy and Biotherapy, Lippincott,
Williams & Wilkins, Phila., Pa.). An effective amount of
therapeutic may decrease the symptoms by at least 10%; by at least
20%; at least about 30%; at least 40%, or at least 50%.
[0340] Additional therapies (e.g., prophylactic or therapeutic
agents), which can be administered in combination with the
antibodies or fragments thereof the invention may be administered
less than 5 minutes apart, less than 30 minutes apart, 1 hour
apart, at about 1 hour apart, at about 1 to about 2 hours apart, at
about 2 hours to about 3 hours apart, at about 3 hours to about 4
hours apart, at about 4 hours to about 5 hours apart, at about 5
hours to about 6 hours apart, at about 6 hours to about 7 hours
apart, at about 7 hours to about 8 hours apart, at about 8 hours to
about 9 hours apart, at about 9 hours to about 10 hours apart, at
about 10 hours to about 11 hours apart, at about 11 hours to about
12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24
hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours
apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60
hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96
hours apart, or 96 hours to 120 hours apart from the antibodies or
fragments thereof the invention. The two or more therapies may be
administered within one same patient visit.
[0341] The antibodies or fragments thereof the invention and the
other therapies may be cyclically administered. Cycling therapy
involves the administration of a first therapy (e.g., a first
prophylactic or therapeutic agent) for a period of time, followed
by the administration of a second therapy (e.g., a second
prophylactic or therapeutic agent) for a period of time,
optionally, followed by the administration of a third therapy
(e.g., prophylactic or therapeutic agent) for a period of time and
so forth, and repeating this sequential administration, i.e., the
cycle in order to reduce the development of resistance to one of
the therapies, to avoid or reduce the side effects of one of the
therapies, and/or to improve the efficacy of the therapies.
[0342] In certain embodiments, the antibodies or fragments thereof
the invention can be formulated to ensure proper distribution in
vivo. For example, the blood-brain barrier (BBB) excludes many
highly hydrophilic compounds. To ensure that the therapeutic
compounds of the invention cross the BBB (if desired), they can be
formulated, for example, in liposomes. For methods of manufacturing
liposomes, see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and
5,399,331. The liposomes may comprise one or more moieties which
are selectively transported into specific cells or organs, thus
enhance targeted drug delivery (see, e.g., Ranade, (1989) J. Clin.
Pharmacol. 29:685). Exemplary targeting moieties include folate or
biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al);
mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun.
153:1038); antibodies (Bloeman et al., (1995) FEBS Lett. 357:140;
Owais et al., (1995) Antimicrob. Agents Chemother. 39:180);
surfactant protein A receptor (Briscoe et al., (1995) Am. J.
Physiol. 1233:134); p 120 (Schreier et al, (1994) J. Biol. Chem.
269:9090); see also K. Keinanen; M. L. Laukkanen (1994) FEBS Lett.
346:123; J. J. Killion; I. J. Fidler (1994) Immunomethods
4:273.
[0343] The invention provides protocols for the administration of
pharmaceutical composition comprising antibodies or fragments
thereof the invention alone or in combination with other therapies
to a subject in need thereof. The therapies (e.g., prophylactic or
therapeutic agents) of the combination therapies of the present
invention can be administered concomitantly or sequentially to a
subject. The therapy (e.g., prophylactic or therapeutic agents) of
the combination therapies of the present invention can also be
cyclically administered. Cycling therapy involves the
administration of a first therapy (e.g., a first prophylactic or
therapeutic agent) for a period of time, followed by the
administration of a second therapy (e.g., a second prophylactic or
therapeutic agent) for a period of time and repeating this
sequential administration, i.e., the cycle, in order to reduce the
development of resistance to one of the therapies (e.g., agents) to
avoid or reduce the side effects of one of the therapies (e.g.,
agents), and/or to improve, the efficacy of the therapies.
[0344] The therapies (e.g., prophylactic or therapeutic agents) of
the combination therapies of the invention can be administered to a
subject concurrently. The term "concurrently" is not limited to the
administration of therapies (e.g., prophylactic or therapeutic
agents) at exactly the same time, but rather it is meant that a
pharmaceutical composition comprising antibodies or fragments
thereof the invention are administered to a subject in a sequence
and within a time interval such that the antibodies of the
invention can act together with the other therapy(ies) to provide
an increased benefit than if they were administered otherwise. For
example, each therapy may be administered to a subject at the same
time or sequentially in any order at different points in time;
however, if not administered at the same time, they should be
administered sufficiently close in time so as to provide the
desired therapeutic or prophylactic effect. Each therapy can be
administered to a subject separately, in any appropriate form and
by any suitable route. In various embodiments, the therapies (e.g.,
prophylactic or therapeutic agents) are administered to a subject
less than 15 minutes, less than 30 minutes, less than 1 hour apart,
at about 1 hour apart, at about 1 hour to about 2 hours apart, at
about 2 hours to about 3 hours apart, at about 3 hours to about 4
hours apart, at about 4 hours to about 5 hours apart, at about 5
hours to about 6 hours apart, at about 6 hours to about 7 hours
apart, at about 7 hours to about 8 hours apart, at about 8 hours to
about 9 hours apart, at about 9 hours to about 10 hours apart, at
about 10 hours to about 11 hours apart, at about 11 hours to about
12 hours apart, 24 hours apart, 48 hours apart, 72 hours apart, or
1 week apart. In other embodiments, two or more therapies (e.g.,
prophylactic or therapeutic agents) are administered to a within
the same patient visit.
[0345] The prophylactic or therapeutic agents of the combination
therapies can be administered to a subject in the same
pharmaceutical composition. Alternatively, the prophylactic or
therapeutic agents of the combination therapies can be administered
concurrently to a subject in separate pharmaceutical compositions.
The prophylactic or therapeutic agents may be administered to a
subject by the same or different routes of administration.
[0346] The invention having been fully described, it is further
illustrated by the following examples and claims, which are
illustrative and are not meant to be further limiting.
EXAMPLES
Example 1
Methods, Materials and Screening for Antibodies
(i) Cell Lines
[0347] SK-Br-3, BT-474 and MCF-7 cell lines were purchased from
ATCC and routinely maintained in growth media supplemented with 10%
fetal bovine serum (FBS).
(Ii) Generation of Recombinant Human, Cyno, Mouse and Rat HER3
Vectors
[0348] Murine HER3 extracellular domain was PCR amplified from
mouse brain cDNA (Clontech) and sequence verified by comparison
with Refseq NM.sub.--010153. Rat HER3 ECD was reverse transcribed
from Rat-2 cell mRNA and sequence verified by comparison with
NM.sub.--017218. Cynomolgus HER3 cDNA template was generated using
RNA from various cyno tissues (Zyagen Laboratories), and the RT-PCR
product cloned into pCR.RTM.-TOPO-XL (Invitrogen) prior to
sequencing of both strands. Human HER3 was derived from a human
fetal brain cDNA library (Source) and sequence verified by
comparison with NM.sub.--001982.
[0349] To generate tagged recombinant proteins, human, mouse, rat
and cyno HER3 was PCR amplified using Pwo Taq polymerase (Roche
Diagnostics). Amplified PCR products were gel purified and cloned
into a pDonR201 (Invitrogen) gateway entry vector that had
previously been modified to include an in-frame N-terminal CD33
leader sequence and a C-terminal TAG, e.g., FLAG TAG. The TAG
allows purification of monomeric proteins via an anti-TAG
monoclonal antibody. The target genes were flanked with AttB1 and
AttB2 allowing recombination into Gateway adapted proprietary
destination vectors (e.g., pcDNA3.1) using the Gateway.RTM. cloning
technology (Invitrogen). Recombination reactions were performed
using a Gateway LR reaction with proprietary destination vectors
containing a CMV promoter to create the TAG expression vectors,
although any commercially available vector can be used.
[0350] Further recombinant HER3 proteins were generated that fused
the HER3 ECD upstream of a C-terminal Factor X cleavage site and
the human IgG hinge and Fc domain to create an Fc-tagged protein.
To achieve this, the various HER3 ECD's were PCR amplified and
cloned into a vector (e.g., pcDNA3.1) modified to contain an
in-frame C-terminal fusion of Factor X site-Hinge-hFc. The
generated open reading frame was flanked with AttB and AttB2 sites
for further cloning with the Gateway.RTM. recombinant cloning
technology (Invitrogen). An LR Gateway reaction was used to
transfer HER3-Fc into a destination expression construct containing
a CMV promoter. HER3 point mutation expression constructs were
generated using standard site directed mutagenesis protocols and
the resultant vectors sequence verified.
TABLE-US-00004 TABLE 3 Generation of HER3 expression vectors. HER3
amino acid numbering is based on NP_001973 (human), NP_034283
(mouse) and NP_058914 (rat). Name Description Hu HER3 CD33-[Human
HER3, residues 20-640]-TAG Mu HER3 CD33-[Murine HER3, residues
20-643]-TAG Rat HER3 CD33-[Rat HER3, residues 20-643]-TAG Cyno HER3
CD33-[Cyno HER3, residues 20-643]-TAG HER3 D1-2 CD33-[Human HER3,
residues 20-329]-TAG HER3 D2 CD33-[Human HER3, residues
185-329]-TAG HER3 D3-4 CD33-[Human HER3, residues 330-643]-TAG HER3
D3 CD33-[Human HER3, residues 330-495]-TAG HER3 D4 CD33-[Human
HER3, residues 496-643]-TAG Hu HER3-Fc [Human HER3, residues
1-643]-Fc Mu HER3-Fc [Murine HER3, residues 1-643]-Fc Cyno HER3-Fc
[Cyno HER3, residues 1-643]-Fc Rat HER3-Fc [Rat HER3, residues
1-643]-Fc HER3 D2-Fc [Human HER3 residues 207-329]-Fc
(iii) Expression of Recombinant HER3 Proteins
[0351] The desired HER3 recombinant proteins were expressed in
HEK293 derived cell lines previously adapted to suspension culture
and grown in a Novartis proprietary serum-free medium. Small scale
expression verification was undertaken in transient 6-well-plate
transfection assays on the basis of lipofection. Large-scale
protein production via transient transfection and was performed at
the 10-20 L scale in the Wave.TM. bioreactor system (Wave Biotech).
DNA Polyethylenimine (Polysciences) was used as a plasmid carrier
at a ratio of 1:3 (w:w). The cell culture supernatants were
harvested 7-10 days post transfection and concentrated by
cross-flow filtration and diafiltration prior to purification.
(iv) Tagged Protein Purification
[0352] Recombinant tagged HER3 proteins (e.g., TAG-HER3) were
purified by collecting the cell culture supernatant and
concentrating 10-fold by cross-flow filtration with a 10 kDa cut
off filter (Fresenius). An anti-TAG column was prepared by coupling
an anti-TAG monoclonal antibody to CNBr activated Sepharose 4B at a
final ratio of 10 mg antibody per mL of resin. Concentrated
supernatant was applied to a 35 ml anti-Tag column at a flow rate
of 1-2 mL/minute. After base-line washing with PBS, bound material
was eluted with 100 mM glycine (pH 2.7), neutralized and sterile
filtered. Protein concentrations were determined by measuring the
absorbance at 280 nm and converting using a theoretical factor of
0.66 AU/mg. The purified protein was finally characterized by
SDS-PAGE, N-terminal sequencing and LC-MS.
(v) Fc Tag Purification
[0353] Concentrated cell culture supernatant was applied to a 50 ml
Protein A Sepharose Fast Flow column at a flow rate of 1 ml/min.
After baseline washing with PBS, the column was washed with 10
column volumes of 10 mM NaH.sub.2PO.sub.4/30% (v/v) Isopropanol, pH
7.3 followed by 5 column volumes of PBS. Finally, bound material
was eluted with 50 mM Citrate/140 mM NaCl (pH 2.7), neutralized and
sterile filtered.
(vi) HuCAL GOLD.RTM. OR PLATINUM.RTM. Pannings
[0354] For the selection of antibodies recognizing human HER3
multiple panning strategies were employed. Therapeutic antibodies
against human HER3 protein were generated by selection of clones
having high binding affinities, using as the source of antibody
variant proteins a commercially available phage display library,
the MorphoSys HuCAL GOLD.RTM. or Platinum.RTM. library. The
phagemid library is based on the HuCAL.RTM. concept (Knappik et
al., (2000) J Mol Biol 296:57-86) and employs the CysDisplay.RTM.
technology for displaying the Fab on the phage surface (WO01/05950
to Lohning).
[0355] For the isolation of anti-HER3 antibodies, standard as well
as RapMAT panning strategies were performed using solid phase,
solution, whole cell and differential whole cell panning
approaches.
(vii) Solid Phase Panning
[0356] To identify anti-HER3 antibodies a variety of solid phase
panning strategies were performed using differing recombinant HER3
proteins. To perform each round of solid phase panning, Maxisorp
plates (Nunc) were coated with HER3 protein. Tagged proteins were
either captured using plates previously coated with anti-Fc (goat
or mouse anti-human IgG, Jackson Immuno Research), anti-Tag
antibody or via passive adsorption. The coated plates were washed
with PBS and blocked. Coated plates were washed twice with PBS
prior to the addition of HuCAL GOLD.RTM. or Platinum.RTM.
phage-antibodies for 2 hours at room temperature on a shaker. Bound
phages were eluted were added to E. coli TG-1 and incubated for
phage infection. Subsequently infected bacteria were isolated and
plated on agar plates. Colonies were scraped off the plates and
phages were rescued and amplified. Each HER3 panning strategy
comprised of individual rounds of panning and contained unique
antigens, antigen concentrations and washing stringency.
(viii) Solution Phase Panning
[0357] Each round of solution phase panning was performed using
various biotinylated recombinant HER3 proteins in the presence or
absence of neuregulin 1-31 (R&D Systems). Proteins were
biotinylated using the EZ-link sulfo-NHS-LC biotinylation kit
(Pierce) according to the manufacturers instructions. 800 .mu.l of
Streptavidin linked magnetic beads (Dynabeads, Dynal) were washed
once with PBS and blocked overnight with Chemiblocker (Chemicon).
HuCAL GOLD.RTM. or Platinum.RTM. phage-antibodies and the
appropriate biotinylated HER3 were incubated in a reaction tube.
Streptavidin magnetic beads were added for 20 minutes and were
collected with a magnetic particle separator (Dynal). Bound phages
were eluted from the Dynabeads by adding DTT containing buffer to
each tube and added to E. coli TG-1. Phage infection was performed
in an identical manner to that described in solid phase panning.
Each HER3 panning strategy comprised of individual rounds of
panning and contained unique antigens, antigen concentrations and
washing stringency. In order to isolate antibodies targeting a
specific epitope, competition pannings were performed. In these
panning strategies HER3 was incubated and pre-blocked with a
reference antibody prior to addition of HuCAL GOLD.RTM. or
Platinum.RTM. phage-antibodies. As an alternative strategy
reference antibodies were used to specifically elute
phage-antibodies complexed with HER3.
(ix) Cell Based Panning
[0358] For cell pannings, HuCAL GOLD.RTM. or Platinum.RTM.
phage-antibodies were incubated with approximately 10.sup.7 cells
on a rotator for 2 hours at room temperature, followed by
centrifugation. The cell pellet was isolated phages were eluted
from the cells The supernatant was collected and added to E. coli
TG-1 culture continued by the process described above. Two cell
based strategies were employed to identify anti-HER3 antibodies:
[0359] a) Whole cell panning: In this strategy a variety of intact
cell lines were used as the antigens. [0360] b) Differential whole
cell panning: In this strategy the antigens sequentially consisted
of cells and recombinant HER3 proteins. The cell based pannings
were performed as described above whilst solid phase panning
protocols were employed when recombinant proteins were utilized as
antigens. The washes were conducted using PBS (2-3.times.) and PBST
(2-3.times.).
(x) RapMAT.TM. Library Generation and Pannings
[0361] In order to increase antibody binding affinity whilst
maintaining library diversity the second round output of both
solution and solid phase pannings were entered into the RapMAT.TM.
process whilst the third round output of the whole cell and
differential whole cell panning strategies were entered (Prassler
et al., (2009) Immunotherapy; 1: 571-583). RapMAT.TM. libraries
were generated by sub-cloning Fab-encoding inserts of phages
selected via panning into the display vector pMORPH.RTM.25_bla_LHC
and were further digested to either generate H-CDR2RapMAT.TM.
libraries and L-CDR3RapMAT.TM. libraries by using specific
restriction enzymes. The inserts were replaced with TRIM maturation
cassettes (Virnekas et al., (1994) Nucleic Acids Research
22:5600-5607) for H-CDR2 or L-CDR3 according to pool composition.
Library sizes were estimated to range between
8.times.10.sup.6-1.times.10.sup.8 clones. RapMAT antibody-phage
were produced and subjected to two further rounds of solution,
solid phase or cell based panning using the experimental methods
described previously.
[0362] This extensive panning strategy, involving an iterative
refinement of library design was specifically developed to bias
screening away from pure ligand-competitive antibodies by including
ligand-blocking antibodies directly in the pannings. Secondly, the
FAB to IgG conversion process was adapted to maximize the recovery
of candidate clones and ensure that all selective binders were
profiled in functional assays. From 44 initial pannings, yielding
around 28 families of specific Her3 binding antibodies, only three
antibody families displayed the desired property of blocking both
ligand-dependent and independent signal transduction. Family A that
binds isolated domains 1-2 and 2 of Her3. Family B that binds
isolated domains 3-4, but not 4 alone; and family C, which binds
domain 3.
Example 2
Transient Expression of Anti-HER3 IgG's
[0363] Suspension adapted HEK293-6E cells were cultivated in a
BioWave20. The cells were transiently transfected with the relevant
sterile DNA: PEI-MIX and further cultivated. After transfection,
cells were removed by crossflow filtration using Fresenius filters.
The cell free material was concentrated with crossflow filtration
using a cut off filter (Fresenius) and the concentrate was sterile
filtered through a stericup filter. The sterile supernatant was
stored at 4.degree. C.
Example 3
Purification of anti-HER3 IgG
[0364] The purification of IgG was performed on a AKTA 100 explorer
Air chromatography system in a cooling cabinet, using a XK16/20
column with 25 mL of self-packed MabSelect SuRe resin (all GE
Healthcare). All flow rates were 3.5 mL/min, except for loading, at
a pressure limit of 5 bar. The column was equilibrated with 3
column volumes of PBS prior to loading the filtered fermentation
supernatant. The column was washed with PBS. IgG was eluted with a
pH gradient, starting at citrate/NaCl (pH 4.5), going linearly down
to citrate/NaCl (pH 2.5), followed by a constant step of the same
pH 2.5 buffer. The IgG containing fractions were pooled and
immediately neutralized and sterile filtered (Millipore Steriflip,
0.22 um). OD.sub.280 was measured and the protein concentration
calculated based on the sequence data. The pools were separately
tested for aggregation (SEC-MALS) and purity (SDS-PAGE and MS).
Example 4
Expression and Purification of HuCAL.RTM.-Fab Antibodies in E.
coli
[0365] Expression of Fab fragments encoded by pMORPH.RTM.X9_Fab_MH
in TG-1 cells was carried out in shaker flask cultures using YT
medium supplemented with chloramphenicol. Cultures were shaken
until the OD600 nm reached 0.5. Expression was induced by addition
of IPTG (isopropyl-.beta.-D-thiogalactopyranoside). Cells were
disrupted using lysozyme. His.sub.6-tagged Fab (`His.sub.6`
disclosed as SEQ ID NO: 702) fragments were isolated via IMAC
(Bio-Rad). Buffer exchange to 1.times. Dulbecco's PBS (pH 7.2) was
performed using PD10 columns. Samples were sterile filtered.
