U.S. patent application number 17/242179 was filed with the patent office on 2021-12-23 for variant nucleic acid libraries for coronavirus.
The applicant listed for this patent is Twist Bioscience Corporation. Invention is credited to Qiang LIU, Aaron SATO, Tom YUAN.
Application Number | 20210395344 17/242179 |
Document ID | / |
Family ID | 1000005883936 |
Filed Date | 2021-12-23 |
United States Patent
Application |
20210395344 |
Kind Code |
A1 |
SATO; Aaron ; et
al. |
December 23, 2021 |
VARIANT NUCLEIC ACID LIBRARIES FOR CORONAVIRUS
Abstract
Provided herein are methods and compositions relating to
libraries of optimized antibodies having nucleic acids encoding for
an antibody comprising modified sequences. Libraries described
herein comprise nucleic acids encoding SARS-CoV-2 or ACE2
antibodies. Further described herein are protein libraries
generated when the nucleic acid libraries are translated. Further
described herein are cell libraries expressing variegated nucleic
acid libraries described herein.
Inventors: |
SATO; Aaron; (Burlingame,
CA) ; LIU; Qiang; (Palo Alto, CA) ; YUAN;
Tom; (San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Twist Bioscience Corporation |
South San Francisco |
CA |
US |
|
|
Family ID: |
1000005883936 |
Appl. No.: |
17/242179 |
Filed: |
April 27, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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63115568 |
Nov 18, 2020 |
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63104465 |
Oct 22, 2020 |
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63073362 |
Sep 1, 2020 |
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63069665 |
Aug 24, 2020 |
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63034896 |
Jun 4, 2020 |
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63016254 |
Apr 27, 2020 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 2317/565 20130101;
C07K 2317/92 20130101; C07K 16/10 20130101; C07K 16/005
20130101 |
International
Class: |
C07K 16/10 20060101
C07K016/10; C07K 16/00 20060101 C07K016/00 |
Claims
1. An antibody or antibody fragment comprising a variable domain,
heavy chain region (VH) and a variable domain, light chain region
(VL), wherein VH comprises complementarity determining regions
CDRH1, CDRH2, and CDRH3, wherein VL comprises complementarity
determining regions CDRL1, CDRL2, and CDRL3, and wherein (a) an
amino acid sequence of CDRH1 is as set forth in any one of SEQ ID
NOs: 1-36 or 217-282; (b) an amino acid sequence of CDRH2 is as set
forth in any one of SEQ ID NOs: 37-72 or 283-348; (c) an amino acid
sequence of CDRH3 is as set forth in any one of SEQ ID NOs: 73-108
or 349-414; (d) an amino acid sequence of CDRL1 is as set forth in
any one of SEQ ID NOs: 109-144 or 415-473; (e) an amino acid
sequence of CDRL2 is as set forth in any one of SEQ ID NOs: 145-180
or 415-473; and (f) an amino acid sequence of CDRL3 is as set forth
in any one of SEQ ID NOs: 181-216 or 533-591.
2. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 30; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 66;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
102; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 138; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 174; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 210.
3. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 35; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 71;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
107; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 143; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 179; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 215.
4. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 12; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 48;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
84; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 120; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 156; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 192.
5. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 31; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 67;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
103; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 139; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 175; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 211.
6. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 240; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 306;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
372; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 437; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 496; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 555.
7. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 244; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 310;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
376; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 437; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 496; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 555.
8. The antibody or antibody fragment of claim 1, wherein (a) an
amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 270; (b)
an amino acid sequence of CDRH2 is as set forth in SEQ ID NO: 336;
(c) an amino acid sequence of CDRH3 is as set forth in SEQ ID NO:
402; (d) an amino acid sequence of CDRL1 is as set forth in SEQ ID
NO: 461; (e) an amino acid sequence of CDRL2 is as set forth in SEQ
ID NO: 520; and (f) an amino acid sequence of CDRL3 is as set forth
in SEQ ID NO: 579.
9. The antibody or antibody fragment of claim 1, wherein the
antibody or antibody fragment binds to a spike glycoprotein.
10. The antibody or antibody fragment of claim 1, wherein the
antibody or antibody fragment binds to a receptor binding domain of
the spike glycoprotein.
11. (canceled)
12. (canceled)
13. The antibody or antibody fragment of claim 1, wherein the
antibody or antibody fragment comprises a K.sub.D of less than 10
nM.
14. The antibody or antibody fragment of claim 1, wherein the
antibody or antibody fragment comprises a K.sub.D of less than 5
nM.
15. An antibody or antibody fragment comprising a variable domain,
heavy chain region (VH) and a variable domain, light chain region
(VL), wherein the VH comprises an amino acid sequence at least
about 90% identical to a sequence as set forth in any one of SEQ ID
NOs: 592-657, and wherein the VL comprises an amino acid sequence
at least about 90% identical to a sequence as set forth in any one
of SEQ ID NOs: 658-716.
16. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 594, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 660.
17. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 595, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 661.
18. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 598, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 664.
19. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 603, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 669.
20. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 615, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 680.
21. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 631, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 691.
22. The antibody or antibody fragment of claim 15, wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 645, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 704.
23.-47. (canceled)
Description
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 63/115,568 filed on Nov. 18, 2020, U.S.
Provisional Patent Application No. 63/104,465 filed on Oct. 22,
2020, U.S. Provisional Patent Application No. 63/073,362 filed on
Sep. 1, 2020, U.S. Provisional Patent Application No. 63/069,665
filed on Aug. 24, 2020, U.S. Provisional Patent Application No.
63/034,896 filed on Jun. 4, 2020, U.S. Provisional Patent
Application No. 63/016,254 filed on Apr. 27, 2020, each of which is
incorporated by reference in its entirety.
BACKGROUND
[0002] Coronaviruses like severe acute respiratory coronavirus 2
(SARS-CoV-2) can cause severe respiratory problems. Therapies are
needed for treating and preventing viral infection caused by
coronaviruses like SARS-CoV-2. Antibodies possess the capability to
bind with high specificity and affinity to biological targets.
However, the design of therapeutic antibodies is challenging due to
balancing of immunological effects with efficacy. Thus, there is a
need to develop compositions and methods for the optimization of
antibody properties in order to develop effective therapies for
treating coronavirus infections.
INCORPORATION BY REFERENCE
[0003] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
BRIEF SUMMARY
[0004] Provided herein are nucleic acid libraries comprising: a
plurality of sequences that when translated encode for antibodies
or antibody fragments that bind to SARS-CoV-2 or ACE2 protein,
wherein each of the sequences comprises a predetermined number of
variants within a CDR relative to an input sequence that encodes an
antibody, and wherein the library comprises at least 50,000 variant
sequences. Further provided herein are nucleic acid libraries,
wherein the antibodies or antibody fragments bind to a spike
glycoprotein, a membrane protein, an envelope protein, a
nucleocapsid protein, or combinations thereof of the SARS-CoV-2.
Further provided herein are nucleic acid libraries, wherein the
antibodies or antibody fragments bind to a spike glycoprotein.
Further provided herein are nucleic acid libraries, wherein the
antibodies or antibody fragment bind to a receptor binding domain
of the spike glycoprotein. Further provided herein are nucleic acid
libraries, wherein the library comprises at least 100,000 variant
sequences. Further provided herein are nucleic acid libraries,
wherein at least some of the sequences encode for an antibody light
chain. Further provided herein are nucleic acid libraries, wherein
at least some of the sequences encode for an antibody heavy chain.
Further provided herein are nucleic acid libraries, wherein each
sequence of the plurality of sequences comprises at least one
variant in the CDR of a heavy chain or light chain relative to the
input sequence. Further provided herein are nucleic acid libraries,
wherein each sequence of the plurality of sequences comprises at
least two variants in the CDR of a heavy chain or light chain
relative to the input sequence. Further provided herein are nucleic
acid libraries, wherein at least one of the variants is present in
at least two individuals. Further provided herein are nucleic acid
libraries, wherein at least one of the variants is present in at
least three individuals. Further provided herein are nucleic acid
libraries, wherein at least one sequence when translated encodes
for an antibody or antibody fragment having at least 5.times.
higher binding affinity than a binding affinity of the input
sequence. Further provided herein are nucleic acid libraries,
wherein at least one sequence when translated encodes for an
antibody or antibody fragment having at least 25.times. higher
binding affinity than a binding affinity of the input sequence.
Further provided herein are nucleic acid libraries, wherein at
least one sequence when translated encodes for an antibody or
antibody fragment having at least 50.times. higher binding affinity
than a binding affinity of the input sequence. Further provided
herein are nucleic acid libraries, wherein each sequence of the
plurality of sequences comprises at least one variant in the CDR of
a heavy chain or light chain relative to a germline sequence of the
input sequence. Further provided herein are nucleic acid libraries,
wherein the CDR is a CDR1, CDR2, and CDR3 on a heavy chain. Further
provided herein are nucleic acid libraries, wherein the CDR is a
CDR1, CDR2, and CDR3 on a light chain. Further provided herein are
nucleic acid libraries, wherein the at least one sequence that when
translated encodes for an antibody or antibody fragment having at
least 70.times. higher binding affinity than the input sequence.
Further provided herein are nucleic acid libraries, wherein the at
least one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 50 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 25 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 10 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 5 nM. Further
provided herein are nucleic acid libraries, wherein the library
encodes a CDR sequence of any one of SEQ ID NOs: 1-591.