Protein concentrations were determined by UV-spectrophotometry. The
purity of the samples was analyzed in denaturing, reducing 15%
SDS-PAGE. The homogeneity of Fab preparations was determined in
native state by size exclusion chromatography (HP-SEC) with
calibration standards.
Example 5
HER3 Antibody Affinity (K.sub.D) Measurements by Solution
Equilibrium Titration (SET)
[0366] Affinity determination in solution was essentially performed
as previously described (Friguet et al., (1985) J Immunol Methods
77:305-19). In order to improve the sensitivity and accuracy of the
SET method, it was transferred from classical ELISA to ECL based
technology (Haenel et al., (2005) Anal biochem 339:182-84).
[0367] Unlabeled HER3-Tag (human, rat, mouse or cyno) described
previously was used for affinity determination by SET.
[0368] The data was evaluated with XLfit software (ID Business
Solutions) applying customized fitting models. For K.sub.D
determination of each IgG the following model was used (modified
according to Piehler, et al (Piehler et al., (1997) J Immunol
Methods 201:189-206).
y = 2 B max [ IgG ] ( [ IgG ] 2 - ( x + [ IgG ] + K D 2 - ( x + [
IgG ] + K D ) 2 4 - x [ IgG ] ) 2 2 [ IgG ] ) ##EQU00001##
[IgG]: applied total IgG concentration x: applied total soluble
antigen concentration (binding sites) B.sub.max: maximal signal of
IgG without antigen K.sub.D: affinity
Example 6
Antibody Cell Binding Determination by FACS
[0369] The binding of antibodies to endogenous human antigen
expressed on human cancer cells was accessed by FACS. In order to
determine antibody EC.sub.50 values SK-Br-3 cells were harvested
with accutase and diluted to 1.times.10.sup.6 cells/mL in FACS
buffer (PBS/3% FBS/0.2% NaN.sub.3). 1.times.10.sup.5 cells/well
were added to each well of a 96-well plate (Nunc) and centrifuged
at 210 g for 5 minutes at 4.degree. C. before removing the
supernatant. Serial dilutions of test antibodies (diluted in 1:4
dilution steps with FACS buffer) were added to the pelleted cells
and incubated for 1 hour on ice. The cells were washed and pelleted
three times with 100 L FACS buffer. PE conjugated goat anti-human
IgG (Jackson ImmunoResearch) diluted 1/200 with FACS buffer were
added to the cells and incubated on ice for 1 hour. Additional
washing steps were performed three times with 100 .mu.L FACS buffer
followed by centrifugation steps at 210 g for 5 minutes at
4.degree. C. Finally, cells were resuspended in 200 .mu.L FACS
buffer and fluorescence values were measured with a FACSArray (BD
Biosciences). The amount of cell surface bound anti-HER3 antibody
was assessed by measuring the mean channel fluorescence.
Example 7
HER3Domain Binding
[0370] 96-well Maxisorp plates (Nunc) were coated overnight with
200 ng of the appropriate recombinant human protein (HER3-Tag,
D1-2-Tag, D2-Tag, D3-4-Tag, D4-Tag, and a tagged irrelevant control
protein). All wells were then washed with PBS/0.1% Tween-20,
blocked with PBS/1% BSA/0.1% Tween-20 and washed with PBS/0.1%
Tween-20. Anti-HER3 antibodies were added to the relevant wells up
to a final concentration of 10 .mu.g/mL and incubated at room
temperature. Plates were washed with PBS/0.1% Tween-20 prior to the
addition of the appropriate peroxidase linked detection antibody
diluted 1/10000 in PBS/1% BSA/0.1% Tween-20. The detection
antibodies used were goat anti-mouse (Pierce, 31432), rabbit
anti-goat (Pierce, 31402) and goat anti-human (Pierce, 31412).
Plates were incubated at room temperature before washing with
PBS/0.1% Tween-20. 100 .mu.l TMB (3,3',5,5' tetramethyl benzidine)
substrate solution (BioFx) was added to all wells before stopping
the reaction with 50 .mu.l 12.5% H.sub.2SO.sub.4. The extent of
HER3 antibody binding to each recombinant protein was determined by
measuring the OD.sub.450 using a SpectraMax plate reader (Molecular
Devices). Where appropriate, dose response curves were analyzed
using Graphpad Prism.
Example 8
X-Ray Crystallographic Structure Determination of the Human
HER3/MOR12604 Fab Complex
[0371] The present example presents the crystal structure of HER3
bound to the Fab fragment of MOR12604 determined at 3.38 .ANG.
resolution. Tagged human HER3 extracellular domainwas further
purified on a HiLoad 26/60 Superdex 200 PrepGrade column (GE
Healthcare) equilibrated in PBS (pH 7.3). MOR12604 Fab was
expressed in E. coli and purified as previously described.
HER3/MOR12604-Fab complex was prepared by mixing excess MOR12604
Fab with tagged HER3 in a molar ratio of 2:1 (concentration
estimated by LCUV methods) and purifying the complex on a Superdex
200 10/300 column (GE Healthcare) equilibrated in 25 mM Tris (pH
7.5), 150 mM NaCl. Peak fractions were analyzed by SDS-PAGE and
LCMS. Fractions containing both HER3 and Fab in an approximate
equimolar ratio were pooled and concentrated to 10 mg/ml.
HER3/MOR12604 crystals were grown at 293K by sitting drop vapor
diffusion from drops containing 150 nl HER3/MOR12604 complex and
150 nl of reservoir solution (200 mM di-potassium hydrogen
phosphate and 20% PEG 3350). Crystals were transferred to 200 mM
di-potassium hydrogen phosphate, 25% PEG 3350 and 15% glycerol and
flash cooled in liquid nitrogen.
[0372] Data were collected at beamline 17-ID at the Advanced Photon
Source (Argonne National Laboratory). HER3/MOR12604 Fab complex
data were processed and scaled at 3.38 .ANG. using autoPROC (Global
Phasing, LTD) in space group P2.sub.12.sub.12.sub.1 with cell
dimensions a=56.15, b=174.71, c=186.64 .ANG., with good statistics.
The HER3/MOR12604 Fab structure was solved by molecular replacement
using Phaser (McCoy et al., (2007) J. Appl. Cryst. 40:658-674) with
the published HER3 ECD structure lmb6 and a proprietary Fab as
search models. The final model, which contains 1 molecule of the
HER3/MOR12604 Fab complex per asymmetric unit, was built in COOT
(Emsley & Cowtan (2004) Acta Cryst. 60:2126-2132) and refined
to R and Rfree values of 19.9 and 23.3%, respectively, with an rmsd
of 0.008 .ANG. and 1.19.degree. for bond lengths and bond angles,
respectively, using BUSTER (Global Phasing, LTD). Residues of HER3
that contain atoms within 5 .ANG. of any atom in MOR12604 Fab as
identified in PyMOL (Schrodinger, LLC) are listed in Tables 5 and
6.
Example 9
Phospho-HER3 In Vitro Cell Assays
[0373] MCF-7 cells were routinely maintained in DMEM/F 12, 15 mM
HEPES, L-glutamine, 10% FBS, BT474 in DMEM, 10% FBS and SK-Br-3 in
McCoy's 5a, 10% FBS, 1.5 mM L-glutamine. Sub-confluent cells were
trypsinized, washed with PBS and diluted to 5.times.10.sup.5
cells/mL. 100 .mu.L of cell suspension was then added to each well
of a 96-well flat bottomed plate (Nunc) to give a final density of
5.times.10.sup.4 cells/well. MCF7 cells were allowed to attach for
approximately 3 hours before the media was exchanged for starvation
media containing 0.5% FBS. All plates were then incubated overnight
at 37.degree. C. prior to treatment with the appropriate
concentration of HER3 antibodies for 80 minutes at 37.degree. C.
MCF7 cells were treated with 50 ng/mL NRG1 for the final 20 minutes
to stimulate HER3 and AKT phosphorylation whilst BT474/SK-Br-3
cells required no additional stimulation. All media was gently
aspirated and the cells washed with ice-cold PBS containing 1 mM
CaCl.sub.2 and 0.5 mM MgCl.sub.2 (Gibco). The cells were lysed by
adding 50 L ice-cold lysis buffer (20 mM Tris (pH8.0)/137 mM
NaCl/10% Glycerol/2 mM EDTA/1% NP-40/1 mM sodium
orthovanadate/1.times. Phospho-Stop/1.times. Complete mini protease
inhibitors (Roche)/0.1 mM PMSF) and incubated on ice with shaking
for 30 minutes. Lysates were then collected and spun at 1800 g for
15 minutes at 4.degree. C. to remove cell debris.
[0374] HER3 capture plates were generated using a carbon plate
(Mesoscale Discovery) coated overnight at 4.degree. C. with 20
.mu.L of 4 .mu.g/mL MAB3481 capture antibody (R&D Systems)
diluted in PBS and subsequently blocked with 3% bovine serum
albumin in 1.times. Tris buffer (Mesoscale Discovery)/0.1%
Tween-20. HER3 was captured by adding the appropriate amount of
lysate and incubating the plate at room temperature for one hour
with shaking before the lysate was aspirated and the wells washed
with 1.times. Tris buffer (Mesoscale Discovery)/0.1% Tween-20.
Phosphorylated HER3 was detected using 1:8000 anti-pY1197 antibody
(Cell Signaling) prepared in 3% milk/1.times. Tris/0.1% Tween-20 by
incubating with shaking at room temperature for 1 hour. The wells
were washed four times with 1.times. Tris/0.1% Tween-20 and
phosphorylated proteins were detected by incubating with S-Tag
labelled goat anti-rabbit Ab (#R32AB) diluted in 3% blocking buffer
for one hour at room temperature. Each well was aspirated and
washed four times with 1.times. Tris/0.1% Tween-20 before adding 20
.mu.L of Read buffer T with surfactant (Mesoscale Discovery) and
the signal quantified using a Mesoscale Sector Imager.
Example 10
Phospho-Akt (S473) In Vitro Cell Assays
[0375] Sub-confluent MCF7, SK-Br-3 and BT-474 cells were grown in
complete media were harvested with accutase (PAA Laboratories) and
resuspended in the appropriate growth media at a final
concentration of 5.times.10.sup.5 cells/mL. 100 .mu.L of cell
suspension was then added to each well of a 96-well flat bottomed
plate (Nunc) to yield a final density of 5.times.10.sup.4
cells/well. MCF7 cells were allowed to attach for approximately 3
hours before the media was exchanged for starvation media
containing 0.5% FBS. All plates were then incubated overnight at
37.degree. C. prior to treatment with the appropriate concentration
of HER3 antibodies for 80 minutes at 37.degree. C. MCF7 cells were
treated with 50 ng/mL NRG1 for the final 20 minutes to stimulate
HER3 and AKT phosphorylation whilst SK-Br-3 cells required no
additional stimulation. All media was gently aspirated and the
cells washed with ice-cold PBS containing 1 mM CaCl.sub.2 and 0.5
mM MgCl.sub.2 (Gibco). The cells were lysed by adding 50 .mu.L
ice-cold lysis buffer (20 mM Tris (pH8.0)/137 mM NaCl/10%
Glycerol/2 mM EDTA/1% NP-40/1 mM sodium orthovanadate/Aprotinin (10
.mu.g/mL)/Leupeptin (10 .mu.g/mL)) and incubated on ice with
shaking for 30 minutes. Lysates were then collected and spun at
1800 g for 15 minutes at 4.degree. C. to remove cell debris. 20
.mu.L of lysate was added to a multi-spot 384-well Phospho-Akt
carbon plate (Mesoscale Discovery) that had previously been blocked
with 3% BSA/1.times. Tris/0.1% Tween-20. The plate was incubated at
room temperature for two hours with shaking before the lysate was
aspirated and the wells washed four times with 1.times. Tris buffer
(Mesoscale Discovery)/0.1% Tween-20. Phosphorylated Akt was
detected using 20 .mu.L of SULFO-TAG anti-phospho-Akt (S473)
antibody (Mesoscale Discovery) diluted 50-fold in 1% BSA/1.times.
Tris/0.1% Tween-20 by incubating with shaking at room temperature
for 2 hours. The wells were washed four times with 1.times.
Tris/0.1% Tween-20 before adding 20 .mu.L of Read buffer T with
surfactant (Mesoscale Discovery) and the signal quantified using a
Mesoscale Sector Imager.
Example 11
Cell-Line Proliferation Assays
[0376] SK-Br-3 cells were routinely cultured in McCoy's 5A medium
modified, supplemented with 10% fetal bovine serum and BT-474 cells
were cultured in DMEM supplemented with 10% FBS. Sub-confluent
cells were trypsinized, washed with PBS, diluted to
5.times.10.sup.4 cells/mL with growth media and plated in 96-well
clear bottom black plates (Costar 3904) at a density of 5000
cells/well. The cells were incubated overnight at 37.degree. C.
before adding the appropriate concentration of HER3 antibody
(typical final concentrations of 10 or 1 .mu.g/mL). The plates were
returned to the incubator for 6 days before assessing cell
viability using CellTiter-Glo (Promega). 100 L of CellTiter-Glo
solution was added to each well and incubated at room temperature
with gentle shaking for 10 minutes. The amount of luminescence was
determined using a SpectraMax plate reader (Molecular Devices). The
extent of growth inhibition obtained with each antibody was
calculated by comparing the luminscence values obtained with each
HER3 antibody to a standard isotype control antibody.
[0377] For proliferation assays MCF-7 cells were routinely cultured
in DMEM/F12 (1:1) containing 4 mM L-Glutamine/15 mM HEPES/10% FBS.
Sub-confluent cells were trypsinized, washed with PBS and diluted
to 1.times.10.sup.5 cells/mL with DMEM/F12 (1:1) containing 4 mM
L-Glutamine/15 mM HEPES/10 .mu.g/mL Human Transferrin/0.2% BSA.
Cells were plated in 96-well clear bottom black plates (Costar) at
a density of 5000 cells/well. The appropriate concentration of HER3
antibody (typical final concentrations of 10 or 1 .mu.g/mL) was
then added. 10 ng/mL of NRG1-.beta.1 EGF domain (R&D Systems)
was also added to the appropriate wells to stimulate cell growth.
The plates were returned to the incubator for 6 days before
assessing cell viability using CellTiter-Glo (Promega). The extent
of growth inhibition obtained with each antibody was calculated by
subtracting the background (no neuregulin) luminscence values and
comparing the resulting values obtained with each anti-HER3
antibody to a standard isotype control antibody.
Example 12
In Vivo BxPC3 Efficacy Studies
[0378] BxPC3 cells were cultured in RPMI-1640 medium containing 10%
heat-inactivated fetal bovine serum without antibiotics until the
time of implantation.
[0379] Female athymic nu/nu Balb/C mice (Harlan Laboratories) were
implanted subcutaneously with 10.times.10.sup.6 cells in a mixture
of 50% phosphate buffered saline with 50% matrigel. The total
injection volume containing cells in suspension was 200 .mu.L. Once
tumors had reached approximately 200 mm3 in size, animals were
enrolled in the efficacy study. In general, a total of 10 animals
per group were enrolled in studies. Animals were excluded from
enrollment if they exhibited unusual tumor growth characteristics
prior to enrollment.
[0380] Animals were dosed intravenously via lateral tail vein
injection. Animals were on a 20 mg/kg, twice weekly schedule for
the duration of the study. Tumor volume and T/C values were
calculated as detailed for the BT-474 studies.
Example 13
In Vivo BT474 Efficacy Studies
[0381] BT-474 cells were cultured in DMEM containing 10%
heat-inactivated fetal bovine serum without antibiotics until the
time of implantation.
[0382] One day before cell inoculation, female athymic nu/nu Balb/C
mice (Harlan Laboratories) were implanted subcutaneously with a
sustained release 17.beta.-estradiol pellet (Innovative Research of
America) to maintain serum estrogen levels. One day after
17.beta.-estradiol pellet implantation, 5.times.10.sup.6 cells were
injected orthotopically into the 4th mammary fatpad in a suspension
containing 50% phenol red-free matrigel (BD Biosciences) in Hank's
balanced salt solution. The total injection volume containing cells
in suspension was 200 .mu.L. 20 days following cell implantation
animals with a tumor volume of approximately 200 mm.sup.3 were
enrolled in the efficacy study. In general, a total of 10 animals
per group were enrolled in efficacy studies.
[0383] For single-agent studies, animals were dosed intravenously
via lateral tail vein injection with control IgG or MOR12606 or
MOR13655. Animals were on a 20 mg/kg, twice weekly dosing schedule
for the duration of the study. For combination studies, animals
were dosed twice weekly at 20 mg/kg for both MOR10703 and MOR12606.
For the duration of the studies, tumor volume was measured by
calipering twice per week. Percent treatment/control (T/C) values
were calculated using the following formula:
% T/C=100.times..DELTA.T/.DELTA.C if .DELTA.T>0
where: T=mean tumor volume of the drug-treated group on the final
day of the study; .DELTA.T=mean tumor volume of the drug-treated
group on the final day of the study-mean tumor volume of the
drug-treated group on initial day of dosing; C=mean tumor volume of
the control group on the final day of the study; and .DELTA.C=mean
tumor volume of the control group on the final day of the
study-mean tumor volume of the control group on initial day of
dosing.
[0384] Body weight was measured twice per week and dose was body
weight adjusted. The % change in body weight was calculated as
(BWcurrent-BWinitial)/(BWinitial).times.100. Data is presented as
percent body weight change from the day of treatment
initiation.
[0385] All data were expressed as mean.+-.standard error of the
mean (SEM). Delta tumor volume and body weight were used for
statistical analysis. Between groups comparisons were carried out
using a one-way ANOVA followed by a post hoc Tukey. For all
statistical evaluations the level of significance was set at
p<0.05. Significance compared to the vehicle control group is
reported.
Results and Discussion
[0386] Collectively, these results show that a class of antibodies
bind to amino acid residues within domain 3 or 4. Binding of these
antibodies inhibits both ligand-dependent and ligand-independent
signaling.
(i) Affinity Determination
[0387] Antibody affinity was determined by solution equilibrium
titration (SET) as described above. The results are summarized in
Table 3 and example titration curves for MOR12615 and MOR12604 are
contained in FIG. 1. The data indicate that a number of antibodies
were identified that tightly bound human HER3.
TABLE-US-00005 TABLE 3 K.sub.D values of anti-HER3 IgGs as
determined by solution equilibrium titration (SET). SET K.sub.D
(pM) hu cy mu ra MOR# HER3-Tag HER3-Tag HER3-Tag HER3-Tag MOR12514
970 1400 2400 nd MOR12515 870 720 1500 nd MOR12516 1800 3600 3900
nd MOR12615 102 257 336 310 MOR12920 nd nd nd nd MOR12921 150 600
560 690 MOR12922 nd nd nd nd MOR13654 110 nd nd nd MOR13655 66 nd
nd nd MOR13656 nd nd nd Nd MOR13657 87 nd nd nd MOR13658 27 nd nd
nd MOR13659 nd nd nd nd MOR13660 nd nd nd nd MOR13661 nd nd nd nd
MOR13662 nd nd nd nd MOR13663 nd nd nd nd MOR13664 nd nd nd nd
MOR13665 nd nd nd nd MOR13666 150 nd nd nd MOR13667 nd nd nd nd
MOR13668 nd nd nd nd MOR13669 nd nd nd nd MOR13670 nd nd nd nd
MOR14537 210 140 220 285 MOR14538 45 26 23 51 MOR12603 2000 6100
4100 11000 MOR12604 1100 2200 1900 5200 MOR12605 1800 2900 2300
9600 MOR12606 1500 2600 1400 8100 MOR14533 640 2950 2000 9650
MOR14534 2150 6350 4000 30000 Hu (human), Cy (cynomolgus monkey),
Mu (murine) and ra (rat), nd (not determined).
(ii) SK-Br-3 Cell EC.sub.50 Determination
[0388] The ability of the identified antibodies to bind HER3
expressing cells was determined by calculating EC.sub.50 values for
their binding to the HER2 amplified cell line SK-Br-3 (see FIG. 2,
Table 4).
TABLE-US-00006 TABLE 4 FACS EC.sub.50 values of anti-HER3 IgG on
cells. MOR# SK-Br-3 FACS EC.sub.50 (pM) 14537 179 14538 279 14533
42 14534 28
(iii) HER3Domain Binding
[0389] A subset of anti-HER3 antibodies were characterized for
their ability to bind the various extracellular domains of human
HER3 in an ELISA assay. To achieve this, the extracellular domain
of HER3 was divided into its four constitutive domains and various
combinations of these domains were cloned, expressed and purified
as independent proteins as described above. Using this strategy the
following domains were successfully generated as soluble proteins:
domains 1 and 2 (D1-2), domain 2 (D2), domains 3 and 4 (D3-4) and
domain 4 (D4). The integrity of each isolated domain was previously
confirmed using a panel of internally generated antibodies as
positive controls.
[0390] As shown in FIG. 3, MOR12615 and MOR12604 were observed to
successfully bind the HER3 extracellular domain and isolated D3-4
protein. No binding was observed with D1-2 or D2 protein. This
binding data suggests that these antibodies recognize an epitope
primarily contained within domains 3 or 4. Interestingly, MOR12604
could bind isolated D3 protein suggesting that its epitope could be
further refined to residues within domain 3. Since MOR12615 and
MOR12604 are representative members of two distinct families of
anti-HER3 antibodies based upon their hCDR3 sequences antibodies
MOR12514, MOR12515, MOR12516, MOR12615, MOR12920, MOR12921,
MOR12922, MOR13654, MOR13655, MOR13656, MOR13657, MOR13658,
MOR13659, MOR13660, MOR13661, MOR13662, MOR13663, MOR13664,
MOR13665, MOR13666, MOR13667, MOR13668, MOR13669, MOR13670,
MOR14537 and MOR14538 can be classed as D3-4 binder. Antibodies
MOR12603, MOR12604, MOR12605, MOR12606, MOR14533 and MOR14534 can
be classed as D3 binders.
(Iv) HER3/MOR12604 Crystal Structure
[0391] The 3.38 .ANG. resolution x-ray crystal structure of
MOR12604 Fab fragment bound to the HER3 extracellular domain was
solved to further define the HER3 epitope that is recognized by
this family of related antibodies (see FIG. 4). Overlay of the
MOR12604/HER3 crystal structure with published HER3 crystal
structures suggested that HER3 bound by MOR12604 is in the tethered
(inactive) conformation (see FIG. 4B). This conformation is
characterized by a significant interaction interface between
domains 2 and 4 mediated by a (3-hairpin dimerization loop in
domain 2. The observed conformation of HER3 is similar to that
previously described by Cho et al. (Cho & Leahy, (2002),
Science 297:1330-1333) who published the crystal structure of the
HER3 extra-cellular domain in the absence of neuregulin. Since
neuregulin can activate HER3, the tethered conformation of HER3 is
presumed to be inactive. Similar tethered conformations have also
been observed when the related EGFR family members HER4 (Bouyain et
al., (2005) Proc. Natl. Acad. Sci. USA, 102:15024-15029) and HER1
(Ferguson et al., (2003) Molec. Cell 11:507-517) have been
crystallized.
[0392] The spatial relationships between domains 1 to 4 of HER3 in
the inactive (tethered) state are significantly different from that
of the extended (active) state. This finding is based upon the
crystal structures of the related EGFR family members HER2 and
ligand-bound HER1 (Cho et al., (2003) Nature 421:756-760; Ogiso et
al., (2002) Cell 110:775-787; Garrett et al., (2002) Cell
110:763-773) both of which are in an extended (active) state. In
the extended state, the domain 2.beta.-hairpin dimerization loop is
released from its inhibitory interaction with 4 and is thus free to
interact with its dimerization partner proteins. Thus, the domain 2
.beta.-hairpin dimerization loop is functionally important both in
maintaining the tethered (inactive) state and in mediating
dimerization of EGF receptors in the extended state, leading to
activation of the intracellular kinase domain.
[0393] In the crystal structure, electron density for MOR12604 Fab,
HER3 domain 3, HER3 domain 4 and a portion of domain 2 (residues
261-278) including the .beta.-hairpin dimerization loop were all
well defined. Weak or no electron density was observed for HER3
residues 20-260 and 279-303 which are located in domain 1 and
domain 2, suggesting that when HER3 is bound by MOR12604 it retains
some degree of flexibility. This finding is consistent with a
comparison of other crystal structures of HER3 alone and bound to
various Fab fragments that showed slight differences in relative
domain positioning within the tethered state.
[0394] The crystal structure also revealed that the HER3 epitope
recognized by MOR12604 is a non-linear epitope that includes
residues from domain 3 (see FIG. 4, Tables 5 and 6). The HER3
epitope recognized by this family of highly related antibodies can
therefore be defined as:
[0395] Domain 3: residues 335-342, 362-376, 398, 400, 424-428, 431,
433-434 and 455.
[0396] The MOR12604 binding surface can be further subdivided into
two surfaces highlighted as solid and dashed circles in FIG.
4D:
[0397] Surface A: residues 362-376
[0398] Surface B: residues 335-342, 398, 400, 424-428, 431, 433-434
and 455
[0399] Surface A or Surface B contribute approximately the same
surface area to the overall HER3/12604 interface (Surface A--640
.ANG..sup.2, Surface B--546 .ANG..sup.2).
[0400] Interestingly, MOR12604 binding to domain 3 resulted in a
significant conformational change in the loop defined by HER3
residues 371-377. This conformation of this loop is different from
other published HER3 structures thus suggesting that it is induced
by MOR12604 binding. The MOR12604 epitope determined from the
crystal structure is consistent with our ELISA domain binding data
where MOR12604 was determined to bind isolated D3 protein.
Furthermore, comparison of the MOR12604 epitope with the EGFR
residues contacted by TGF.alpha. highlighted a high degree of
overlap (Garrett et al., (2002) Cell 110:763-773). Since neuregulin
is thought to interact with HER3 in a similar manner to
TGF.alpha./EGFR it is highly likely that MOR12604 will prevent
ligand binding thus blocking neuregulin induced HER3
activation.
[0401] Binding within domain 3 by MOR12604 would suggest that
MOR12604 could function by any (or a combination) of the following
mechanisms:
[0402] by blocking HER3 residues required for ligand binding
[0403] by preventing HER3 adopting the active conformation due to
steric hindrance between the antibody and domains of HER3
[0404] by preventing HER3 adopting the active conformation by
reducing the degree of flexibility in HER3 hinge regions (e.g.
domain 3)
[0405] by inducing a conformational change in domain 3 loop 371-377
that prevents HER3 from transitioning to the open conformation
[0406] by destabilizing HER3 such that it is prone to
degradation
[0407] by acting as a partial agonist to accelerate the down
regulation of HER3
[0408] by inhibiting dimerization with a binding partner
[0409] by each arm of MOR12604 binding a molecule of HER3 such that
the antibody generates an un-natural HER3 dimer that is either
prone to proteolytic degradation or cannot dimerize with other
receptor tyrosine kinases
TABLE-US-00007 TABLE 5 Interactions between MOR12604 Fab heavy
chain and human HER3. Fab VH residues are numbered based upon their
linear amino acid sequence (SEQ ID NO: 1). HER3 residues are
numbered based upon NP_001973. HER3 residues shown have at least
one atom within 5 .ANG. of an atom in the MOR12604 Fab. MOR12604
Fab Human HER3 Residue Number Chain Residue Number Domain GLN 1 H
PRO 372 3 TRP 373 3 HIS 374 3 LYS 375 3 VAL 2 H PRO 372 3 TRP 373 3
LEU 4 H TRP 373 3 ALA 24 H TRP 373 3 THR 28 H TRP 373 3 PHE 29 H
TRP 373 3 TYR 32 H GLY 370 3 ASP 371 3 PRO 372 3 TRP 373 3 ILE 34 H
TRP 373 3 ARG 98 H ASP 371 3 TRP 373 3 TRP 100 H ILE 365 3 THR 366
3 ASN 369 3 GLY 370 3 ASP 371 3 PRO 101 H ILE 365 3 THR 366 3 TYR
102 H ILE 365 3 GLN 400 3 LYS 434 3 ASP 106 H ASP 371 3 PHE 107 H
ASP 371 3 TRP 373 3 HIS 374 3
TABLE-US-00008 TABLE 6 Interactions between MOR12604 Fab light
chain and human HER3. Fab VL residues are numbered based upon their
linear amino acid sequence (SEQ ID NO: 1). HER3 residues are
numbered based upon NP_001973. HER3 residues shown have at least
one atom within 5 .ANG. of an atom in the MOR12604 Fab. MOR12604
Fab Human HER3 Residue Number Chain Residue Number Domain VAL 30 L
MET 433 3 TYR 455 3 PHE 31 L ASN 425 3 PHE 428 3 LEU 431 3 MET 433
3 TYR 455 3 TYR 49 L LEU 364 3 ILE 365 3 THR 366 3 ASP 50 L GLN 400
3 TYR 424 3 LYS 434 3 ALA 51 L ASN 425 3 SER 52 L TYR 424 3 ASN 425
3 ASN 53 L ASP 362 3 LEU 364 3 ASN 398 3 GLN 400 3 TYR 424 3 ARG 54
L GLY 335 3 SER 336 3 GLY 337 3 SER 338 3 PHE 340 3 GLN 341 3 LEU
364 3 THR 366 3 ALA 55 L GLN 341 3 THR 56 L GLN 341 3 THR 366 3 HIS
374 3 THR 56 L ILE 376 3 GLY 57 L GLN 341 3 VAL 58 L GLN 341 3 ALA
60 L GLY 337 3 SER 338 3 GLY 64 L ASN 425 3 SER 65 L ASN 425 3 ARG
426 3 GLY 66 L ASN 425 3 ARG 426 3 SER 67 L ASN 425 3 ARG 426 3 LYS
91 L LYS 434 3
(v) Inhibition of Cell Signaling
[0410] To ascertain the effect of anti-HER3 antibodies upon ligand
dependent HER3 activity MCF7 cells were incubated with IgG prior to
stimulation with neuregulin. Example inhibition curves are
illustrated in FIG. 5 and summarized in Table 7. The effect of
anti-HER3 antibodies upon HER2-mediated HER3 activation was also
studied using the HER2 amplified cell lines SK-Br-3 and BT474 (FIG.
6, FIG. 7, and Table 7).
TABLE-US-00009 TABLE 7 pHER3 IC.sub.50 and extent of inhibition
values of anti-HER3 IgG in MCF7, BT474 and SK-Br-3 cells. MCF7
pHER3 SK-Br-3 pHER3 BT474 pHER3 IC.sub.50 % IC.sub.50 % IC.sub.50 %
MOR# (pM) inhibition (pM) inhibition (pM) inhibition MOR12514 435
67 223 77 707 70 MOR12515 674 71 278 76 365 71 MOR12516 590 62 1873
74 nd 63 MOR12615 447 75 179 71 421 56 MOR12920 3066 66 851 57 2021
57 MOR12921 1230 79 252 68 418 65 MOR12922 788 62 81 64 702 58
MOR13654 331 77 182 69 195 61 MOR13655 149 80 90 69 19 61 MOR13656
504 73 86 60 nd nd MOR13657 283 75 142 71 372 63 MOR13658 459 83
347 74 571 67 MOR13659 505 66 277 51 nd nd MOR13660 533 49 188 54
nd nd MOR13661 649 55 421 55 nd nd MOR13662 550 52 331 56 nd nd
MOR13663 449 58 290 56 nd nd MOR13664 480 55 388 57 nd nd MOR13665
795 62 546 59 nd nd MOR13666 168 73 166 69 420 65 MOR13667 603 72
267 59 nd nd MOR13668 1640 77 657 58 nd nd MOR13669 nd 66 743 58 nd
nd MOR13670 643 69 730 60 nd nd MOR14537 200 73 97 69 nd nd
MOR14538 615 83 263 71 nd nd MOR12603 11 77 18 74 79 70 MOR12604 57
79 29 71 142 62 MOR12605 318 89 7 73 1486 64 MOR12606 34 87 25 75
108 73 MOR14533 50 67 20 68 nd nd MOR14534 16 71 10 63 nd nd
[0411] To determine whether inhibition of HER3 activity impacted
downstream cell signaling, Akt, phosphorylation was measured in NRG
stimulated MCF7 cells and HER2 amplified SK-Br-3/BT474 cells
following treatment with anti-HER3 antibodies (see FIG. 5, FIG. 6,
and Table 8)
TABLE-US-00010 TABLE 8 pAkt (S.sup.473) IC.sub.50 and extent of
inhibition values of anti-HER3 IgG in SK-Br-3, BT-474 and MCF7
cells SK-Br-3 pAkt BT-474 pAkt MCF7 pAkt IC.sub.50 % IC.sub.50 %
IC.sub.50 % MOR# (pM) inhibition (pM) inhibition (pM) inhibition
MOR12514 nd nd nd nd nd nd MOR12515 nd nd nd nd nd nd MOR12516 nd
nd nd nd nd nd MOR12615 101 86 466 63 815 78 MOR12920 nd nd nd nd
nd nd MOR12921 nd nd nd nd nd nd MOR12922 nd nd nd nd nd nd
MOR13654 89 92 142 58 244 72 MOR13655 62 86 nd 50 251 79 MOR13656
nd nd nd nd nd nd MOR13657 33 91 586 53 385 75 MOR13658 172 92 461
56 341 81 MOR13659 nd nd nd nd nd nd MOR13660 nd nd nd nd nd nd
MOR13661 nd nd nd nd nd nd MOR13662 nd nd nd nd nd nd MOR13663 nd
nd nd nd nd nd MOR13664 nd nd nd nd nd nd MOR13665 nd nd nd nd nd
nd MOR13666 78 90 275 50 49 72 MOR13667 nd nd nd nd nd nd MOR13668
nd nd nd nd nd nd MOR13669 nd nd nd nd nd nd MOR13670 nd nd nd nd
nd nd MOR14537 nd nd nd nd nd nd MOR14538 nd nd nd nd nd nd
MOR12603 17 84 137 77 nd nd MOR12604 17 85 225 70 235 74 MOR12605
140 84 173 67 533 76 MOR12606 8 85 91 77 nd nd MOR14533 nd nd nd nd
nd nd MOR14534 nd nd nd nd nd nd
[0412] In summary MOR12514, MOR12515, MOR12516, MOR12615, MOR12920,
MOR12921, MOR12922, MOR13654, MOR13655, MOR13656, MOR13657,
MOR13658, MOR13659, MOR13660, MOR13661, MOR13662, MOR13663,
MOR13664, MOR13665, MOR13666, MOR13667, MOR13668, MOR13669,
MOR13670, MOR14537, MOR14538, MOR12603, MOR12604, MOR12605,
MOR12606, MOR14533 and MOR14534 are each capable of inhibiting
cellular HER3 activity and downstream signaling in both a
ligand-dependent and ligand-independent manner.
(vi) Inhibition of Proliferation
[0413] Since MOR12514, MOR12515, MOR12516, MOR12615, MOR12920,
MOR12921, MOR12922, MOR13654, MOR13655, MOR13656, MOR13657,
MOR13658, MOR13659, MOR13660, MOR13661, MOR13662, MOR13663,
MOR13664, MOR13665, MOR13666, MOR13667, MOR13668, MOR13669,
MOR13670, MOR14537, MOR14538, MOR12603, MOR12604, MOR12605,
MOR12606, MOR14533 and MOR14534 are capable of inhibiting HER3
activity a sub-set were tested for their ability to block ligand
dependent and independent in vitro cell growth (example data is
shown in FIG. 8, FIG. 9, FIG. 10 and summarized in Table 9). The
anti-HER3 antibodies tested were all effective inhibitors of cell
proliferation thus confirming that antibodies that bind D3 or D3-4
are capable of inhibiting HER3 driven phenotypes.
TABLE-US-00011 TABLE 9 Inhibition of proliferation following
treatment with anti-HER3 IgG in SK-Br-3, BT-474 and MCF7 cells.
SK-Br-3 BT-474 MCF7 IC.sub.50 % IC.sub.50 % IC.sub.50 % in- MOR#
(pM) inhibition (pM) inhibition (pM) hibition MOR12514 44 36 nd nd
317 29 MOR12515 278 36 nd nd 1091 26 MOR12516 2082 34 nd nd 492 34
MOR12615 121 40 459 35 2537 42 MOR12920 2910 32 nd nd 1921 22
MOR12921 432 42 nd nd 2310 31 MOR12922 709 36 nd nd 467 27 MOR13654
136 34 632 27 nd nd MOR13655 74 39 141 31 86 46 MOR13656 nd nd nd
nd nd nd MOR13657 179 39 473 30 nd nd MOR13658 191 42 423 34 174 49
MOR13659 nd nd nd nd nd nd MOR13660 nd nd nd nd nd nd MOR13661 nd
nd nd nd nd nd MOR13662 nd nd nd nd nd nd MOR13663 nd nd nd nd nd
nd MOR13664 nd nd nd nd nd nd MOR13665 nd nd nd nd nd nd MOR13666
870 39 1120 31 nd nd MOR13667 nd nd nd nd nd nd MOR13668 nd nd nd
nd nd nd MOR13669 nd nd nd nd nd nd MOR13670 nd nd nd nd nd nd
MOR14537 47 48 nd nd nd nd MOR14538 81 53 nd nd nd nd MOR12603 34
36 136 37 58 44 MOR12604 15 42 nd nd 73 39 MOR12605 0.01 29 nd nd
28 45 MOR12606 nd 36 127 40 52 39 MOR14533 26 46 nd nd nd nd
MOR14534 27 40 nd nd nd nd
(vii) In Vivo Inhibition of Tumor Growth
[0414] To determine the in vivo activity of the described anti-HER3
antibodies, MOR12606 and MOR13655 were tested for anti-tumor
activity in both BxPC3 and BT-474 tumor models. Repeated dosing of
the BxPC3 model using MOR12606 or MOR13655 yielded 25% regression
and 5% T/C, respectively FIG. 11A).
[0415] Single agent treatment of the HER2-driven BT474 model with
either MOR12606 or MOR13655 resulted in 53% or 46% T/C,
respectively (FIG. 11B).
[0416] We also investigated the effect of combining two
HER3-targeted antibodies that bind two distinct, non-overlapping
epitopes. Repeated dosing of the BT474 model with a combination of
MOR10703 and MOR12606 yielded 7% T/C (FIG. 12).
INCORPORATION BY REFERENCE
[0417] All references cited herein, including patents, patent
applications, papers, text books, and the like, and the references
cited therein, to the extent that they are not already, are hereby
incorporated herein by reference in their entirety.
EQUIVALENTS
[0418] The foregoing written specification is considered to be
sufficient to enable one skilled in the art to practice the
invention. The foregoing description and examples detail certain
preferred embodiments of the invention and describe the best mode
contemplated by the inventors. It will be appreciated, however,
that no matter how detailed the foregoing may appear in text, the
invention may be practiced in many ways and the invention should be
construed in accordance with the appended claims and any
equivalents thereof.