[0005] Provided herein are nucleic acid libraries comprising: a
plurality of sequences that when translated encode for antibodies
or antibody fragments that bind to a coronavirus or a receptor of
the coronavirus, wherein each of the sequences comprises a
predetermined number of variants within a CDR relative to an input
sequence that encodes an antibody, and wherein the library
comprises at least 50,000 variant sequences. Further provided
herein are nucleic acid libraries, wherein the coronavirus is
SARS-CoV, MERS-CoV, CoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1.
Further provided herein are nucleic acid libraries, wherein the
receptor of the coronavirus is ACE2 or dipeptidyl peptidase 4
(DPP4). Further provided herein are nucleic acid libraries, wherein
the library comprises at least 100,000 variant sequences. Further
provided herein are nucleic acid libraries, wherein at least some
of the sequences encode for an antibody light chain. Further
provided herein are nucleic acid libraries, wherein at least some
of the sequences encode for an antibody heavy chain. Further
provided herein are nucleic acid libraries, wherein each sequence
of the plurality of sequences comprises at least one variant in the
CDR of a heavy chain or light chain relative to the input sequence.
Further provided herein are nucleic acid libraries, wherein each
sequence of the plurality of sequences comprises at least two
variants in the CDR of a heavy chain or light chain relative to the
input sequence. Further provided herein are nucleic acid libraries,
wherein at least one of the variants is present in at least two
individuals. Further provided herein are nucleic acid libraries,
wherein at least one of the variants is present in at least three
individuals. Further provided herein are nucleic acid libraries,
wherein at least one sequence when translated encodes for an
antibody or antibody fragment having at least 5.times. higher
binding affinity than a binding affinity of the input sequence.
Further provided herein are nucleic acid libraries, wherein at
least one sequence when translated encodes for an antibody or
antibody fragment having at least 25.times. higher binding affinity
than a binding affinity of the input sequence. Further provided
herein are nucleic acid libraries, wherein at least one sequence
when translated encodes for an antibody or antibody fragment having
at least 50.times. higher binding affinity than a binding affinity
of the input sequence. Further provided herein are nucleic acid
libraries, wherein each sequence of the plurality of sequences
comprises at least one variant in the CDR of a heavy chain or light
chain relative to a germline sequence of the input sequence.
Further provided herein are nucleic acid libraries, wherein the CDR
is a CDR1, CDR2, and CDR3 on a heavy chain. Further provided herein
are nucleic acid libraries, wherein the CDR is a CDR1, CDR2, and
CDR3 on a light chain. Further provided herein are nucleic acid
libraries, wherein the at least one sequence that when translated
encodes for an antibody or antibody fragment having at least
70.times. higher binding affinity than the input sequence. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 50 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 25 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 10 nM. Further
provided herein are nucleic acid libraries, wherein the at least
one sequence that when translated encodes for an antibody or
antibody fragment having a K.sub.D of less than 5 nM.
[0006] Provided herein are antibodies, wherein the antibody
comprises a sequence comprising at least 90% sequence identity to
any one of SEQ ID NOs: 1-716.
[0007] Provided herein are antibodies, wherein the antibody
comprises a sequence comprising at least 90% sequence identity to
SEQ ID NOs: 1-716; and wherein the antibody is a monoclonal
antibody, a polyclonal antibody, a bi-specific antibody, a
multispecific antibody, a grafted antibody, a human antibody, a
humanized antibody, a synthetic antibody, a chimeric antibody, a
camelized antibody, a single-chain Fvs (scFv), a single chain
antibody, a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv
fragment, a single-domain antibody, an isolated complementarity
determining region (CDR), a diabody, a fragment comprised of only a
single monomeric variable domain, disulfide-linked Fvs (sdFv), an
intrabody, an anti-idiotypic (anti-Id) antibody, or ab
antigen-binding fragments thereof.
[0008] Provided herein are methods of treating a SARS-CoV-2
infection, comprising administering the antibody as described
herein. Further provided herein are methods, wherein the antibody
is administered prior to exposure to SARS-CoV-2. Further provided
herein are methods, wherein the antibody is administered at least
about 1 week prior to exposure to SARS-CoV-2. Further provided
herein are methods, wherein the antibody is administered at least
about 1 month prior to exposure to SARS-CoV-2. Further provided
herein are methods, wherein the antibody is administered at least
about 5 months prior to exposure to SARS-CoV-2. Further provided
herein are methods, wherein the antibody is administered after
exposure to SARS-CoV-2. Further provided herein are methods,
wherein the antibody is administered at most about 24 hours after
exposure to SARS-CoV-2. Further provided herein are methods,
wherein the antibody is administered at most about 1 week after
exposure to SARS-CoV-2. Further provided herein are methods,
wherein the antibody is administered at most about 1 month after
exposure to SARS-CoV-2.