Sequence CWU 1
1
70211342PRTHomo sapiens 1Met Arg Ala Asn Asp Ala Leu Gln Val Leu
Gly Leu Leu Phe Ser Leu 1 5 10 15 Ala Arg Gly Ser Glu Val Gly Asn
Ser Gln Ala Val Cys Pro Gly Thr 20 25 30 Leu Asn Gly Leu Ser Val
Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr 35 40 45 Leu Tyr Lys Leu
Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu 50 55 60 Ile Val
Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile 65 70 75 80
Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr 85
90 95 Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr
Asp 100 105 110 Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr
Asn Ser Ser 115 120 125 His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu
Thr Glu Ile Leu Ser 130 135 140 Gly Gly Val Tyr Ile Glu Lys Asn Asp
Lys Leu Cys His Met Asp Thr 145 150 155 160 Ile Asp Trp Arg Asp Ile
Val Arg Asp Arg Asp Ala Glu Ile Val Val 165 170 175 Lys Asp Asn Gly
Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly 180 185 190 Arg Cys
Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr 195 200 205
Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn 210
215 220 Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln
Asp 225 230 235 240 Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser
Gly Ala Cys Val 245 250 255 Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn
Lys Leu Thr Phe Gln Leu 260 265 270 Glu Pro Asn Pro His Thr Lys Tyr
Gln Tyr Gly Gly Val Cys Val Ala 275 280 285 Ser Cys Pro His Asn Phe
Val Val Asp Gln Thr Ser Cys Val Arg Ala 290 295 300 Cys Pro Pro Asp
Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys 305 310 315 320 Glu
Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser 325 330
335 Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val
340 345 350 Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr
Gly Leu 355 360 365 Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp
Pro Glu Lys Leu 370 375 380 Asn Val Phe Arg Thr Val Arg Glu Ile Thr
Gly Tyr Leu Asn Ile Gln 385 390 395 400 Ser Trp Pro Pro His Met His
Asn Phe Ser Val Phe Ser Asn Leu Thr 405 410 415 Thr Ile Gly Gly Arg
Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile 420 425 430 Met Lys Asn
Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu 435 440 445 Ile
Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr 450 455
460 His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu
465 470 475 480 Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys
Val Ala Glu 485 490 495 Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly
Gly Cys Trp Gly Pro 500 505 510 Gly Pro Gly Gln Cys Leu Ser Cys Arg
Asn Tyr Ser Arg Gly Gly Val 515 520 525 Cys Val Thr His Cys Asn Phe
Leu Asn Gly Glu Pro Arg Glu Phe Ala 530 535 540 His Glu Ala Glu Cys
Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu 545 550 555 560 Gly Thr
Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys 565 570 575
Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly 580
585 590 Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln
Asn 595 600 605 Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys
Lys Gly Pro 610 615 620 Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val
Leu Ile Gly Lys Thr 625 630 635 640 His Leu Thr Met Ala Leu Thr Val
Ile Ala Gly Leu Val Val Ile Phe 645 650 655 Met Met Leu Gly Gly Thr
Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln 660 665 670 Asn Lys Arg Ala
Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu 675 680 685 Pro Leu
Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe 690 695 700
Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe 705
710 715 720 Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser
Ile Lys 725 730 735 Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser
Gly Arg Gln Ser 740 745 750 Phe Gln Ala Val Thr Asp His Met Leu Ala
Ile Gly Ser Leu Asp His 755 760 765 Ala His Ile Val Arg Leu Leu Gly
Leu Cys Pro Gly Ser Ser Leu Gln 770 775 780 Leu Val Thr Gln Tyr Leu
Pro Leu Gly Ser Leu Leu Asp His Val Arg 785 790 795 800 Gln His Arg
Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val 805 810 815 Gln
Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His 820 825
830 Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val
835 840 845 Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp
Asp Lys 850 855 860 Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys
Trp Met Ala Leu 865 870 875 880 Glu Ser Ile His Phe Gly Lys Tyr Thr
His Gln Ser Asp Val Trp Ser 885 890 895 Tyr Gly Val Thr Val Trp Glu
Leu Met Thr Phe Gly Ala Glu Pro Tyr 900 905 910 Ala Gly Leu Arg Leu
Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu 915 920 925 Arg Leu Ala
Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met 930 935 940 Val
Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu 945 950
955 960 Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr
Leu 965 970 975 Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly
Pro Glu Pro 980 985 990 His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val
Glu Leu Glu Pro Glu 995 1000 1005 Leu Asp Leu Asp Leu Asp Leu Glu
Ala Glu Glu Asp Asn Leu Ala 1010 1015 1020 Thr Thr Thr Leu Gly Ser
Ala Leu Ser Leu Pro Val Gly Thr Leu 1025 1030 1035 Asn Arg Pro Arg
Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly 1040 1045 1050 Tyr Met
Pro Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu 1055 1060 1065
Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser 1070
1075 1080 Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser
Glu 1085 1090 1095 Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu
Lys Val Ser 1100 1105 1110 Met Cys Arg Ser Arg Ser Arg Ser Arg Ser
Pro Arg Pro Arg Gly 1115 1120 1125 Asp Ser Ala Tyr His Ser Gln Arg
His Ser Leu Leu Thr Pro Val 1130 1135 1140 Thr Pro Leu Ser Pro Pro
Gly Leu Glu Glu Glu Asp Val Asn Gly 1145 1150 1155 Tyr Val Met Pro
Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg 1160 1165 1170 Glu Gly
Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr 1175 1180 1185
Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg 1190
1195 1200 Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu
Glu 1205 1210 1215 Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp
Leu Ser Ala 1220 1225 1230 Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu
His Pro Val Pro Ile 1235 1240 1245 Met Pro Thr Ala Gly Thr Thr Pro
Asp Glu Asp Tyr Glu Tyr Met 1250 1255 1260 Asn Arg Gln Arg Asp Gly
Gly Gly Pro Gly Gly Asp Tyr Ala Ala 1265 1270 1275 Met Gly Ala Cys
Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg 1280 1285 1290 Ala Phe
Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala 1295 1300 1305
Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe 1310
1315 1320 Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala
Asn 1325 1330 1335 Ala Gln Arg Thr 1340 25PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 2Ser
Tyr Ala Ile Ser 1 5 317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 3Leu Ile Ile Pro Arg Tyr Gly
Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly 49PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 4Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 57PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 5Gly
Gly Thr Phe Ser Ser Tyr 1 5 66PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 6Ile Pro Arg Tyr Gly Lys 1 5
79PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 7Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
811PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 8Arg Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5
10 97PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 9Asp Ala Ser Asn Arg Ala Thr 1 5 109PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 10Gln
Gln His Gly Ser Gly Pro Thr Thr 1 5 117PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 11Ser
Gln Asn Ile Val Phe Asn 1 5 123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 12Asp Ala Ser 1
136PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 13His Gly Ser Gly Pro Thr 1 5 14118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
14Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1
5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser
Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg
Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp
Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg
Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro
Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr
Val Ser Ser 115 15107PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 15Asp Ile Val Leu Thr Gln
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Gly Ser
Gly Pro Thr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 16354DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 16caggtgcaat tggttcagtc
tggcgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg
cacttttagc agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg
gtctcgagtg gatgggcctt attattcctc gttatggtaa ggctcgttat
180gctcagaagt ttcagggtcg ggtgaccatt accgcggatg aaagcaccag
caccgcgtat 240atggaactga gcagcctgcg tagcgaagat acggccgtgt
attattgcgc gcgtaattgg 300ccttattatt atatggattt ttggggccaa
ggcaccctgg tgacggttag ctca 35417321DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
17gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc
60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtttatta ttgccagcag
catggttctg gtcctactac ctttggccag 300ggtacgaaag ttgaaattaa a
32118448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 18Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro
Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg
Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215
220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315
320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr
Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
445 19214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 19Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Gly Ser Gly Pro Thr 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 201344DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 20caggtgcaat
tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag
cctccggagg cacttttagc agctatgcga ttagctgggt gcgccaagcc
120cctgggcagg gtctcgagtg gatgggcctt attattcctc gttatggtaa
ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt accgcggatg
aaagcaccag caccgcgtat 240atggaactga gcagcctgcg tagcgaagat
acggccgtgt attattgcgc gcgtaattgg 300ccttattatt atatggattt
ttggggccaa ggcaccctgg tgacggttag ctcagcctcc 360accaagggtc
catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca
420gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt
gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg
tcctacagtc ctcaggactc 540tactccctca gcagcgtggt gaccgtgccc
tccagcagct tgggcaccca gacctacatc 600tgcaacgtga atcacaagcc
cagcaacacc aaggtggaca agagagttga gcccaaatct 660tgtgacaaaa
ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca
720gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac
ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa gaccctgagg
tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa tgccaagaca
aagccgcggg aggagcagta caacagcacg 900taccgggtgg tcagcgtcct
caccgtcctg caccaggact ggctgaatgg caaggagtac 960aagtgcaagg
tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc
1020aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga
ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc aaaggcttct
atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca gccggagaac
aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct ccttcttcct
ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260gggaacgtct
tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag
1320agcctctccc tgtctccggg taaa 134421642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
21gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc
60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtttatta ttgccagcag
catggttctg gtcctactac ctttggccag 300ggtacgaaag ttgaaattaa
acgtacggtg gccgctccca gcgtgttcat cttccccccc 360agcgacgagc
agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac
420ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg
caacagccag 480gaaagcgtca ccgagcagga cagcaaggac tccacctaca
gcctgagcag caccctgacc 540ctgagcaagg ccgactacga gaagcacaag
gtgtacgcct gcgaggtgac ccaccagggc 600ctgtccagcc ccgtgaccaa
gagcttcaac cggggcgagt gt 642225PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 22Ser Tyr Ala Ile Ser 1 5
2317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 23Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala
Gln Lys Phe Gln 1 5 10 15 Gly 249PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 24Asn Trp Pro Tyr Tyr Tyr
Met Asp Phe 1 5 257PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 25Gly Gly Thr Phe Ser Ser Tyr 1 5
266PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 26Ile Pro Arg Tyr Gly Lys 1 5 279PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 27Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 2811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 28Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 297PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 29Asp
Ala Ser Asn Arg Ala Thr 1 5 309PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 30Gln Gln Thr Lys Asn Arg Pro
Pro Thr 1 5 317PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 31Ser Gln Asn Ile Val Phe Asn 1 5
323PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 32Asp Ala Ser 1 336PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 33Thr
Lys Asn Arg Pro Pro 1 5 34118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 34Gln Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe
Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
35107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 35Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Asn Arg Pro Pro 85 90
95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
36354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 36caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 35437321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 37gatatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
actaagaatc gtcctcctac ctttggccag 300ggtacgaaag ttgaaattaa a
32138448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 38Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro
Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg
Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215
220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340
345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
39214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 39Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Asn Arg Pro Pro 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 401344DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 40caggtgcaat
tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag
cctccggagg cacttttagc agctatgcga ttagctgggt gcgccaagcc
120cctgggcagg gtctcgagtg gatgggcctt attattcctc gttatggtaa
ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt accgcggatg
aaagcaccag caccgcgtat 240atggaactga gcagcctgcg tagcgaagat
acggccgtgt attattgcgc gcgtaattgg 300ccttattatt atatggattt
ttggggccaa ggcaccctgg tgacggttag ctcagcctcc 360accaagggtc
catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca
420gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt
gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg
tcctacagtc ctcaggactc 540tactccctca gcagcgtggt gaccgtgccc
tccagcagct tgggcaccca gacctacatc 600tgcaacgtga atcacaagcc
cagcaacacc aaggtggaca agagagttga gcccaaatct 660tgtgacaaaa
ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca
720gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac
ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa gaccctgagg
tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa tgccaagaca
aagccgcggg aggagcagta caacagcacg 900taccgggtgg tcagcgtcct
caccgtcctg caccaggact ggctgaatgg caaggagtac 960aagtgcaagg
tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc
1020aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga
ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc aaaggcttct
atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca gccggagaac
aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct ccttcttcct
ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260gggaacgtct
tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag
1320agcctctccc tgtctccggg taaa 134441642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
41gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc
60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
actaagaatc gtcctcctac ctttggccag 300ggtacgaaag ttgaaattaa
acgtacggtg gccgctccca gcgtgttcat cttccccccc 360agcgacgagc
agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac
420ccccgggagg ccaaggtgca gtggaaggtg
gacaacgccc tgcagagcgg caacagccag 480gaaagcgtca ccgagcagga
cagcaaggac tccacctaca gcctgagcag caccctgacc 540ctgagcaagg
ccgactacga gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc
600ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gt
642425PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 42Ser Tyr Ala Ile Ser 1 5 4317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 43Leu
Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 449PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 44Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
457PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 45Gly Gly Thr Phe Ser Ser Tyr 1 5
466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 46Ile Pro Arg Tyr Gly Lys 1 5 479PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 47Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 4811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 48Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 497PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 49Asp
Ala Ser Asn Arg Ala Thr 1 5 509PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 50Gln Gln Lys Lys Ser Met Pro
Leu Thr 1 5 517PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 51Ser Gln Asn Ile Val Phe Asn 1 5
523PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 52Asp Ala Ser 1 536PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 53Lys
Lys Ser Met Pro Leu 1 5 54118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 54Gln Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe
Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
55107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 55Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Lys Lys Ser Met Pro Leu 85 90
95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
56354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 56caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 35457321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 57gatatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
aagaagtcta tgcctcttac ctttggccag 300ggtacgaaag ttgaaattaa a
32158448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 58Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro
Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg
Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215
220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340
345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
59214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 59Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Lys Lys Ser Met Pro Leu 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 601344DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 60caggtgcaat
tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag
cctccggagg cacttttagc agctatgcga ttagctgggt gcgccaagcc
120cctgggcagg gtctcgagtg gatgggcctt attattcctc gttatggtaa
ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt accgcggatg
aaagcaccag caccgcgtat 240atggaactga gcagcctgcg tagcgaagat
acggccgtgt attattgcgc gcgtaattgg 300ccttattatt atatggattt
ttggggccaa ggcaccctgg tgacggttag ctcagcctcc 360accaagggtc
catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca
420gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt
gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg
tcctacagtc ctcaggactc 540tactccctca gcagcgtggt gaccgtgccc
tccagcagct tgggcaccca gacctacatc 600tgcaacgtga atcacaagcc
cagcaacacc aaggtggaca agagagttga gcccaaatct 660tgtgacaaaa
ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca
720gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac
ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa gaccctgagg
tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa tgccaagaca
aagccgcggg aggagcagta caacagcacg 900taccgggtgg tcagcgtcct
caccgtcctg caccaggact ggctgaatgg caaggagtac 960aagtgcaagg
tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc
1020aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga
ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc aaaggcttct
atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca gccggagaac
aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct ccttcttcct
ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260gggaacgtct
tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag
1320agcctctccc tgtctccggg taaa 134461642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
61gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc
60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
aagaagtcta tgcctcttac ctttggccag 300ggtacgaaag ttgaaattaa
acgtacggtg gccgctccca gcgtgttcat cttccccccc 360agcgacgagc
agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac
420ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg
caacagccag 480gaaagcgtca ccgagcagga cagcaaggac tccacctaca
gcctgagcag caccctgacc 540ctgagcaagg ccgactacga gaagcacaag
gtgtacgcct gcgaggtgac ccaccagggc 600ctgtccagcc ccgtgaccaa
gagcttcaac cggggcgagt gt 642625PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 62Ser Tyr Ala Ile Ser 1 5
6317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 63Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala
Gln Lys Phe Gln 1 5 10 15 Gly 649PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 64Asn Trp Pro Tyr Tyr Tyr
Met Asp Phe 1 5 657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 65Gly Gly Thr Phe Ser Ser Tyr 1 5
666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 66Ile Pro Arg Tyr Gly Lys 1 5 679PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 67Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 6811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 68Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 697PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 69Asp
Ala Ser Asn Arg Ala Thr 1 5 709PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 70Gln Gln Phe Arg Arg Lys Ser
Asn Thr 1 5 717PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 71Ser Gln Asn Ile Val Phe Asn 1 5
723PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 72Asp Ala Ser 1 736PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 73Phe
Arg Arg Lys Ser Asn 1 5 74118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 74Gln Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe
Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
75107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 75Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Arg Arg Lys Ser Asn 85 90
95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
76354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 76caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 35477321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 77gatatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
tttcgtcgta agtctaatac ctttggccag 300ggtacgaaag ttgaaattaa a
32178448PRTArtificial SequenceDescription of Artificial
Sequence
Synthetic polypeptide 78Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro
Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg
Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215
220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340
345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
79214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 79Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Arg Arg Lys Ser Asn 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 801344DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 80caggtgcaat
tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag
cctccggagg cacttttagc agctatgcga ttagctgggt gcgccaagcc
120cctgggcagg gtctcgagtg gatgggcctt attattcctc gttatggtaa
ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt accgcggatg
aaagcaccag caccgcgtat 240atggaactga gcagcctgcg tagcgaagat
acggccgtgt attattgcgc gcgtaattgg 300ccttattatt atatggattt
ttggggccaa ggcaccctgg tgacggttag ctcagcctcc 360accaagggtc
catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca
420gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt
gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg
tcctacagtc ctcaggactc 540tactccctca gcagcgtggt gaccgtgccc
tccagcagct tgggcaccca gacctacatc 600tgcaacgtga atcacaagcc
cagcaacacc aaggtggaca agagagttga gcccaaatct 660tgtgacaaaa
ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca
720gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac
ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa gaccctgagg
tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa tgccaagaca
aagccgcggg aggagcagta caacagcacg 900taccgggtgg tcagcgtcct
caccgtcctg caccaggact ggctgaatgg caaggagtac 960aagtgcaagg
tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc
1020aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga
ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc aaaggcttct
atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca gccggagaac
aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct ccttcttcct
ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260gggaacgtct
tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag
1320agcctctccc tgtctccggg taaa 134481642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
81gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc
60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
tttcgtcgta agtctaatac ctttggccag 300ggtacgaaag ttgaaattaa
acgtacggtg gccgctccca gcgtgttcat cttccccccc 360agcgacgagc
agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac
420ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg
caacagccag 480gaaagcgtca ccgagcagga cagcaaggac tccacctaca
gcctgagcag caccctgacc 540ctgagcaagg ccgactacga gaagcacaag
gtgtacgcct gcgaggtgac ccaccagggc 600ctgtccagcc ccgtgaccaa
gagcttcaac cggggcgagt gt 642825PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 82Ser Tyr Ala Ile Ser 1 5
8317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 83Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala
Gln Lys Phe Gln 1 5 10 15 Gly 849PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 84Asn Trp Pro Tyr Tyr Tyr
Met Asp Phe 1 5 857PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 85Gly Gly Thr Phe Ser Ser Tyr 1 5
866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 86Ile Pro Arg Tyr Gly Lys 1 5 879PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 87Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 8811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 88Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 897PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 89Asp
Ala Ser Asn Arg Ala Thr 1 5 9010PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 90Gln Gln Thr Lys Ser Lys
Pro Ser Pro Thr 1 5 10 917PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 91Ser Gln Asn Ile Val Phe Asn
1 5 923PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 92Asp Ala Ser 1 937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 93Thr
Lys Ser Lys Pro Ser Pro 1 5 94118PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 94Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
95108PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 95Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Ser Lys Pro Ser 85 90
95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
96354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 96caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 35497324DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 97gatatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
actaagtcta agccttctcc tacctttggc 300cagggtacga aagttgaaat taaa
32498448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 98Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro
Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg
Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met
Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215
220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340
345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
99215PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 99Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu
Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn
Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Ser Lys Pro Ser 85 90
95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205
Ser Phe Asn Arg Gly Glu Cys 210 215 1001344DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
100caggtgcaat tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag
cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc agctatgcga ttagctgggt
gcgccaagcc 120cctgggcagg gtctcgagtg gatgggcctt attattcctc
gttatggtaa ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt
accgcggatg aaagcaccag caccgcgtat 240atggaactga gcagcctgcg
tagcgaagat acggccgtgt attattgcgc gcgtaattgg 300ccttattatt
atatggattt ttggggccaa ggcaccctgg tgacggttag ctcagcctcc
360accaagggtc catcggtctt ccccctggca ccctcctcca agagcacctc
tgggggcaca 420gcggccctgg gctgcctggt caaggactac ttccccgaac
cggtgacggt gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc
ttcccggctg tcctacagtc ctcaggactc 540tactccctca gcagcgtggt
gaccgtgccc tccagcagct tgggcaccca gacctacatc 600tgcaacgtga
atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct
660tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg
gggaccgtca 720gtcttcctct tccccccaaa acccaaggac accctcatga
tctcccggac ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa
gaccctgagg tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa
tgccaagaca aagccgcggg aggagcagta caacagcacg 900taccgggtgg
tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac
960aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat
ctccaaagcc 1020aaagggcagc cccgagaacc acaggtgtac accctgcccc
catcccggga ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc
aaaggcttct atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca
gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct
ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag
1260gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta
cacgcagaag 1320agcctctccc tgtctccggg taaa 1344101645DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
101gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga
acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca
gcagaaacca 120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc
gtgcaactgg ggtcccggcg 180cgttttagcg gctctggatc cggcacggat
tttaccctga ccattagcag cctggaacct 240gaagactttg cggtgtatta
ttgccagcag actaagtcta agccttctcc tacctttggc 300cagggtacga
aagttgaaat taaacgtacg gtggccgctc ccagcgtgtt catcttcccc
360cccagcgacg agcagctgaa gagcggcacc gccagcgtgg tgtgcctgct
gaacaacttc 420tacccccggg aggccaaggt gcagtggaag gtggacaacg
ccctgcagag cggcaacagc 480caggaaagcg tcaccgagca ggacagcaag
gactccacct acagcctgag cagcaccctg 540accctgagca aggccgacta
cgagaagcac aaggtgtacg cctgcgaggt gacccaccag 600ggcctgtcca
gccccgtgac caagagcttc aaccggggcg agtgt 6451025PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 102Ser