[0009] Provided herein are methods of treating an individual with a
SARS-CoV-2 infection with the antibody as described herein
comprising: (a) obtaining or having obtained a sample from the
individual; (b) performing or having performed an expression level
assay on the sample to determine expression levels of SARS-CoV-2
antibodies; and (c) if the sample has an expression level of the
SARS-CoV-2 antibodies then administering to the individual the
antibody as described herein, thereby treating the SARS-CoV-2
infection.
[0010] Provided herein are methods for optimizing an antibody
comprising: (a) providing a plurality of polynucleotide sequences
encoding for an antibody or antibody fragment, wherein the antibody
or antibody fragment is derived from a subject having SARS-CoV-2;
(b) generating a nucleic acid library comprising the plurality of
sequences that when translated encode for antibodies or antibody
fragments that bind SARS-CoV-2 or ACE2 protein, wherein each of the
sequences comprises a predetermined number of variants within a CDR
relative to an input sequence that encodes an antibody; wherein the
library comprises at least 50,000 variant sequences; and (c)
synthesizing the at least 50,000 variant sequences. Further
provided herein are methods, wherein the antibody library comprises
at least 100,000 sequences. Further provided herein are methods,
wherein the method further comprises enriching a subset of the
variant sequences. Further provided herein are methods, wherein the
method further comprises expressing the antibody or antibody
fragments corresponding to the variant sequences. Further provided
herein are methods, wherein the polynucleotide sequence is a
murine, human, or chimeric antibody sequence. Further provided
herein are methods, wherein each sequence of the plurality of
variant sequences comprises at least one variant in each CDR of a
heavy chain or light chain, relative to the input sequence. Further
provided herein are methods, wherein each sequence of the plurality
of variant sequences comprises at least two variants in each CDR of
a heavy chain or light chain relative to the input sequence.
Further provided herein are methods, wherein at least one sequence
when translated encodes for an antibody or antibody fragment having
at least 5.times. higher binding affinity than a binding affinity
of the input sequence. Further provided herein are methods, wherein
at least one sequence when translated encodes for an antibody or
antibody fragment having at least 25.times. higher binding affinity
than a binding affinity of the input sequence. Further provided
herein are methods, wherein at least one sequence when translated
encodes for an antibody or antibody fragment having at least
50.times. higher binding affinity than a binding affinity of the
input sequence. Further provided herein are methods, wherein each
sequence comprises at least one variant in each CDR of a heavy
chain or light chain relative to a germline sequence of the input
sequence. Further provided herein are methods, wherein the nucleic
acid library has a theoretical diversity of at least 10.sup.10
sequences. Further provided herein are methods, wherein the nucleic
acid library has a theoretical diversity of at least 10.sup.12
sequences.
[0011] Provided herein are antibodies or antibody fragments
comprising a variable domain, heavy chain region (VH) and a
variable domain, light chain region (VL), wherein VH comprises
complementarity determining regions CDRH1, CDRH2, and CDRH3,
wherein VL comprises complementarity determining regions CDRL1,
CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1
is as set forth in any one of SEQ ID NOs: 1-36 or 217-282; (b) an
amino acid sequence of CDRH2 is as set forth in any one of SEQ ID
NOs: 37-72 or 283-348; (c) an amino acid sequence of CDRH3 is as
set forth in any one of SEQ ID NOs: 73-108 or 349-414; (d) an amino
acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs:
109-144 or 415-473; (e) an amino acid sequence of CDRL2 is as set
forth in any one of SEQ ID NOs: 145-180 or 415-473; and (f) an
amino acid sequence of CDRL3 is as set forth in any one of SEQ ID
NOs: 181-216 or 533-591. Further provided herein are antibodies or
antibody fragments, wherein (a) an amino acid sequence of CDRH1 is
as set forth in SEQ ID NO: 30; (b) an amino acid sequence of CDRH2
is as set forth in SEQ ID NO: 66; (c) an amino acid sequence of
CDRH3 is as set forth in SEQ ID NO: 102; (d) an amino acid sequence
of CDRL1 is as set forth in SEQ ID NO: 138; (e) an amino acid
sequence of CDRL2 is as set forth in SEQ ID NO: 174; and (f) an
amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 210.
Further provided herein are antibodies or antibody fragments,
wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ
ID NO: 35; (b) an amino acid sequence of CDRH2 is as set forth in
SEQ ID NO: 71; (c) an amino acid sequence of CDRH3 is as set forth
in SEQ ID NO: 107; (d) an amino acid sequence of CDRL1 is as set
forth in SEQ ID NO: 143; (e) an amino acid sequence of CDRL2 is as
set forth in SEQ ID NO: 179; and (f) an amino acid sequence of
CDRL3 is as set forth in SEQ ID NO: 215. Further provided herein
are antibodies or antibody fragments, wherein (a) an amino acid
sequence of CDRH1 is as set forth in SEQ ID NO: 12; (b) an amino
acid sequence of CDRH2 is as set forth in SEQ ID NO: 48; (c) an
amino acid sequence of CDRH3 is as set forth in SEQ ID NO: 84; (d)
an amino acid sequence of CDRL1 is as set forth in SEQ ID NO: 120;
(e) an amino acid sequence of CDRL2 is as set forth in SEQ ID NO:
156; and (f) an amino acid sequence of CDRL3 is as set forth in SEQ
ID NO: 192. Further provided herein are antibodies or antibody
fragments, wherein (a) an amino acid sequence of CDRH1 is as set
forth in SEQ ID NO: 31; (b) an amino acid sequence of CDRH2 is as
set forth in SEQ ID NO: 67; (c) an amino acid sequence of CDRH3 is
as set forth in SEQ ID NO: 103; (d) an amino acid sequence of CDRL1
is as set forth in SEQ ID NO: 139; (e) an amino acid sequence of
CDRL2 is as set forth in SEQ ID NO: 175; and (f) an amino acid
sequence of CDRL3 is as set forth in SEQ ID NO: 211. Further
provided herein are antibodies or antibody fragments, wherein (a)
an amino acid sequence of CDRH1 is as set forth in SEQ ID NO: 240;
(b) an amino acid sequence of CDRH2 is as set forth in SEQ ID NO:
306; (c) an amino acid sequence of CDRH3 is as set forth in SEQ ID
NO: 372; (d) an amino acid sequence of CDRL1 is as set forth in SEQ
ID NO: 437; (e) an amino acid sequence of CDRL2 is as set forth in
SEQ ID NO: 496; and (f) an amino acid sequence of CDRL3 is as set
forth in SEQ ID NO: 555. Further provided herein are antibodies or
antibody fragments, wherein (a) an amino acid sequence of CDRH1 is
as set forth in SEQ ID NO: 244; (b) an amino acid sequence of CDRH2
is as set forth in SEQ ID NO: 310; (c) an amino acid sequence of
CDRH3 is as set forth in SEQ ID NO: 376; (d) an amino acid sequence
of CDRL1 is as set forth in SEQ ID NO: 437; (e) an amino acid
sequence of CDRL2 is as set forth in SEQ ID NO: 496; and (f) an
amino acid sequence of CDRL3 is as set forth in SEQ ID NO: 555.
Further provided herein are antibodies or antibody fragments,
wherein (a) an amino acid sequence of CDRH1 is as set forth in SEQ
ID NO: 270; (b) an amino acid sequence of CDRH2 is as set forth in
SEQ ID NO: 336; (c) an amino acid sequence of CDRH3 is as set forth
in SEQ ID NO: 402; (d) an amino acid sequence of CDRL1 is as set
forth in SEQ ID NO: 461; (e) an amino acid sequence of CDRL2 is as
set forth in SEQ ID NO: 520; and (f) an amino acid sequence of
CDRL3 is as set forth in SEQ ID NO: 579. Further provided herein
are antibodies or antibody fragments, wherein the antibody or
antibody fragment binds to a spike glycoprotein. Further provided
herein are antibodies or antibody fragments, wherein the antibody
or antibody fragment binds to a receptor binding domain of the
spike glycoprotein. Further provided herein are antibodies or
antibody fragments, wherein the antibody or antibody fragment
comprises a K.sub.D of less than 50 nM. Further provided herein are
antibodies or antibody fragments, wherein the antibody or antibody
fragment comprises a K.sub.D of less than 25 nM. Further provided
herein are antibodies or antibody fragments, wherein the antibody
or antibody fragment comprises a K.sub.D of less than 10 nM.
Further provided herein are antibodies or antibody fragments,
wherein the antibody or antibody fragment comprises a K.sub.D of
less than 5 nM.