Tyr Ala Ile Ser 1 5 10317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 103Leu Ile Ile Pro Arg Tyr
Gly Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
1049PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 104Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
1057PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 105Gly Gly Thr Phe Ser Ser Tyr 1 5
1066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 106Ile Pro Arg Tyr Gly Lys 1 5 1079PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 107Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 10811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 108Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 1097PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 109Asp
Ala Ser Asn Arg Ala Thr 1 5 1109PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 110Gln Gln Val Lys Lys Arg
Pro Phe Thr 1 5 1117PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 111Ser Gln Asn Ile Val Phe Asn 1 5
1123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 112Asp Ala Ser 1 1136PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 113Val
Lys Lys Arg Pro Phe 1 5 114118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 114Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
115107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 115Asp Ile Val Leu Thr Gln Ser Pro Ala Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser
Asn Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Val Lys Lys Arg Pro Phe 85
90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
116354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 116caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 354117321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 117gatatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
ggtcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
gttaagaagc gtccttttac ctttggccag 300ggtacgaaag ttgaaattaa a
321118448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 118Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile
Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly
Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu
Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser
Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210
215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp
Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val
Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330
335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
119214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 119Asp Ile Val Leu Thr Gln Ser Pro Ala Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser
Asn Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Val Lys Lys Arg Pro Phe 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 1201344DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
120caggtgcaat tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag
cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc agctatgcga ttagctgggt
gcgccaagcc 120cctgggcagg gtctcgagtg gatgggcctt attattcctc
gttatggtaa ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt
accgcggatg aaagcaccag caccgcgtat 240atggaactga gcagcctgcg
tagcgaagat acggccgtgt attattgcgc gcgtaattgg 300ccttattatt
atatggattt ttggggccaa ggcaccctgg tgacggttag ctcagcctcc
360accaagggtc catcggtctt ccccctggca ccctcctcca agagcacctc
tgggggcaca 420gcggccctgg gctgcctggt caaggactac ttccccgaac
cggtgacggt gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc
ttcccggctg tcctacagtc ctcaggactc 540tactccctca gcagcgtggt
gaccgtgccc tccagcagct tgggcaccca gacctacatc 600tgcaacgtga
atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct
660tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg
gggaccgtca 720gtcttcctct tccccccaaa acccaaggac accctcatga
tctcccggac ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa
gaccctgagg tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa
tgccaagaca aagccgcggg aggagcagta caacagcacg 900taccgggtgg
tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac
960aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat
ctccaaagcc 1020aaagggcagc cccgagaacc acaggtgtac accctgcccc
catcccggga ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc
aaaggcttct atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca
gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct
ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag
1260gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta
cacgcagaag 1320agcctctccc tgtctccggg taaa 1344121642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
121gatatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga
acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca
gcagaaacca 120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc
gtgcaactgg ggtcccggcg 180cgttttagcg gctctggatc cggcacggat
tttaccctga ccattagcag cctggaacct 240gaagactttg cggtgtatta
ttgccagcag gttaagaagc gtccttttac ctttggccag 300ggtacgaaag
ttgaaattaa acgtacggtg gccgctccca gcgtgttcat cttccccccc
360agcgacgagc agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa
caacttctac 420ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc
tgcagagcgg caacagccag 480gaaagcgtca ccgagcagga cagcaaggac
tccacctaca gcctgagcag caccctgacc 540ctgagcaagg ccgactacga
gaagcacaag gtgtacgcct gcgaggtgac ccaccagggc 600ctgtccagcc
ccgtgaccaa gagcttcaac cggggcgagt gt 6421225PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 122Ser
Tyr Ala Ile Ser 1 5 12317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 123Leu Ile Ile Pro Arg Tyr
Gly Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
1249PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 124Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
1257PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 125Gly Gly Thr Phe Ser Ser Tyr 1 5
1266PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 126Ile Pro Arg Tyr Gly Lys 1 5 1279PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 127Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 12811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 128Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 1297PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 129Asp
Ala Ser Asn Arg Ala Thr 1 5 1309PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 130Gln Gln Ser Tyr Thr Arg
Pro Thr Thr 1 5 1317PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 131Ser Gln Asn Ile Val Phe Asn 1 5
1323PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 132Asp Ala Ser 1 1336PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 133Ser
Tyr Thr Arg Pro Thr 1 5 134118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 134Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro
Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro Arg Tyr
Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr
Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu
Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr 100 105
110 Leu Val Thr Val Ser Ser 115 135107PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
135Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Val
Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val
Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Ser Tyr Thr Arg Pro Thr 85 90 95 Thr Phe Gly Gln
Gly Thr Lys Val Glu Ile Lys 100 105 136354DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
136caggtgcaat tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag
cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc agctatgcga ttagctgggt
gcgccaagcc 120cctgggcagg gtctcgagtg gatgggcctt attattcctc
gttatggtaa ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt
accgcggatg aaagcaccag caccgcgtat 240atggaactga gcagcctgcg
tagcgaagat acggccgtgt attattgcgc gcgtaattgg 300ccttattatt
atatggattt ttggggccaa ggcaccctgg tgacggttag ctca
354137321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 137gatatcgtgc tgacccagag cccggcgacc
ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt
tttaatctgg cttggtacca gcagaaacca 120ggtcaagcac cgcgtctatt
aatttatgat gcttctaatc gtgcaactgg ggtcccggcg 180cgttttagcg
gctctggatc cggcacggat tttaccctga ccattagcag cctggaacct
240gaagactttg cggtgtatta ttgccagcag tcttatactc gtcctactac
ctttggccag 300ggtacgaaag ttgaaattaa a 321138448PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
138Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala
Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala
Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp
Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130
135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gln Thr Tyr Ile
Cys Asn Val Asn His Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210 215 220 His Thr Cys Pro
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250
255 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375
380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 445 139214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
139Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Val
Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Val
Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Ser Tyr Thr Arg Pro Thr 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 1401344DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 140caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctcagcctcc 360accaagggtc catcggtctt ccccctggca
ccctcctcca agagcacctc tgggggcaca 420gcggccctgg gctgcctggt
caaggactac ttccccgaac cggtgacggt gtcgtggaac 480tcaggcgccc
tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc
540tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca
gacctacatc 600tgcaacgtga atcacaagcc cagcaacacc aaggtggaca
agagagttga gcccaaatct 660tgtgacaaaa ctcacacatg cccaccgtgc
ccagcacctg aactcctggg gggaccgtca 720gtcttcctct tccccccaaa
acccaaggac accctcatga tctcccggac ccctgaggtc 780acatgcgtgg
tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg
840gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta
caacagcacg 900taccgggtgg tcagcgtcct caccgtcctg caccaggact
ggctgaatgg caaggagtac 960aagtgcaagg tctccaacaa agccctccca
gcccccatcg agaaaaccat ctccaaagcc 1020aaagggcagc cccgagaacc
acaggtgtac accctgcccc catcccggga ggagatgacc 1080aagaaccagg
tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg
1140gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc
cgtgctggac 1200tccgacggct ccttcttcct ctacagcaag ctcaccgtgg
acaagagcag gtggcagcag 1260gggaacgtct tctcatgctc cgtgatgcat
gaggctctgc acaaccacta cacgcagaag 1320agcctctccc tgtctccggg taaa
1344141642DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 141gatatcgtgc tgacccagag cccggcgacc
ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt
tttaatctgg cttggtacca gcagaaacca 120ggtcaagcac cgcgtctatt
aatttatgat gcttctaatc gtgcaactgg ggtcccggcg 180cgttttagcg
gctctggatc cggcacggat tttaccctga ccattagcag cctggaacct
240gaagactttg cggtgtatta ttgccagcag tcttatactc gtcctactac
ctttggccag 300ggtacgaaag ttgaaattaa acgtacggtg gccgctccca
gcgtgttcat cttccccccc 360agcgacgagc agctgaagag cggcaccgcc
agcgtggtgt gcctgctgaa caacttctac 420ccccgggagg ccaaggtgca
gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480gaaagcgtca
ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc
540ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac
ccaccagggc 600ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gt
6421425PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 142Ser Tyr Ala Ile Ser 1 5 14317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 143Leu
Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 1449PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 144Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
1457PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 145Gly Gly Thr Phe Ser Ser Tyr 1 5
1466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 146Ile Pro Arg Tyr Gly Lys 1 5 1479PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 147Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 14811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 148Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 1497PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 149Asp
Ala Ser Asn Arg Ala Thr 1 5 15010PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 150Gln Gln Thr Lys Ser Lys
Pro Ser Pro Thr 1 5 10 1517PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 151Ser Gln Asn Ile Val Phe
Asn 1 5 1523PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 152Asp Ala Ser 1 1537PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 153Thr
Lys Ser Lys Pro Ser Pro 1 5 154118PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 154Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
155108PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 155Glu Ile Val Leu Thr Gln Ser Pro Ala Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser
Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Ser Lys Pro Ser 85
90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
156354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 156caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 354157324DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 157gagatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
gatcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
actaagtcta agccttctcc tacctttggc 300cagggtacga aagttgaaat taaa
324158448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 158Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile
Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly
Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu
Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser
Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210
215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp
Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val
Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295
300 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr 325 330 335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys
Asn Gln Val Ser Leu Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420
425 430 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 435 440 445 159215PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 159Glu Ile Val Leu Thr
Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala
Thr Leu Ser Cys Arg Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40
45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys
Ser Lys Pro Ser 85 90 95 Pro Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170
175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215
1601344DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 160caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctcagcctcc 360accaagggtc catcggtctt ccccctggca
ccctcctcca agagcacctc tgggggcaca 420gcggccctgg gctgcctggt
caaggactac ttccccgaac cggtgacggt gtcgtggaac 480tcaggcgccc
tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc
540tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca
gacctacatc 600tgcaacgtga atcacaagcc cagcaacacc aaggtggaca
agagagttga gcccaaatct 660tgtgacaaaa ctcacacatg cccaccgtgc
ccagcacctg aactcctggg gggaccgtca 720gtcttcctct tccccccaaa
acccaaggac accctcatga tctcccggac ccctgaggtc 780acatgcgtgg
tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg
840gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta
caacagcacg 900taccgggtgg tcagcgtcct caccgtcctg caccaggact
ggctgaatgg caaggagtac 960aagtgcaagg tctccaacaa agccctccca
gcccccatcg agaaaaccat ctccaaagcc 1020aaagggcagc cccgagaacc
acaggtgtac accctgcccc catcccggga ggagatgacc 1080aagaaccagg
tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg
1140gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc
cgtgctggac 1200tccgacggct ccttcttcct ctacagcaag ctcaccgtgg
acaagagcag gtggcagcag 1260gggaacgtct tctcatgctc cgtgatgcat
gaggctctgc acaaccacta cacgcagaag 1320agcctctccc tgtctccggg taaa
1344161645DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 161gagatcgtgc tgacccagag cccggcgacc
ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt
tttaatctgg cttggtacca gcagaaacca 120ggtcaagcac cgcgtctatt
aatttatgat gcttctaatc gtgcaactgg gatcccggcg 180cgttttagcg
gctctggatc cggcacggat tttaccctga ccattagcag cctggaacct
240gaagactttg cggtgtatta ttgccagcag actaagtcta agccttctcc
tacctttggc 300cagggtacga aagttgaaat taaacgtacg gtggccgctc
ccagcgtgtt catcttcccc 360cccagcgacg agcagctgaa gagcggcacc
gccagcgtgg tgtgcctgct gaacaacttc 420tacccccggg aggccaaggt
gcagtggaag gtggacaacg ccctgcagag cggcaacagc 480caggaaagcg
tcaccgagca ggacagcaag gactccacct acagcctgag cagcaccctg
540accctgagca aggccgacta cgagaagcac aaggtgtacg cctgcgaggt
gacccaccag 600ggcctgtcca gccccgtgac caagagcttc aaccggggcg agtgt
6451625PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 162Ser Tyr Ala Ile Ser 1 5 16317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 163Leu
Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 1649PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 164Asn Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5
1657PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 165Gly Gly Thr Phe Ser Ser Tyr 1 5
1666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 166Ile Pro Arg Tyr Gly Lys 1 5 1679PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 167Asn
Trp Pro Tyr Tyr Tyr Met Asp Phe 1 5 16811PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 168Arg
Ala Ser Gln Asn Ile Val Phe Asn Leu Ala 1 5 10 1697PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 169Asp
Ala Ser Asn Arg Ala Thr 1 5 1709PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 170Gln Gln Thr Lys Asn Arg
Pro Pro Thr 1 5 1717PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 171Ser Gln Asn Ile Val Phe Asn 1 5
1723PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 172Asp Ala Ser 1 1736PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 173Thr
Lys Asn Arg Pro Pro 1 5 174118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 174Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Leu Ile Ile Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
175107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 175Glu Ile Val Leu Thr Gln Ser Pro Ala Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser
Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Asn Arg Pro Pro 85
90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
176354DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 176caggtgcaat tggttcagtc tggcgcggaa
gtgaaaaaac cgggcagcag cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc
agctatgcga ttagctgggt gcgccaagcc 120cctgggcagg gtctcgagtg
gatgggcctt attattcctc gttatggtaa ggctcgttat 180gctcagaagt
ttcagggtcg ggtgaccatt accgcggatg aaagcaccag caccgcgtat
240atggaactga gcagcctgcg tagcgaagat acggccgtgt attattgcgc
gcgtaattgg 300ccttattatt atatggattt ttggggccaa ggcaccctgg
tgacggttag ctca 354177321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 177gagatcgtgc
tgacccagag cccggcgacc ctgagcctgt ctccgggcga acgtgcgacc 60ctgagctgca
gagcgagcca gaatattgtt tttaatctgg cttggtacca gcagaaacca
120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc gtgcaactgg
gatcccggcg 180cgttttagcg gctctggatc cggcacggat tttaccctga
ccattagcag cctggaacct 240gaagactttg cggtgtatta ttgccagcag
actaagaatc gtcctcctac ctttggccag 300ggtacgaaag ttgaaattaa a
321178448PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 178Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Leu Ile Ile
Pro Arg Tyr Gly Lys Ala Arg Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Asn Trp Pro Tyr Tyr Tyr Met Asp Phe Trp Gly Gln Gly
Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
Val Phe Pro 115 120 125 Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
Thr Ala Ala Leu Gly 130 135 140 Cys Leu Val Lys Asp Tyr Phe Pro Glu
Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ala Leu Thr Ser
Gly Val His Thr Phe Pro Ala Val Leu Gln 165 170 175 Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser 195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr 210
215 220 His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
Met Ile Ser Arg 245 250 255 Thr Pro Glu Val Thr Cys Val Val Val Asp
Val Ser His Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn Trp Tyr Val
Asp Gly Val Glu Val His Asn Ala 275 280 285 Lys Thr Lys Pro Arg Glu
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 325 330
335 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
Thr Cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser 370 375 380 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg Trp Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala 420 425 430 Leu His Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445
179214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 179Glu Ile Val Leu Thr Gln Ser Pro Ala Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Asn Ile Val Phe Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser
Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys Asn Arg Pro Pro 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 1801344DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
180caggtgcaat tggttcagtc tggcgcggaa gtgaaaaaac cgggcagcag
cgtgaaagtg 60agctgcaaag cctccggagg cacttttagc agctatgcga ttagctgggt
gcgccaagcc 120cctgggcagg gtctcgagtg gatgggcctt attattcctc
gttatggtaa ggctcgttat 180gctcagaagt ttcagggtcg ggtgaccatt
accgcggatg aaagcaccag caccgcgtat 240atggaactga gcagcctgcg
tagcgaagat acggccgtgt attattgcgc gcgtaattgg 300ccttattatt
atatggattt ttggggccaa ggcaccctgg tgacggttag ctcagcctcc
360accaagggtc catcggtctt ccccctggca ccctcctcca agagcacctc
tgggggcaca 420gcggccctgg gctgcctggt caaggactac ttccccgaac
cggtgacggt gtcgtggaac 480tcaggcgccc tgaccagcgg cgtgcacacc
ttcccggctg tcctacagtc ctcaggactc 540tactccctca gcagcgtggt
gaccgtgccc tccagcagct tgggcaccca gacctacatc 600tgcaacgtga
atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct
660tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg
gggaccgtca 720gtcttcctct tccccccaaa acccaaggac accctcatga
tctcccggac ccctgaggtc 780acatgcgtgg tggtggacgt gagccacgaa
gaccctgagg tcaagttcaa ctggtacgtg 840gacggcgtgg aggtgcataa
tgccaagaca aagccgcggg aggagcagta caacagcacg 900taccgggtgg
tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac
960aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat
ctccaaagcc 1020aaagggcagc cccgagaacc acaggtgtac accctgcccc
catcccggga ggagatgacc 1080aagaaccagg tcagcctgac ctgcctggtc
aaaggcttct atcccagcga catcgccgtg 1140gagtgggaga gcaatgggca
gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200tccgacggct
ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag
1260gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta
cacgcagaag 1320agcctctccc tgtctccggg taaa 1344181642DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
181gagatcgtgc tgacccagag cccggcgacc ctgagcctgt ctccgggcga
acgtgcgacc 60ctgagctgca gagcgagcca gaatattgtt tttaatctgg cttggtacca
gcagaaacca 120ggtcaagcac cgcgtctatt aatttatgat gcttctaatc
gtgcaactgg gatcccggcg 180cgttttagcg gctctggatc cggcacggat
tttaccctga ccattagcag cctggaacct 240gaagactttg cggtgtatta
ttgccagcag
actaagaatc gtcctcctac ctttggccag 300ggtacgaaag ttgaaattaa
acgtacggtg gccgctccca gcgtgttcat cttccccccc 360agcgacgagc
agctgaagag cggcaccgcc agcgtggtgt gcctgctgaa caacttctac
420ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tgcagagcgg
caacagccag 480gaaagcgtca ccgagcagga cagcaaggac tccacctaca
gcctgagcag caccctgacc 540ctgagcaagg ccgactacga gaagcacaag
gtgtacgcct gcgaggtgac ccaccagggc 600ctgtccagcc ccgtgaccaa
gagcttcaac cggggcgagt gt 6421825PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 182Ser Tyr Asp Ile His 1 5
18317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 183Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr
Ala Gln Lys Phe Gln 1 5 10 15 Gly 18412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 184Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
1857PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 185Gly Tyr Thr Phe Thr Ser Tyr 1 5
1866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 186Asp Pro Tyr Ser Gly Asn 1 5 18712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 187Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
18814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 188Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 1897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 189Gly Val Ser Lys Arg Pro
Ser 1 5 19010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 190Gln Val Arg Asp Met Ser Leu Phe Asp
Val 1 5 10 19110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 191Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 1923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 192Gly Val Ser 1 1937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 193Arg
Asp Met Ser Leu Phe Asp 1 5 194121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 194Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 195110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 195Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Val Arg Asp
Met Ser 85 90 95 Leu Phe Asp Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 196363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 196caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363197330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 197gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc caggttcgtg acatgtctct
gttcgacgtg 300tttggcggcg gcacgaagtt aaccgtccta
330198451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 198Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 199216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 199Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Val Arg Asp
Met Ser 85 90 95 Leu Phe Asp Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
2001353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 200caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353201648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 201gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
caggttcgtg acatgtctct gttcgacgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6482025PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 202Ser
Tyr Asp Ile His 1 5 20317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 203Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
20412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 204Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 2057PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 205Gly Tyr Thr Phe Thr Ser Tyr 1 5
2066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 206Asp Pro Tyr Ser Gly Asn 1 5 20712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 207Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
20814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 208Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 2097PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 209Gly Val Ser Lys Arg Pro
Ser 1 5 21010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 210Tyr Ser Arg Asp Ser Pro Met Asp Gln
Val 1 5 10 21110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 211Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 2123PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 212Gly Val Ser 1 2137PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 213Arg
Asp Ser Pro Met Asp Gln 1 5 214121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 214Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 215110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 215Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Tyr Ser Arg Asp
Ser Pro 85 90 95 Met Asp Gln Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 216363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 216caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tca 363217330DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
217gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tactctcgtg actctccgat ggaccaggtg 300tttggcggcg
gcacgaagtt aaccgtccta 330218451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 218Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 219216PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
219Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Tyr Ser Arg Asp Ser Pro 85 90 95 Met Asp Gln Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130
135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro
Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr
His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu
Cys Ser 210 215 2201353DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 220caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tcagcctcca
ccaagggtcc atcggtcttc cccctggcac cctcctccaa gagcacctct
420gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc
ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc gtgcacacct
tcccggctgt cctacagtcc 540tcaggactct actccctcag cagcgtggtg
accgtgccct ccagcagctt gggcacccag 600acctacatct gcaacgtgaa
tcacaagccc agcaacacca aggtggacaa gagagttgag 660cccaaatctt
gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg
720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat
ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg agccacgaag
accctgaggt caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat
gccaagacaa agccgcggga ggagcagtac 900aacagcacgt accgggtggt
cagcgtcctc accgtcctgc accaggactg gctgaatggc 960aaggagtaca
agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc
1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc
atcccgggag 1080gagatgacca agaaccaggt cagcctgacc tgcctggtca
aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag
ccggagaaca actacaagac cacgcctccc 1200gtgctggact ccgacggctc
cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg
ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac
1320acgcagaaga gcctctccct gtctccgggt aaa 1353221648DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
221gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tactctcgtg actctccgat ggaccaggtg 300tttggcggcg
gcacgaagtt aaccgtccta ggtcagccca aggctgcccc ctcggtcact
360ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt
gtgtctcata 420agtgacttct acccgggagc cgtgacagtg gcctggaagg
cagatagcag ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa
caaagcaaca acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga
gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600catgaaggga
gcaccgtgga gaagacagtg gcccctacag aatgttca 6482225PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 222Ser
Tyr Asp Ile His 1 5 22317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 223Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
22412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 224Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 2257PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 225Gly Tyr Thr Phe Thr Ser Tyr 1 5
2266PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 226Asp Pro Tyr Ser Gly Asn 1 5 22712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 227Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
22814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 228Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 2297PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 229Gly Val Ser Lys Arg Pro
Ser 1 5 23011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 230Gln Ser Arg Asp Thr Tyr Arg Pro Val
Lys Val 1 5 10 23110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 231Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 2323PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 232Gly Val Ser 1 2338PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 233Arg
Asp Thr Tyr Arg Pro Val Lys 1 5 234121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
234Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 235111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
235Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gln Ser Arg Asp Thr Tyr 85 90 95 Arg Pro Val Lys
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
236363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 236caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363237333DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
237gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc cagtctcgtg acacttaccg tccggttaaa 300gtgtttggcg
gcggcacgaa gttaaccgtc cta 333238451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
238Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
239217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 239Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50
55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly
Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Arg
Asp Thr Tyr 85 90 95 Arg Pro Val Lys Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr
Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala
Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val
Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180
185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215
2401353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 240caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353241651DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 241gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
cagtctcgtg acacttaccg tccggttaaa 300gtgtttggcg gcggcacgaa
gttaaccgtc ctaggtcagc ccaaggctgc cccctcggtc 360actctgttcc
cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc
420ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag
cagccccgtc 480aaggcgggag tggagaccac cacaccctcc aaacaaagca
acaacaagta cgcggccagc 540agctatctga gcctgacgcc tgagcagtgg
aagtcccaca gaagctacag ctgccaggtc 600acgcatgaag ggagcaccgt
ggagaagaca gtggccccta cagaatgttc a 6512425PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 242Ser
Tyr Asp Ile His 1 5 24317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 243Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
24412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 244Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 2457PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 245Gly Tyr Thr Phe Thr Ser Tyr 1 5
2466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 246Asp Pro Tyr Ser Gly Asn 1 5 24712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 247Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
24814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 248Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 2497PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 249Gly Val Ser Lys Arg Pro
Ser 1 5 25010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 250Ser Ser Arg Asp Leu Ile Gly His Tyr
Val 1 5 10 25110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 251Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 2523PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 252Gly Val Ser 1 2537PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 253Arg
Asp Leu Ile Gly His Tyr 1 5 254121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 254Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 255110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 255Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp
Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 256363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 256caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363257330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 257gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tcttctcgtg acctgatcgg
tcattacgtg 300tttggcggcg gcacgaagtt aaccgtccta
330258451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 258Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 259216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 259Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp
Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
2601353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 260caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353261648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 261gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
tcttctcgtg acctgatcgg tcattacgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6482625PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 262Gly
Tyr Tyr Met His 1 5 26317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 263Asp Ile Glu Pro Tyr His
Gly Lys Pro Leu Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
26412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 264Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 2657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 265Gly Tyr Thr Phe Thr Gly Tyr 1 5
2666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 266Glu Pro Tyr His Gly Lys 1 5 26712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 267Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr
Phe Asp Val 1 5 10 26814PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 268Thr Gly Thr Ser Ser Asp
Val Gly Thr Tyr Asn Gln Val Ser 1 5 10 2697PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 269Gly
Val Ser Lys Arg Pro Ser 1 5 27010PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 270Ser Ser Arg Asp Leu Ile
Gly His Tyr Val 1 5 10 27110PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 271Thr Ser Ser Asp Val Gly
Thr Tyr Asn Gln 1 5 10 2723PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 272Gly Val Ser 1
2737PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 273Arg Asp Leu Ile Gly His Tyr 1 5
274121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 274Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Glu
Pro Tyr His Gly Lys Pro Leu Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
275110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 275Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Asn Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Leu Ile 85
90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100
105 110 276378DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 276caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggcgaaag cctgaaaatt 60agctgcaaag gctccggata
tagcttcact aactcttggg ttgcttgggt gcgccagatg 120ccgggcaaag
gtctcgagtg gatgggcatc atctacccgg gtaacagcga caccatctat
180agcccgagct ttcagggcca ggtgaccatt agcgcggata aaagcatcag
caccgcgtat 240ctgcaatgga gcagcctgaa agcgagcgat accgcgatgt
attattgcgc gcgtgttcat 300atcatccagc cgccgtctgc ttggtcttac
aacgctatgg atgtttgggg ccaaggcacc 360ctggtgactg ttagctca
378277321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 277gatatccaga tgacccagag cccgagcagc
ctgagcgcca gcgtgggcga tcgcgtgacc 60attacctgca gagccagcca gtctatttct
acttacctga actggtacca gcagaaaccg 120ggcaaagcgc cgaaactatt
aatcttcggt gcttctaacc tgcaaagcgg cgtgccgagc 180cgctttagcg
gcagcggatc cggcaccgat ttcaccctga ccattagctc tctgcaaccg
240gaagactttg cgacctatta ttgccagcag tctatcactg aactgttcac
ctttggccag 300ggcacgaaag ttgaaattaa a 321278451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
278Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Gly Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Asp Ile Glu Pro Tyr His Gly Lys Pro
Leu Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
279216PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 279Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Asn Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp Leu Ile 85
90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser
Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu
Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys
Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr
Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser
Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205
Thr Val Ala Pro Thr Glu Cys Ser 210 215 2801368DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
280caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggcgaaag
cctgaaaatt 60agctgcaaag gctccggata tagcttcact aactcttggg ttgcttgggt
gcgccagatg 120ccgggcaaag gtctcgagtg gatgggcatc atctacccgg
gtaacagcga caccatctat 180agcccgagct ttcagggcca ggtgaccatt
agcgcggata aaagcatcag caccgcgtat 240ctgcaatgga gcagcctgaa
agcgagcgat accgcgatgt attattgcgc gcgtgttcat 300atcatccagc
cgccgtctgc ttggtcttac aacgctatgg atgtttgggg ccaaggcacc
360ctggtgactg ttagctcagc ctccaccaag ggtccatcgg tcttccccct
ggcaccctcc 420tccaagagca cctctggggg cacagcggcc ctgggctgcc
tggtcaagga ctacttcccc 480gaaccggtga cggtgtcgtg gaactcaggc
gccctgacca gcggcgtgca caccttcccg 540gctgtcctac agtcctcagg
actctactcc ctcagcagcg tggtgaccgt gccctccagc 600agcttgggca
cccagaccta catctgcaac gtgaatcaca agcccagcaa caccaaggtg
660gacaagagag ttgagcccaa atcttgtgac aaaactcaca catgcccacc
gtgcccagca 720cctgaactcc tggggggacc gtcagtcttc ctcttccccc
caaaacccaa ggacaccctc 780atgatctccc ggacccctga ggtcacatgc
gtggtggtgg acgtgagcca cgaagaccct 840gaggtcaagt tcaactggta
cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 900cgggaggagc
agtacaacag cacgtaccgg gtggtcagcg tcctcaccgt cctgcaccag
960gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct
cccagccccc 1020atcgagaaaa ccatctccaa agccaaaggg cagccccgag
aaccacaggt gtacaccctg 1080cccccatccc gggaggagat gaccaagaac
caggtcagcc tgacctgcct ggtcaaaggc 1140ttctatccca gcgacatcgc
cgtggagtgg gagagcaatg ggcagccgga gaacaactac 1200aagaccacgc
ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc
1260gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat
gcatgaggct 1320ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaa
1368281642DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 281gatatccaga tgacccagag cccgagcagc
ctgagcgcca gcgtgggcga tcgcgtgacc 60attacctgca gagccagcca gtctatttct
acttacctga actggtacca gcagaaaccg 120ggcaaagcgc cgaaactatt
aatcttcggt gcttctaacc tgcaaagcgg cgtgccgagc 180cgctttagcg
gcagcggatc cggcaccgat ttcaccctga ccattagctc tctgcaaccg
240gaagactttg cgacctatta ttgccagcag tctatcactg aactgttcac
ctttggccag 300ggcacgaaag ttgaaattaa acgtacggtg gccgctccca
gcgtgttcat cttccccccc 360agcgacgagc agctgaagag cggcaccgcc
agcgtggtgt gcctgctgaa caacttctac 420ccccgggagg ccaaggtgca
gtggaaggtg gacaacgccc tgcagagcgg caacagccag 480gaaagcgtca
ccgagcagga cagcaaggac tccacctaca gcctgagcag caccctgacc
540ctgagcaagg ccgactacga gaagcacaag gtgtacgcct gcgaggtgac
ccaccagggc 600ctgtccagcc ccgtgaccaa gagcttcaac cggggcgagt gt
6422825PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 282Gly Tyr Tyr Met His 1 5 28317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 283Asp
Ile Asp Pro His Ser Gly Asn Ala Val Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 28412PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 284Gly Ser Phe Tyr Thr Arg Asp Ser Tyr
Phe Asp Val 1 5 10 2857PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 285Gly Tyr Thr Phe Thr Gly
Tyr 1 5 2866PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 286Asp Pro His Ser Gly Asn 1 5
28712PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 287Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 28814PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 288Thr Gly Thr Ser Ser Asp Val Gly Thr
Tyr Asn Gln Val Ser 1 5 10 2897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 289Gly Val Ser Lys Arg Pro
Ser 1 5 29010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 290Ser Ser Arg Asp Leu Ile Gly His Tyr
Val 1 5 10 29110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 291Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 2923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 292Gly Val Ser 1 2937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 293Arg
Asp Leu Ile Gly His Tyr 1 5 294121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 294Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Asp Ile Asp Pro His Ser Gly Asn Ala Val Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 295110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 295Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp
Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 296363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 296caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcacc ggctattaca tgcattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggcgac atcgacccgc attctggcaa
cgctgtttac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363297330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 297gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tcttctcgtg acctgatcgg
tcattacgtg 300tttggcggcg gcacgaagtt aaccgtccta
330298451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 298Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Asp Ile Asp
Pro His Ser Gly Asn Ala Val Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70
75
80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val
Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200
205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys
Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe
Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325
330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445
Pro Gly Lys 450 299216PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 299Asp Ile Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn
Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40
45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser
Arg Asp Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr
Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala
Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val
Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala
Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170
175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
3001353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 300caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcacc
ggctattaca tgcattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggcgac atcgacccgc attctggcaa cgctgtttac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353301648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 301gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
tcttctcgtg acctgatcgg tcattacgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6483025PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 302Gly
Tyr Tyr Met His 1 5 30317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 303Val Ile Asp Pro Tyr Ser
Gly Trp Thr Glu Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
30412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 304Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 3057PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 305Gly Tyr Thr Phe Thr Gly Tyr 1 5
3066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 306Asp Pro Tyr Ser Gly Trp 1 5 30712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 307Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
30814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 308Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 3097PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 309Gly Val Ser Lys Arg Pro
Ser 1 5 31010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 310Ser Ser Arg Asp Leu Ile Gly His Tyr
Val 1 5 10 31110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 311Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 3123PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 312Gly Val Ser 1 3137PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 313Arg
Asp Leu Ile Gly His Tyr 1 5 314121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 314Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Val Ile Asp Pro Tyr Ser Gly Trp Thr Glu Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 315110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 315Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp
Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 316363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 316caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcacc ggctattaca tgcattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggcgtt attgacccgt actctggctg
gactgaatac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363317330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 317gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tcttctcgtg acctgatcgg
tcattacgtg 300tttggcggcg gcacgaagtt aaccgtccta
330318451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 318Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Val Ile Asp
Pro Tyr Ser Gly Trp Thr Glu Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 319216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 319Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Arg Asp
Leu Ile 85 90 95 Gly His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
3201353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 320caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcacc ggctattaca tgcattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggcgtt attgacccgt actctggctg gactgaatac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc
atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag
cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg
480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt
cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct
ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc
agcaacacca aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac
tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag
tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc
780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt
caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa
agccgcggga ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc
accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt
ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca
aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag
1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta
tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca
actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc
tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt
ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320acgcagaaga
gcctctccct gtctccgggt aaa 1353321648DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
321gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tcttctcgtg acctgatcgg tcattacgtg 300tttggcggcg
gcacgaagtt aaccgtccta ggtcagccca aggctgcccc ctcggtcact
360ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt
gtgtctcata 420agtgacttct acccgggagc cgtgacagtg gcctggaagg
cagatagcag ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa
caaagcaaca acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga
gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600catgaaggga
gcaccgtgga gaagacagtg gcccctacag aatgttca 6483225PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 322Ser
Tyr Asp Ile His 1 5 32317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 323Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
32412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 324Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 3257PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 325Gly Tyr Thr Phe Thr Ser Tyr 1 5
3266PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 326Asp Pro Tyr Ser Gly Asn 1 5 32712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 327Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
32814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 328Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 3297PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 329Gly Val Ser Lys Arg Pro
Ser 1 5 33011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 330Gln Ser Arg Gly Glu Tyr Arg Pro Gly
Trp Val 1 5 10 33110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 331Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 3323PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 332Gly Val Ser 1 3338PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 333Arg
Gly Glu Tyr Arg Pro Gly Trp 1 5 334121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
334Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 335111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
335Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gln Ser Arg Gly Glu Tyr 85 90 95 Arg Pro Gly Trp
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
336363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 336caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363337333DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
337gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc cagtctcgtg gtgaataccg tccgggttgg 300gtgtttggcg
gcggcacgaa gttaaccgtc cta 333338451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
338Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
339217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 339Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Arg Gly Glu Tyr 85
90 95 Arg Pro Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys
Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp
Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr
Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 3401353DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
340caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc
360tcagcctcca ccaagggtcc atcggtcttc cccctggcac cctcctccaa
gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact
tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc
gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag
cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct
gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag
660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga
actcctgggg 720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca
ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg
agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353341651DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 341gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc cagtctcgtg gtgaataccg
tccgggttgg 300gtgtttggcg gcggcacgaa gttaaccgtc ctaggtcagc
ccaaggctgc cccctcggtc 360actctgttcc cgccctcctc tgaggagctt
caagccaaca aggccacact ggtgtgtctc 420ataagtgact tctacccggg
agccgtgaca gtggcctgga aggcagatag cagccccgtc 480aaggcgggag
tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc
540agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag
ctgccaggtc 600acgcatgaag ggagcaccgt ggagaagaca gtggccccta
cagaatgttc a 6513425PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 342Ser Tyr Asp Ile His 1 5
34317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 343Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr
Ala Gln Lys Phe Gln 1 5 10 15 Gly 34412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 344Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
3457PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 345Gly Tyr Thr Phe Thr Ser Tyr 1 5
3466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 346Asp Pro Tyr Ser Gly Asn 1 5 34712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 347Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
34814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 348Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 3497PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 349Gly Val Ser Lys Arg Pro
Ser 1 5 35011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 350Ser Ser Ala Thr Gln Lys Pro Asp Val
Thr Val 1 5 10 35110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 351Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 3523PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 352Gly Val Ser 1 3538PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 353Ala
Thr Gln Lys Pro Asp Val Thr 1 5 354121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
354Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35
40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp
Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 355111PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 355Asp Ile Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn
Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40
45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser
Ala Thr Gln Lys 85 90 95 Pro Asp Val Thr Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110 356363DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
356caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363357333DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 357gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tcttctgcta ctcagaaacc
ggacgttact 300gtgtttggcg gcggcacgaa gttaaccgtc cta
333358451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 358Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 359217PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 359Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Ala Thr
Gln Lys 85 90 95 Pro Asp Val Thr Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu
Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr
Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr
Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185
190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215
3601353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 360caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353361651DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 361gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
tcttctgcta ctcagaaacc ggacgttact 300gtgtttggcg gcggcacgaa
gttaaccgtc ctaggtcagc ccaaggctgc cccctcggtc 360actctgttcc
cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc
420ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag
cagccccgtc 480aaggcgggag tggagaccac cacaccctcc aaacaaagca
acaacaagta cgcggccagc 540agctatctga gcctgacgcc tgagcagtgg
aagtcccaca gaagctacag ctgccaggtc 600acgcatgaag ggagcaccgt
ggagaagaca gtggccccta cagaatgttc a 6513625PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 362Ser
Tyr Asp Ile His 1 5 36317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 363Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
36412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 364Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 3657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 365Gly Tyr Thr Phe Thr Ser Tyr 1 5
3666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 366Asp Pro Tyr Ser Gly Asn 1 5 36712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 367Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
36814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 368Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 3697PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 369Gly Val Ser Lys Arg Pro
Ser 1 5 3709PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 370Ala Val Arg Asp Ser Val Trp His Val 1
5 37110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 371Thr Ser Ser Asp Val Gly Thr Tyr Asn Gln 1 5 10
3723PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 372Gly Val Ser 1 3736PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 373Arg
Asp Ser Val Trp His 1 5 374121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 374Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 375109PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 375Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Arg Asp
Ser Val 85 90 95 Trp His Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 376363DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 376caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tca 363377327DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
377gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc gctgttcgtg actccgtttg gcatgtgttt 300ggcggcggca
cgaagttaac cgtccta 327378451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 378Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280
285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405
410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser 435 440 445 Pro Gly Lys 450 379215PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
379Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ala Val Arg Asp Ser Val 85 90 95 Trp His Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130
135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
Ala 145 150 155 160 Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn
Asn Lys Tyr Ala 165 170 175 Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
Gln Trp Lys Ser His Arg 180 185 190 Ser Tyr Ser Cys Gln Val Thr His
Glu Gly Ser Thr Val Glu Lys Thr 195 200 205 Val Ala Pro Thr Glu Cys
Ser 210 215 3801353DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 380caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc
atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag
cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg
480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt
cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct
ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc
agcaacacca aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac
tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag
tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc
780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt
caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa
agccgcggga ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc
accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt
ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca
aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag
1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta
tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca
actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc
tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt
ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320acgcagaaga
gcctctccct gtctccgggt aaa 1353381645DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
381gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc gctgttcgtg actccgtttg gcatgtgttt 300ggcggcggca
cgaagttaac cgtcctaggt cagcccaagg ctgccccctc ggtcactctg
360ttcccgccct cctctgagga gcttcaagcc aacaaggcca cactggtgtg
tctcataagt 420gacttctacc cgggagccgt gacagtggcc tggaaggcag
atagcagccc cgtcaaggcg 480ggagtggaga ccaccacacc ctccaaacaa
agcaacaaca agtacgcggc cagcagctat 540ctgagcctga cgcctgagca
gtggaagtcc cacagaagct acagctgcca ggtcacgcat 600gaagggagca
ccgtggagaa gacagtggcc cctacagaat gttca 6453825PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 382Ser
Tyr Asp Ile His 1 5 38317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 383Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
38412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 384Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 3857PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 385Gly Tyr Thr Phe Thr Ser Tyr 1 5
3866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 386Asp Pro Tyr Ser Gly Asn 1 5 38712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 387Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
38814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 388Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 3897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 389Gly Val Ser Lys Arg Pro
Ser 1 5 39010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 390Ser Ala Arg Asp Gly Trp Ser Glu Tyr
Val 1 5 10 39110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 391Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 3923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 392Gly Val Ser 1 3937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 393Arg