[0012] Provided herein are antibodies or antibody fragments
comprising a variable domain, heavy chain region (VH) and a
variable domain, light chain region (VL), wherein the VH comprises
an amino acid sequence at least about 90% identical to a sequence
as set forth in any one of SEQ ID NOs: 592-657, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in any one of SEQ ID NOs: 658-716. Further
provided herein are antibodies or antibody fragments, wherein the
VH comprises an amino acid sequence at least about 90% identical to
a sequence as set forth in SEQ ID NO: 594, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 660. Further provided herein
are antibodies or antibody fragments, wherein the VH comprises an
amino acid sequence at least about 90% identical to a sequence as
set forth in SEQ ID NO: 595, and wherein the VL comprises an amino
acid sequence at least about 90% identical to a sequence as set
forth in SEQ ID NO: 661. Further provided herein are antibodies or
antibody fragments, wherein the VH comprises an amino acid sequence
at least about 90% identical to a sequence as set forth in SEQ ID
NO: 598, and wherein the VL comprises an amino acid sequence at
least about 90% identical to a sequence as set forth in SEQ ID NO:
664. Further provided herein are antibodies or antibody fragments,
wherein the VH comprises an amino acid sequence at least about 90%
identical to a sequence as set forth in SEQ ID NO: 603, and wherein
the VL comprises an amino acid sequence at least about 90%
identical to a sequence as set forth in SEQ ID NO: 669. Further
provided herein are antibodies or antibody fragments, wherein the
VH comprises an amino acid sequence at least about 90% identical to
a sequence as set forth in SEQ ID NO: 615, and wherein the VL
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in SEQ ID NO: 680. Further provided herein
are antibodies or antibody fragments, wherein the VH comprises an
amino acid sequence at least about 90% identical to a sequence as
set forth in SEQ ID NO: 631, and wherein the VL comprises an amino
acid sequence at least about 90% identical to a sequence as set
forth in SEQ ID NO: 691. Further provided herein are antibodies or
antibody fragments, wherein the VH comprises an amino acid sequence
at least about 90% identical to a sequence as set forth in SEQ ID
NO: 645, and wherein the VL comprises an amino acid sequence at
least about 90% identical to a sequence as set forth in SEQ ID NO:
704. Further provided herein are antibodies, wherein the antibody
comprises a sequence comprising at least 90% sequence identity to
any one of SEQ ID NOs: 1-716; and wherein the antibody is a
monoclonal antibody, a polyclonal antibody, a bi-specific antibody,
a multispecific antibody, a grafted antibody, a human antibody, a
humanized antibody, a synthetic antibody, a chimeric antibody, a
camelized antibody, a single-chain Fvs (scFv), a single chain
antibody, a Fab fragment, a F(ab')2 fragment, a Fd fragment, a Fv
fragment, a single-domain antibody, an isolated complementarity
determining region (CDR), a diabody, a fragment comprised of only a
single monomeric variable domain, disulfide-linked Fvs (sdFv), an
intrabody, an anti-idiotypic (anti-Id) antibody, or ab
antigen-binding fragments thereof.
[0013] Provided herein are nucleic acid compositions comprising: a)
a first nucleic acid encoding a variable domain, heavy chain region
(VH) comprising an amino acid sequence at least about 90% identical
to a sequence as set forth in any one of SEQ ID NOs: 592-657; b) a
second nucleic acid encoding a variable domain, light chain region
(VL) comprising at least about 90% identical to a sequence as set
forth in any one of SEQ ID NOs: 658-716; and an excipient.
[0014] Provided herein are methods of treating a SARS-CoV-2
infection, comprising administering the antibody or antibody
fragment described herein. Further provided herein are methods,
wherein the antibody is administered prior to exposure to
SARS-CoV-2. Further provided herein are methods, wherein the
antibody is administered at least about 1 week prior to exposure to
SARS-CoV-2. Further provided herein are methods, wherein the
antibody is administered at least about 1 month prior to exposure
to SARS-CoV-2. Further provided herein are methods, wherein the
antibody is administered at least about 5 months prior to exposure
to SARS-CoV-2. Further provided herein are methods, wherein the
antibody is administered after exposure to SARS-CoV-2. Further
provided herein are methods, wherein the antibody is administered
at most about 24 hours after exposure to SARS-CoV-2. Further
provided herein are methods, wherein the antibody is administered
at most about 1 week after exposure to SARS-CoV-2. Further provided
herein are methods, wherein the antibody is administered at most
about 1 month after exposure to SARS-CoV-2.
[0015] Provided herein are methods of treating an individual with a
SARS-CoV-2 infection with the antibody or antibody fragment
described herein comprising: a) obtaining or having obtained a
sample from the individual; b) performing or having performed an
expression level assay on the sample to determine expression levels
of SARS-CoV-2 antibodies; and if the sample has an expression level
of the SARS-CoV-2 antibodies then administering to the individual
the antibody or antibody fragment described herein, thereby
treating the SARS-CoV-2 infection.
[0016] Provided herein are methods for optimizing an antibody
comprising: a) providing a plurality of polynucleotide sequences
encoding for an antibody or antibody fragment, wherein the antibody
or antibody fragment is derived from a subject having SARS-CoV-2;
b) generating a nucleic acid library comprising the plurality of
sequences that when translated encode for antibodies or antibody
fragments that bind SARS-CoV-2 or ACE2 protein, wherein each of the
sequences comprises a predetermined number of variants within a CDR
relative to an input sequence that encodes an antibody; wherein the
library comprises at least 50,000 variant sequences; and c)
synthesizing the at least 50,000 variant sequences. Further
provided herein are methods, wherein the antibody library comprises
at least 100,000 sequences. Further provided herein are methods,
wherein the method further comprises enriching a subset of the
variant sequences. Further provided herein are methods, wherein the
method further comprises expressing the antibody or antibody
fragments corresponding to the variant sequences. Further provided
herein are methods, wherein the polynucleotide sequence is a
murine, human, or chimeric antibody sequence. Further provided
herein are methods, wherein each sequence of the plurality of
variant sequences comprises at least one variant in each CDR of a
heavy chain or light chain, relative to the input sequence. Further
provided herein are methods, wherein each sequence of the plurality
of variant sequences comprises at least two variants in each CDR of
a heavy chain or light chain relative to the input sequence.
Further provided herein are methods, wherein at least one sequence
when translated encodes for an antibody or antibody fragment having
at least 5.times. higher binding affinity than a binding affinity
of the input sequence. Further provided herein are methods, wherein
at least one sequence when translated encodes for an antibody or
antibody fragment having at least 25.times. higher binding affinity
than a binding affinity of the input sequence. Further provided
herein are methods, wherein at least one sequence when translated
encodes for an antibody or antibody fragment having at least
50.times. higher binding affinity than a binding affinity of the
input sequence. Further provided herein are methods, wherein each
sequence comprises at least one variant in each CDR of a heavy
chain or light chain relative to a germline sequence of the input
sequence. Further provided herein are methods, wherein the nucleic
acid library has a theoretical diversity of at least 10.sup.10
sequences. Further provided herein are methods, wherein the nucleic
acid library has a theoretical diversity of at least 10.sup.12
sequences.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 depicts a workflow for antibody optimization.
[0018] FIG. 2 presents a diagram of steps demonstrating an
exemplary process workflow for gene synthesis as disclosed
herein.
[0019] FIG. 3 illustrates an example of a computer system.
[0020] FIG. 4 is a block diagram illustrating an architecture of a
computer system.
[0021] FIG. 5 is a diagram demonstrating a network configured to
incorporate a plurality of computer systems, a plurality of cell
phones and personal data assistants, and Network Attached Storage
(NAS).
[0022] FIG. 6 is a block diagram of a multiprocessor computer
system using a shared virtual address memory space.
[0023] FIG. 7 is a schema of a panning workflow.
[0024] FIGS. 8A-8B are graphs of panning data from round 4 for
antibody 1.
[0025] FIGS. 8C-8D are graphs of panning data from round 4 for
antibody 2.
[0026] FIGS. 9A-9B are graphs of panning data from round 4 for
antibody 3.
[0027] FIGS. 9C-9D are graphs of panning data from round 4 for
antibody 4.
[0028] FIG. 10 shows graphs of ACE2 binding to SARS-CoV-2 variant
antibodies.
[0029] FIGS. 11A-11B are graphs of affinity data for SARS-CoV-2
variant antibodies.
[0030] FIG. 12 is a graph of binding of SARS-CoV-2 variant
antibodies to 51 protein.
[0031] FIG. 13A is a graph of SARS-CoV-2 and ACE2 competition
ELISAs from a first set.
[0032] FIG. 13B is a graph of SARS-CoV-2 and ACE2 competition
ELISAs from a first set showing SARS-CoV-2 variant antibodies.
[0033] FIGS. 14A-14B are graphs from a first set (FIG. 14A) and
second set (FIG. 14B) showing ACE2 variant antibodies.
[0034] FIGS. 14C-14D are graphs of SARS-CoV-2 variant antibodies in
neutralization assays.
[0035] FIG. 15 is a graph of SARS-CoV-2 and ACE2 inhibition.
[0036] FIGS. 16A-16B are graphs of SARS-CoV-2 variant antibodies on
VERO E6 inhibition measured by FACS.
[0037] FIG. 17A is a graph of SARS-CoV-2 variant antibodies on VERO
E6 inhibition measured by FACS as compared to CR3022.
[0038] FIGS. 17B-17C are graphs of affinity of SARS-CoV-2 variant
antibodies determined by coating ELISA plates with SARS-CoV-2 Spike
Glycoprotein 51 (FIG. 17B) or S protein trimer (FIG. 17C).
[0039] FIG. 17D is a graph of mean fluorescent intensity (MFI)
plotted for each SARS-CoV-2 variant antibody dilution.
[0040] FIGS. 18A-18C are graphs of mean fluorescent intensity (MFI)
plotted for each SARS-CoV-2 variant antibody dilution.
[0041] FIGS. 19A-19B are graphs of antibody kinetics for variants
2-5, 2-2, and 2-6 (FIG. 19A) and variants 1-12, 1-42, 1-20, and
1-19 (FIG. 19B).
[0042] FIG. 19C is a graph of percent neutralization for variants
1-12, 1-42 and 1-20.
[0043] FIG. 19D is a graph of percent neutralization for variants
1-12, 1-42 and 1-20 using live virus.
[0044] FIGS. 20A-20D are graphs of variant antibodies neutralizing
live virus.
[0045] FIG. 20E is a graph of variant antibodies neutralizing live
virus FRNT.