Asp Gly Trp Ser Glu Tyr 1 5 394121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 394Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 395110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 395Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Arg Asp
Gly Trp 85 90 95 Ser Glu Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 396363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 396caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363397330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 397gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tctgctcgtg acggttggtc
tgaatacgtg 300tttggcggcg gcacgaagtt aaccgtccta
330398451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 398Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 399216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 399Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Arg Asp
Gly Trp 85 90 95 Ser Glu Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
4001353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 400caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353401648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 401gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
tctgctcgtg acggttggtc tgaatacgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6484025PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 402Ser
Tyr Asp Ile His 1 5 40317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 403Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
40412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 404Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 4057PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 405Gly Tyr Thr Phe Thr Ser Tyr 1 5
4066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 406Asp Pro Tyr Ser Gly Asn 1 5 40712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 407Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
40814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 408Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 4097PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 409Gly Val Ser Lys Arg Pro
Ser 1 5 41010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 410Ala Ser Ala Asp His Ser Tyr His Thr
Val 1 5 10 41110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 411Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 4123PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 412Gly Val Ser 1 4137PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 413Ala
Asp His Ser Tyr His Thr 1 5 414121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 414Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 415110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 415Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Ala Asp
His Ser 85 90 95 Tyr His Thr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 416363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 416caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363417330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 417gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc gcttctgctg accattctta
ccatactgtg 300tttggcggcg gcacgaagtt aaccgtccta
330418451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 418Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 419216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 419Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Ala Asp
His Ser 85 90 95 Tyr His Thr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
4201353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 420caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353421648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 421gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
gcttctgctg accattctta ccatactgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6484225PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 422Ser
Tyr Asp Ile His 1 5 42317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 423Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
42412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 424Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 4257PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 425Gly Tyr Thr Phe Thr Ser Tyr 1 5
4266PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 426Asp Pro Tyr Ser Gly Asn 1 5 42712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 427Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
42814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 428Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 4297PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 429Gly Val Ser Lys Arg Pro
Ser 1 5 4309PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 430Gly Ser Arg Thr Ser His Asn Trp Val 1
5 43110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 431Thr Ser Ser Asp Val Gly Thr Tyr Asn Gln 1 5 10
4323PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 432Gly Val Ser 1 4336PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 433Arg
Thr Ser His Asn Trp 1 5 434121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 434Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 435109PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 435Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Arg Thr
Ser His 85
90 95 Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
436363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 436caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363437327DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
437gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc ggttctcgta cttctcataa ctgggtgttt 300ggcggcggca
cgaagttaac cgtccta 327438451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 438Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 439215PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
439Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gly Ser Arg Thr Ser His 85 90 95 Asn Trp Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130
135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
Ala 145 150 155 160 Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn
Asn Lys Tyr Ala 165 170 175 Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
Gln Trp Lys Ser His Arg 180 185 190 Ser Tyr Ser Cys Gln Val Thr His
Glu Gly Ser Thr Val Glu Lys Thr 195 200 205 Val Ala Pro Thr Glu Cys
Ser 210 215 4401353DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 440caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc
atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag
cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg
480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt
cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct
ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc
agcaacacca aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac
tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag
tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc
780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt
caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa
agccgcggga ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc
accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt
ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca
aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag
1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta
tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca
actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc
tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt
ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320acgcagaaga
gcctctccct gtctccgggt aaa 1353441645DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
441gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc ggttctcgta cttctcataa ctgggtgttt 300ggcggcggca
cgaagttaac cgtcctaggt cagcccaagg ctgccccctc ggtcactctg
360ttcccgccct cctctgagga gcttcaagcc aacaaggcca cactggtgtg
tctcataagt 420gacttctacc cgggagccgt gacagtggcc tggaaggcag
atagcagccc cgtcaaggcg 480ggagtggaga ccaccacacc ctccaaacaa
agcaacaaca agtacgcggc cagcagctat 540ctgagcctga cgcctgagca
gtggaagtcc cacagaagct acagctgcca ggtcacgcat 600gaagggagca
ccgtggagaa gacagtggcc cctacagaat gttca 6454425PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 442Ser
Tyr Asp Ile His 1 5 44317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 443Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
44412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 444Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 4457PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 445Gly Tyr Thr Phe Thr Ser Tyr 1 5
4466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 446Asp Pro Tyr Ser Gly Asn 1 5 44712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 447Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
44814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 448Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 4497PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 449Gly Val Ser Lys Arg Pro
Ser 1 5 4509PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 450Ala Val Arg Gly Ser Gln Thr Leu Val 1
5 45110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 451Thr Ser Ser Asp Val Gly Thr Tyr Asn Gln 1 5 10
4523PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 452Gly Val Ser 1 4536PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 453Arg
Gly Ser Gln Thr Leu 1 5 454121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 454Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 455109PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 455Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val Arg Gly
Ser Gln 85 90 95 Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 456363DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 456caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tca 363457327DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
457gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc gctgttcgtg gttctcagac tctggtgttt 300ggcggcggca
cgaagttaac cgtccta 327458451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 458Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445
Pro Gly Lys 450 459215PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 459Asp Ile Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn
Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40
45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Val
Arg Gly Ser Gln 85 90 95 Thr Leu Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala Ala Pro Ser Val Thr Leu
Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125 Gln Ala Asn Lys Ala Thr
Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130 135 140 Gly Ala Val Thr
Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala 145 150 155 160 Gly
Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala 165 170
175 Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg
180 185 190 Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
Lys Thr 195 200 205 Val Ala Pro Thr Glu Cys Ser 210 215
4601353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 460caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353461645DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 461gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
gctgttcgtg gttctcagac tctggtgttt 300ggcggcggca cgaagttaac
cgtcctaggt cagcccaagg ctgccccctc ggtcactctg 360ttcccgccct
cctctgagga gcttcaagcc aacaaggcca cactggtgtg tctcataagt
420gacttctacc cgggagccgt gacagtggcc tggaaggcag atagcagccc
cgtcaaggcg 480ggagtggaga ccaccacacc ctccaaacaa agcaacaaca
agtacgcggc cagcagctat 540ctgagcctga cgcctgagca gtggaagtcc
cacagaagct acagctgcca ggtcacgcat 600gaagggagca ccgtggagaa
gacagtggcc cctacagaat gttca 6454625PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 462Ser
Tyr Asp Ile His 1 5 46317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 463Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
46412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 464Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 4657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 465Gly Tyr Thr Phe Thr Ser Tyr 1 5
4666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 466Asp Pro Tyr Ser Gly Asn 1 5 46712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 467Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
46814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 468Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 4697PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 469Gly Val Ser Lys Arg Pro
Ser 1 5 4709PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 470Gly Ser Arg Asp Ser Trp Ala His Val 1
5 47110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 471Thr Ser Ser Asp Val Gly Thr Tyr Asn Gln 1 5 10
4723PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 472Gly Val Ser 1 4736PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 473Arg
Asp Ser Trp Ala His 1 5 474121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 474Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 475109PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 475Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Arg Asp
Ser Trp 85 90 95 Ala His Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 476363DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 476caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tca 363477327DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
477gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc ggttctcgtg actcttgggc tcatgtgttt 300ggcggcggca
cgaagttaac cgtccta 327478451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 478Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 479215PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
479Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gly Ser Arg Asp Ser Trp 85 90 95 Ala His Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130
135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
Ala 145 150 155 160 Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn
Asn Lys Tyr Ala 165 170 175 Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
Gln Trp Lys Ser His Arg 180 185 190 Ser Tyr Ser Cys Gln Val Thr His
Glu Gly Ser Thr Val Glu Lys Thr 195 200 205 Val Ala Pro Thr Glu Cys
Ser 210 215 4801353DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 480caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc
atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag
cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg
480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt
cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct
ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc
agcaacacca aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac
tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag
tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc
780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt
caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa
agccgcggga ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc
accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt
ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca
aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag
1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta
tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca
actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc
tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt
ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320acgcagaaga
gcctctccct gtctccgggt aaa 1353481645DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
481gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc ggttctcgtg actcttgggc tcatgtgttt 300ggcggcggca
cgaagttaac cgtcctaggt cagcccaagg ctgccccctc ggtcactctg
360ttcccgccct cctctgagga gcttcaagcc aacaaggcca cactggtgtg
tctcataagt 420gacttctacc cgggagccgt gacagtggcc tggaaggcag
atagcagccc cgtcaaggcg 480ggagtggaga ccaccacacc ctccaaacaa
agcaacaaca agtacgcggc cagcagctat 540ctgagcctga cgcctgagca
gtggaagtcc cacagaagct acagctgcca ggtcacgcat 600gaagggagca
ccgtggagaa gacagtggcc cctacagaat gttca 6454825PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 482Ser
Tyr Asp Ile His 1 5 48317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 483Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
48412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptide 484Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
4857PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 485Gly Tyr Thr Phe Thr Ser Tyr 1 5
4866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 486Asp Pro Tyr Ser Gly Asn 1 5 48712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 487Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
48814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 488Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 4897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 489Gly Val Ser Lys Arg Pro
Ser 1 5 49011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 490Tyr Ser Arg Ala Lys Thr His Trp Thr
Asp Val 1 5 10 49110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 491Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 4923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 492Gly Val Ser 1 4938PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 493Arg
Ala Lys Thr His Trp Thr Asp 1 5 494121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
494Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 495111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
495Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Tyr Ser Arg Ala Lys Thr 85 90 95 His Trp Thr Asp
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
496363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 496caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363497333DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
497gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tactctcgtg ctaaaactca ttggactgac 300gtgtttggcg
gcggcacgaa gttaaccgtc cta 333498451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
498Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
499217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 499Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Tyr Ser Arg Ala Lys Thr 85
90 95 His Trp Thr Asp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys
Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp
Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr
Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 5001353DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
500caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc
360tcagcctcca ccaagggtcc atcggtcttc cccctggcac cctcctccaa
gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact
tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc
gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag
cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct
gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag
660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga
actcctgggg 720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca
ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg
agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353501651DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 501gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tactctcgtg ctaaaactca
ttggactgac 300gtgtttggcg gcggcacgaa gttaaccgtc ctaggtcagc
ccaaggctgc cccctcggtc 360actctgttcc cgccctcctc tgaggagctt
caagccaaca aggccacact ggtgtgtctc 420ataagtgact tctacccggg
agccgtgaca gtggcctgga aggcagatag cagccccgtc 480aaggcgggag
tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc
540agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag
ctgccaggtc 600acgcatgaag ggagcaccgt ggagaagaca gtggccccta
cagaatgttc a 6515025PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 502Ser Tyr Asp Ile His 1 5
50317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 503Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr
Ala Gln Lys Phe Gln 1 5 10 15 Gly 50412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 504Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
5057PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 505Gly Tyr Thr Phe Thr Ser Tyr 1 5
5066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 506Asp Pro Tyr Ser Gly Asn 1 5 50712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 507Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
50814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 508Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 5097PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 509Gly Val Ser Lys Arg Pro
Ser 1 5 51010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 510Ser Val Trp Thr Ser Ile Lys Val Phe
Val 1 5 10 51110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 511Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 5123PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 512Gly Val Ser 1 5137PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 513Trp
Thr Ser Ile Lys Val Phe 1 5 514121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 514Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 515110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 515Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Val Trp Thr
Ser Ile 85 90 95 Lys Val Phe Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 516363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 516caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363517330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 517gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tctgtttgga cttctatcaa
agttttcgtg 300tttggcggcg gcacgaagtt aaccgtccta
330518451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 518Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1
5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser
Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn
Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp
Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg
Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe
Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135
140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr
Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val
Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260
265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln
Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser
Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385
390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
519216PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 519Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Val Trp Thr Ser Ile 85
90 95 Lys Val Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser
Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu
Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys
Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr
Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser
Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser
Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205
Thr Val Ala Pro Thr Glu Cys Ser 210 215 5201353DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
520caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc
360tcagcctcca ccaagggtcc atcggtcttc cccctggcac cctcctccaa
gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact
tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc
gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag
cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct
gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag
660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga
actcctgggg 720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca
ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg
agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353521648DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 521gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tctgtttgga cttctatcaa
agttttcgtg 300tttggcggcg gcacgaagtt aaccgtccta ggtcagccca
aggctgcccc ctcggtcact 360ctgttcccgc cctcctctga ggagcttcaa
gccaacaagg ccacactggt gtgtctcata 420agtgacttct acccgggagc
cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480gcgggagtgg
agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc
540tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg
ccaggtcacg 600catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca
6485225PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 522Ser Tyr Asp Ile His 1 5 52317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 523Arg
Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 52412PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 524Gly Ser Phe Tyr Thr Arg Asp Ser Tyr
Phe Asp Val 1 5 10 5257PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 525Gly Tyr Thr Phe Thr Ser
Tyr 1 5 5266PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 526Asp Pro Tyr Ser Gly Asn 1 5
52712PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 527Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 52814PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 528Thr Gly Thr Ser Ser Asp Val Gly Thr
Tyr Asn Gln Val Ser 1 5 10 5297PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 529Gly Val Ser Lys Arg Pro
Ser 1 5 53010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 530Ser Ala Tyr Asp Ala Ser Thr Gln Val
Val 1 5 10 53110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 531Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 5323PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 532Gly Val Ser 1 5337PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 533Tyr
Asp Ala Ser Thr Gln Val 1 5 534121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 534Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 535110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 535Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Asp
Ala Ser 85 90 95 Thr Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 536363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 536caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363537330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 537gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tctgcttacg acgcttctac
tcaggttgtg 300tttggcggcg gcacgaagtt aaccgtccta
330538451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 538Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 539216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 539Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Tyr Asp
Ala Ser 85 90 95 Thr Gln Val Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser
Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
5401353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 540caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353541648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 541gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
tctgcttacg acgcttctac tcaggttgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6485425PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 542Ser
Tyr Asp Ile His 1 5 54317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 543Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
54412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 544Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 5457PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 545Gly Tyr Thr Phe Thr Ser Tyr 1 5
5466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 546Asp Pro Tyr Ser Gly Asn 1 5 54712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 547Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
54814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 548Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 5497PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 549Gly Val Ser Lys Arg Pro
Ser 1 5 5509PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 550Gln Ser Ala Ala Ile Ala Thr Ser Val 1
5 55110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 551Thr Ser Ser Asp Val Gly Thr Tyr Asn Gln 1 5 10
5523PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 552Gly Val Ser 1 5536PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 553Ala
Ala Ile Ala Thr Ser 1 5 554121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 554Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 555109PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 555Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Ala
Ile Ala 85 90 95 Thr Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 556363DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 556caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tca 363557327DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
557gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc cagtctgctg ctatcgctac ttctgtgttt 300ggcggcggca
cgaagttaac cgtccta 327558451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 558Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 559215PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
559Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gln Ser Ala Ala Ile Ala 85 90 95 Thr Ser Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro 100 105 110 Lys Ala
Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu 115 120 125
Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro 130
135 140 Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
Ala 145 150 155 160 Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn
Asn Lys Tyr Ala 165 170 175 Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu
Gln Trp Lys Ser His Arg 180 185 190 Ser Tyr Ser Cys Gln Val Thr His
Glu Gly Ser Thr Val Glu Lys Thr 195 200 205 Val Ala Pro Thr Glu Cys
Ser 210 215 5601353DNAArtificial SequenceDescription of Artificial
Sequence Synthetic polynucleotide 560caggtgcaat tggtgcagag
cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata
taccttcact tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg
gcctcgagtg gatgggccgt atcgacccgt actctggcaa cacgaactac
180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata ccagcattag
caccgcgtat 240atggaactga gccgtctgcg tagcgaagat acggccgtgt
attattgcgc gcgtggttct 300ttctacactc gtgactctta cttcgatgtt
tggggccaag gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc
atcggtcttc cccctggcac cctcctccaa gagcacctct 420gggggcacag
cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg
480tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt
cctacagtcc 540tcaggactct actccctcag cagcgtggtg accgtgccct
ccagcagctt gggcacccag 600acctacatct gcaacgtgaa tcacaagccc
agcaacacca aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac
tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag
tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc
780cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt
caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa
agccgcggga ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc
accgtcctgc accaggactg gctgaatggc 960aaggagtaca agtgcaaggt
ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca
aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag
1080gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta
tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag ccggagaaca
actacaagac cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc
tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt
ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320acgcagaaga
gcctctccct gtctccgggt aaa 1353561645DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
561gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc cagtctgctg ctatcgctac ttctgtgttt 300ggcggcggca
cgaagttaac cgtcctaggt cagcccaagg ctgccccctc ggtcactctg
360ttcccgccct cctctgagga gcttcaagcc aacaaggcca cactggtgtg
tctcataagt 420gacttctacc cgggagccgt gacagtggcc tggaaggcag
atagcagccc cgtcaaggcg 480ggagtggaga ccaccacacc ctccaaacaa
agcaacaaca agtacgcggc cagcagctat 540ctgagcctga cgcctgagca
gtggaagtcc cacagaagct acagctgcca ggtcacgcat 600gaagggagca
ccgtggagaa gacagtggcc cctacagaat gttca 6455625PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 562Ser
Tyr Asp Ile His 1 5 56317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 563Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
56412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 564Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 5657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 565Gly Tyr Thr Phe Thr Ser Tyr 1 5
5666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 566Asp Pro Tyr Ser Gly Asn 1 5 56712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 567Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
56814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 568Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 5697PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 569Gly Val Ser Lys Arg Pro
Ser 1 5 57010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 570Ser Thr Thr Thr Tyr Ser Phe His Met
Val 1 5 10 57110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 571Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 5723PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 572Gly Val Ser 1 5737PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptide 573Thr Thr Tyr Ser Phe His Met 1 5 574121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
574Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 575110PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
575Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Thr Thr Thr Tyr Ser 85 90 95 Phe His Met Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
576363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 576caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363577330DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
577gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tctactacta cttactcttt ccatatggtg 300tttggcggcg
gcacgaagtt aaccgtccta 330578451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 578Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170
175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 579216PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
579Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Thr Thr Thr Tyr Ser 85 90 95 Phe His Met Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130
135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro
Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr
His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu
Cys Ser 210 215 5801353DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 580caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tcagcctcca
ccaagggtcc atcggtcttc cccctggcac cctcctccaa gagcacctct
420gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc
ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc gtgcacacct
tcccggctgt cctacagtcc 540tcaggactct actccctcag cagcgtggtg
accgtgccct ccagcagctt gggcacccag 600acctacatct gcaacgtgaa
tcacaagccc agcaacacca aggtggacaa gagagttgag 660cccaaatctt
gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg
720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat
ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg agccacgaag
accctgaggt caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat
gccaagacaa agccgcggga ggagcagtac 900aacagcacgt accgggtggt
cagcgtcctc accgtcctgc accaggactg gctgaatggc 960aaggagtaca
agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc
1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc
atcccgggag 1080gagatgacca agaaccaggt cagcctgacc tgcctggtca
aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag
ccggagaaca actacaagac cacgcctccc 1200gtgctggact ccgacggctc
cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg
ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac
1320acgcagaaga gcctctccct gtctccgggt aaa 1353581648DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
581gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tctactacta cttactcttt ccatatggtg 300tttggcggcg
gcacgaagtt aaccgtccta ggtcagccca aggctgcccc ctcggtcact
360ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt
gtgtctcata 420agtgacttct acccgggagc cgtgacagtg gcctggaagg
cagatagcag ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa
caaagcaaca acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga
gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600catgaaggga
gcaccgtgga gaagacagtg gcccctacag aatgttca 6485825PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 582Ser
Tyr Asp Ile His 1 5 58317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 583Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
58412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 584Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 5857PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 585Gly Tyr Thr Phe Thr Ser Tyr 1 5
5866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 586Asp Pro Tyr Ser Gly Asn 1 5 58712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 587Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
58814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 588Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 5897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 589Gly Val Ser Lys Arg Pro
Ser 1 5 59010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 590Gln Ala Trp Asp Tyr Arg Gln Thr Ile
Val 1 5 10 59110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 591Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 5923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 592Gly Val Ser 1 5937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 593Trp
Asp Tyr Arg Gln Thr Ile 1 5 594121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 594Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 595110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 595Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp
Tyr Arg 85 90 95 Gln Thr Ile Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 596363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 596caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363597330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 597gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc caggcttggg actaccgtca
gactatcgtg 300tttggcggcg gcacgaagtt aaccgtccta
330598451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 598Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro
Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295
300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu
Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420
425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 435 440 445 Pro Gly Lys 450 599216PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
599Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Gln Ala Trp Asp Tyr Arg 85 90 95 Gln Thr Ile Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys
Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130
135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser
Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro
Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr
His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu
Cys Ser 210 215 6001353DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 600caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tcagcctcca
ccaagggtcc atcggtcttc cccctggcac cctcctccaa gagcacctct
420gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc
ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc gtgcacacct
tcccggctgt cctacagtcc 540tcaggactct actccctcag cagcgtggtg
accgtgccct ccagcagctt gggcacccag 600acctacatct gcaacgtgaa
tcacaagccc agcaacacca aggtggacaa gagagttgag 660cccaaatctt
gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg
720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat
ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg agccacgaag
accctgaggt caagttcaac 840tggtacgtgg acggcgtgga ggtgcataat
gccaagacaa agccgcggga ggagcagtac 900aacagcacgt accgggtggt
cagcgtcctc accgtcctgc accaggactg gctgaatggc 960aaggagtaca
agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc
1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc
atcccgggag 1080gagatgacca agaaccaggt cagcctgacc tgcctggtca
aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag caatgggcag
ccggagaaca actacaagac cacgcctccc 1200gtgctggact ccgacggctc
cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260tggcagcagg
ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac
1320acgcagaaga gcctctccct gtctccgggt aaa 1353601648DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
601gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc caggcttggg actaccgtca gactatcgtg 300tttggcggcg
gcacgaagtt aaccgtccta ggtcagccca aggctgcccc ctcggtcact
360ctgttcccgc cctcctctga ggagcttcaa gccaacaagg ccacactggt
gtgtctcata 420agtgacttct acccgggagc cgtgacagtg gcctggaagg
cagatagcag ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa
caaagcaaca acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga
gcagtggaag tcccacagaa gctacagctg ccaggtcacg 600catgaaggga
gcaccgtgga gaagacagtg gcccctacag aatgttca 6486025PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 602Ser
Tyr Asp Ile His 1 5 60317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 603Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
60412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 604Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 6057PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 605Gly Tyr Thr Phe Thr Ser Tyr 1 5
6066PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 606Asp Pro Tyr Ser Gly Asn 1 5 60712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 607Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
60814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 608Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 6097PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 609Gly Val Ser Lys Arg Pro
Ser 1 5 61010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 610Gln Val Trp Asp Ser Asp Gln Ala Met
Val 1 5 10 61110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 611Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 6123PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 612Gly Val Ser 1 6137PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 613Trp
Asp Ser Asp Gln Ala Met 1 5 614121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 614Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 615110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 615Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp
Ser Asp 85 90 95 Gln Ala Met Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 616363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 616caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgaagat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363617330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 617gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc caggtttggg actctgacca
ggctatggtg 300tttggcggcg gcacgaagtt aaccgtccta
330618451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 618Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 619216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 619Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp
Ser Asp 85 90 95 Gln Ala Met Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
6201353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 620caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353621648DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 621gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc caggtttggg actctgacca
ggctatggtg 300tttggcggcg gcacgaagtt aaccgtccta ggtcagccca
aggctgcccc ctcggtcact 360ctgttcccgc cctcctctga ggagcttcaa
gccaacaagg ccacactggt gtgtctcata 420agtgacttct acccgggagc
cgtgacagtg gcctggaagg cagatagcag ccccgtcaag 480gcgggagtgg
agaccaccac accctccaaa caaagcaaca acaagtacgc ggccagcagc
540tatctgagcc tgacgcctga gcagtggaag tcccacagaa gctacagctg
ccaggtcacg 600catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca
6486225PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 622Ser Tyr Asp Ile His 1 5 62317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 623Arg
Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10
15 Gly 62412PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 624Gly Ser Phe Tyr Thr Arg Asp Ser Tyr
Phe Asp Val 1 5 10 6257PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 625Gly Tyr Thr Phe Thr Ser
Tyr 1 5 6266PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 626Asp Pro Tyr Ser Gly Asn 1 5
62712PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 627Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 62814PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 628Thr Gly Thr Ser Ser Asp Val Gly Thr
Tyr Asn Gln Val Ser 1 5 10 6297PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 629Gly Val Ser Lys Arg Pro
Ser 1 5 63011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 630Ser Thr Ala Thr Ala Met Thr Val Ser
Leu Val 1 5 10 63110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 631Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 6323PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 632Gly Val Ser 1 6338PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 633Ala
Thr Ala Met Thr Val Ser Leu 1 5 634121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
634Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 635111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
635Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Thr Ala Thr Ala Met 85 90 95 Thr Val Ser Leu
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
636363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 636caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363637333DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
637gatatcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tctactgcta ctgctatgac tgtttctctg 300gtgtttggcg
gcggcacgaa gttaaccgtc cta 333638451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
638Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
639217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 639Asp Ile Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Ala Thr Ala Met 85
90 95 Thr Val Ser Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys
Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp
Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr
Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 6401353DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
640caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc
360tcagcctcca ccaagggtcc atcggtcttc cccctggcac cctcctccaa
gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact
tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc
gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag
cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct
gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag
660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga
actcctgggg 720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca
ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg
agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353641651DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 641gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tctactgcta ctgctatgac
tgtttctctg 300gtgtttggcg gcggcacgaa gttaaccgtc ctaggtcagc
ccaaggctgc cccctcggtc 360actctgttcc cgccctcctc tgaggagctt
caagccaaca aggccacact ggtgtgtctc 420ataagtgact tctacccggg
agccgtgaca gtggcctgga aggcagatag cagccccgtc 480aaggcgggag
tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc
540agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag
ctgccaggtc 600acgcatgaag ggagcaccgt ggagaagaca gtggccccta
cagaatgttc a 6516425PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 642Ser Tyr Asp Ile His 1 5
64317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 643Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr
Ala Gln Lys Phe Gln 1 5 10 15 Gly 64412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 644Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
6457PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 645Gly Tyr Thr Phe Thr Ser Tyr 1 5
6466PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 646Asp Pro Tyr Ser Gly Asn 1 5 64712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 647Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
64814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 648Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 6497PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 649Gly Val Ser Lys Arg Pro
Ser 1 5 65010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 650Gln Val Ala Asp Gln Gly Trp His Gln
Val 1 5 10 65110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 651Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 6523PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 652Gly Val Ser 1 6537PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 653Ala
Asp Gln Gly Trp His Gln 1 5 654121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 654Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 655110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 655Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30
Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35
40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg
Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
Val Ala Asp Gln Gly 85 90 95 Trp His Gln Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110 656363DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
656caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgaagat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363657330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 657gatatcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc caggttgctg accagggttg
gcatcaggtg 300tttggcggcg gcacgaagtt aaccgtccta
330658451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 658Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 659216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 659Asp Ile Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Val Ala Asp
Gln Gly 85 90 95 Trp His Gln Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
6601353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 660caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgaagat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353661648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 661gatatcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
caggttgctg accagggttg gcatcaggtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc tgacgcctga gcagtggaag
tcccacagaa gctacagctg ccaggtcacg 600catgaaggga gcaccgtgga
gaagacagtg gcccctacag aatgttca 6486625PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 662Ser
Tyr Asp Ile His 1 5 66317PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 663Arg Ile Asp Pro Tyr Ser
Gly Asn Thr Asn Tyr Ala Gln Lys Phe Gln 1 5 10 15 Gly
66412PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 664Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp
Val 1 5 10 6657PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 665Gly Tyr Thr Phe Thr Ser Tyr 1 5
6666PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 666Asp Pro Tyr Ser Gly Asn 1 5 66712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 667Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
66814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 668Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 6697PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 669Gly Val Ser Lys Arg Pro
Ser 1 5 67011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 670Ser Ser Ala Thr Gln Lys Pro Asp Val
Thr Val 1 5 10 67110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 671Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 6723PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 672Gly Val Ser 1 6738PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 673Ala
Thr Gln Lys Pro Asp Val Thr 1 5 674121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
674Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 675111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
675Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Ser Ala Thr Gln Lys 85 90 95 Pro Asp Val Thr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
676363DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 676caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgacgat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tca 363677333DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
677cagagcgcgc tgacccagcc ggcgagcgtg agcggtagcc cgggccagag
cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc acttacaacc aggtgtcttg
gtaccagcag 120catccgggca aggcgccgaa actgatgatc tacggtgttt
ctaaacgtcc gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc
aacaccgcga gcctgaccat tagcggcctg 240caagcggaag acgaagcgga
ttattactgc tcttctgcta ctcagaaacc ggacgttact 300gtgtttggcg
gcggcacgaa gttaaccgtc cta 333678451PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
678Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Asp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu
Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser
Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130
135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln
Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250
255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His
Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val
Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375
380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385
390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450
679217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 679Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly
Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Gly
Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Ala Thr Gln Lys 85
90 95 Pro Asp Val Thr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys
Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp
Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr
Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser
Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg
Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 6801353DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
680caggtgcaat tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag
cgtgaaagtt 60agctgcaaag cgtccggata taccttcact tcttacgaca tccattgggt
gcgccaggcc 120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt
actctggcaa cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg
acccgtgata ccagcattag caccgcgtat 240atggaactga gccgtctgcg
tagcgacgat acggccgtgt attattgcgc gcgtggttct 300ttctacactc
gtgactctta cttcgatgtt tggggccaag gcaccctggt gactgttagc
360tcagcctcca ccaagggtcc atcggtcttc cccctggcac cctcctccaa
gagcacctct 420gggggcacag cggccctggg ctgcctggtc aaggactact
tccccgaacc ggtgacggtg 480tcgtggaact caggcgccct gaccagcggc
gtgcacacct tcccggctgt cctacagtcc 540tcaggactct actccctcag
cagcgtggtg accgtgccct ccagcagctt gggcacccag 600acctacatct
gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag
660cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga
actcctgggg 720ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca
ccctcatgat ctcccggacc 780cctgaggtca catgcgtggt ggtggacgtg
agccacgaag accctgaggt caagttcaac 840tggtacgtgg acggcgtgga
ggtgcataat gccaagacaa agccgcggga ggagcagtac 900aacagcacgt
accgggtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc
960aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga
gaaaaccatc 1020tccaaagcca aagggcagcc ccgagaacca caggtgtaca
ccctgccccc atcccgggag 1080gagatgacca agaaccaggt cagcctgacc
tgcctggtca aaggcttcta tcccagcgac 1140atcgccgtgg agtgggagag
caatgggcag ccggagaaca actacaagac cacgcctccc 1200gtgctggact
ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg
1260tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca
caaccactac 1320acgcagaaga gcctctccct gtctccgggt aaa
1353681651DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 681cagagcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc tcttctgcta ctcagaaacc
ggacgttact 300gtgtttggcg gcggcacgaa gttaaccgtc ctaggtcagc
ccaaggctgc cccctcggtc 360actctgttcc cgccctcctc tgaggagctt
caagccaaca aggccacact ggtgtgtctc 420ataagtgact tctacccggg
agccgtgaca gtggcctgga aggcagatag cagccccgtc 480aaggcgggag
tggagaccac cacaccctcc aaacaaagca acaacaagta cgcggccagc
540agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag
ctgccaggtc 600acgcatgaag ggagcaccgt ggagaagaca gtggccccta
cagaatgttc a 6516825PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 682Ser Tyr Asp Ile His 1 5
68317PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 683Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr
Ala Gln Lys Phe Gln 1 5 10 15 Gly 68412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 684Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
6857PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 685Gly Tyr Thr Phe Thr Ser Tyr 1 5
6866PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 686Asp Pro Tyr Ser Gly Asn 1 5 68712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 687Gly
Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val 1 5 10
68814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 688Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln Val Ser 1 5 10 6897PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 689Gly Val Ser Lys Arg Pro
Ser 1 5 69010PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 690Ala Ser Ala Asp His Ser Tyr His Thr
Val 1 5 10 69110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 691Thr Ser Ser Asp Val Gly Thr Tyr Asn
Gln 1 5 10 6923PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 692Gly Val Ser 1 6937PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 693Ala
Asp His Ser Tyr His Thr 1 5 694121PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 694Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp
Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Ile Asp Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser
Tyr Phe Asp Val Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 695110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 695Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Ala Asp
His Ser 85 90 95 Tyr His Thr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 696363DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 696caggtgcaat
tggtgcagag cggtgcggaa gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag
cgtccggata taccttcact tcttacgaca tccattgggt gcgccaggcc
120ccgggccagg gcctcgagtg gatgggccgt atcgacccgt actctggcaa
cacgaactac 180gcgcagaaat ttcagggccg ggtgaccatg acccgtgata
ccagcattag caccgcgtat 240atggaactga gccgtctgcg tagcgacgat
acggccgtgt attattgcgc gcgtggttct 300ttctacactc gtgactctta
cttcgatgtt tggggccaag gcaccctggt gactgttagc 360tca
363697330DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 697cagagcgcgc tgacccagcc ggcgagcgtg
agcggtagcc cgggccagag cattaccatt 60agctgcaccg gcaccagcag cgatgtgggc
acttacaacc aggtgtcttg gtaccagcag 120catccgggca aggcgccgaa
actgatgatc tacggtgttt ctaaacgtcc gagcggcgtg 180agcaaccgtt
ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg
240caagcggaag acgaagcgga ttattactgc gcttctgctg accattctta
ccatactgtg 300tttggcggcg gcacgaagtt aaccgtccta
330698451PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 698Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asp Ile His Trp Val Arg
Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Asp
Pro Tyr Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Gly Ser Phe Tyr Thr Arg Asp Ser Tyr Phe Asp Val Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210
215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val
Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330
335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser
Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro
Gly Lys 450 699216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 699Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Thr Tyr 20 25 30 Asn Gln Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Gly Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Ala Asp
His Ser 85 90 95 Tyr His Thr Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe
Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu
Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val
Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala
Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185
190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
7001353DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 700caggtgcaat tggtgcagag cggtgcggaa
gtgaaaaaac cgggtgccag cgtgaaagtt 60agctgcaaag cgtccggata taccttcact
tcttacgaca tccattgggt gcgccaggcc 120ccgggccagg gcctcgagtg
gatgggccgt atcgacccgt actctggcaa cacgaactac 180gcgcagaaat
ttcagggccg ggtgaccatg acccgtgata ccagcattag caccgcgtat
240atggaactga gccgtctgcg tagcgacgat acggccgtgt attattgcgc
gcgtggttct 300ttctacactc gtgactctta cttcgatgtt tggggccaag
gcaccctggt gactgttagc 360tcagcctcca ccaagggtcc atcggtcttc
cccctggcac cctcctccaa gagcacctct 420gggggcacag cggccctggg
ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480tcgtggaact
caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc
540tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt
gggcacccag 600acctacatct gcaacgtgaa tcacaagccc agcaacacca
aggtggacaa gagagttgag 660cccaaatctt gtgacaaaac tcacacatgc
ccaccgtgcc cagcacctga actcctgggg 720ggaccgtcag tcttcctctt
ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780cctgaggtca
catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac
840tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga
ggagcagtac 900aacagcacgt accgggtggt cagcgtcctc accgtcctgc
accaggactg gctgaatggc 960aaggagtaca agtgcaaggt ctccaacaaa
gccctcccag cccccatcga gaaaaccatc 1020tccaaagcca aagggcagcc
ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080gagatgacca
agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac
1140atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac
cacgcctccc 1200gtgctggact ccgacggctc cttcttcctc tacagcaagc
tcaccgtgga caagagcagg 1260tggcagcagg ggaacgtctt ctcatgctcc
gtgatgcatg aggctctgca caaccactac 1320acgcagaaga gcctctccct
gtctccgggt aaa 1353701648DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 701cagagcgcgc
tgacccagcc ggcgagcgtg agcggtagcc cgggccagag cattaccatt 60agctgcaccg
gcaccagcag cgatgtgggc acttacaacc aggtgtcttg gtaccagcag
120catccgggca aggcgccgaa actgatgatc tacggtgttt ctaaacgtcc
gagcggcgtg 180agcaaccgtt ttagcggatc caaaagcggc aacaccgcga
gcctgaccat tagcggcctg 240caagcggaag acgaagcgga ttattactgc
gcttctgctg accattctta ccatactgtg 300tttggcggcg gcacgaagtt
aaccgtccta ggtcagccca aggctgcccc ctcggtcact 360ctgttcccgc
cctcctctga ggagcttcaa gccaacaagg ccacactggt gtgtctcata
420agtgacttct acccgggagc cgtgacagtg gcctggaagg cagatagcag
ccccgtcaag 480gcgggagtgg agaccaccac accctccaaa caaagcaaca
acaagtacgc ggccagcagc 540tatctgagcc
tgacgcctga gcagtggaag tcccacagaa gctacagctg ccaggtcacg
600catgaaggga gcaccgtgga gaagacagtg gcccctacag aatgttca
6487026PRTArtificial SequenceDescription of Artificial Sequence
Synthetic 6xHis tag 702His His His His His His 1 5
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References