[0046] FIG. 20E-20I show data of variant antibodies neutralizing
live virus PRNT.
[0047] FIG. 21A shows a graph of percent weight change (y-axis)
versus day post injection (PI, x-axis) for positive control
convalescent plasma and negative control Mab c7d11.
[0048] FIG. 21B shows a graph of percent weight change (y-axis)
versus day post injection (PI, x-axis) for variant antibody
6-63.
[0049] FIG. 21C shows a graph of percent weight change (y-axis)
versus day post injection (PI, x-axis) for variant antibody
6-3.
[0050] FIG. 21D shows a graph of percent weight change (y-axis)
versus day post injection (PI, x-axis) for variant antibody
6-36.
[0051] FIG. 21E shows graphs of percent weight change (y-axis)
versus day post injection (PI, x-axis) based on dose.
[0052] FIG. 21F shows graphs of percent weight change (y-axis)
versus day post injection (PI, x-axis) based on dose for variant
antibodies 2-3, 2-63, and 1-20.
[0053] FIG. 21G shows a graph of data from a plaque assay to detect
infectious virus in Day 9 lungs. The indicated antibodies were
administered Day -1. Lungs were collected on Day 9, the right lobe
was homogenized, clarified and supernatants were quantified by
plaque titration. Individual hamster values are shown as symbols.
White symbols indicate no infectious virus detected. The geometric
mean PFU/gram is shown as bars. Limit of assay shown as dotted
line.
[0054] FIG. 21H shows a graph of data from in situ hybridization
(ISH) to detect infected cells in Day 9 lungs. The indicated
antibodies were administered Day -1. Three animals per group were
analyzed. Individual hamster values are shown as symbols. Median
ISH scores are shown as bars.
[0055] FIG. 21I shows a graph of data from cumulative inflammation
and edema scores for Day 9 lungs. The indicated antibodies were
administered Day -1. Three animals per group were analyzed.
Individual hamster cumulative pathology scores are shown as
symbols. Median scores are shown as bars.
[0056] FIG. 22A shows a graph of the positive control pAb in a
neutralization assay.
[0057] FIG. 22B shows a graph of neutralization of antibodies 6-63,
6-3, and 1-12 in VSV-SARS B.135 strain.
[0058] FIG. 23A shows a graph of the positive control in a
neutralization assay.
[0059] FIGS. 23B-23C show graphs of neutralization by antibodies
described herein.
[0060] FIG. 24A shows graphs weight change. Animals were
immunosuppressed and then exposed to SARS-CoV-2 virus, WA1 strain,
on Day 0. Top graph indicates data from the control group that
received the cocktail on Day -1 (D-1, Group A). A group was
immunosuppressed but not exposed to virus (CYP Control, Group I).
Negative control is an IgG monoclonal (Group H). The cocktail was
administered on the indicated day post-exposure (Groups B-G; middle
and bottom graphs). Arrows indicate day of antibody administration.
Symbols are mean.+-.SEM. Statistical differences in the area under
the curve (AOC) are shown to the right of each line. * indicates p
value <0.05, ns=not significant.
[0061] FIG. 24B shows a graph of data from FIG. 24A plotted on one
graph.
[0062] FIG. 24C shows a graph of infectious virus in lungs on Day
14. Plaque assays were run on Day 14 lung homogenates. Plaque
forming units (PFU) per gram of tissue were calculated and plotted.
The limit of the assay is shown as a dotted line. Bars are the
geometric means for each group. Group ID are in parentheses. White
symbols indicated no infectious virus was detected.
CYP=cyclophosphamide; Neg=Negative; Cont=control.
[0063] FIG. 24D shows a graph infectious virus in lungs of
untreated control hamsters. CYP-treated animals were exposed to
1,000 pfu of virus by intranasal route on Day 0. Groups of four
animals were euthanized and lungs were collected on the indicated
days. Lung homogenates were assayed for infectious virus by plaque
assay. Plaque forming units (PFU) per gram lung tissue are plotted.
Geometric mean titers and SD are shown.
DETAILED DESCRIPTION
[0064] The present disclosure employs, unless otherwise indicated,
conventional molecular biology techniques, which are within the
skill of the art. Unless defined otherwise, all technical and
scientific terms used herein have the same meaning as is commonly
understood by one of ordinary skill in the art.
Definitions
[0065] Throughout this disclosure, various embodiments are
presented in a range format. It should be understood that the
description in range format is merely for convenience and brevity
and should not be construed as an inflexible limitation on the
scope of any embodiments. Accordingly, the description of a range
should be considered to have specifically disclosed all the
possible subranges as well as individual numerical values within
that range to the tenth of the unit of the lower limit unless the
context clearly dictates otherwise. For example, description of a
range such as from 1 to 6 should be considered to have specifically
disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5,
from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual
values within that range, for example, 1.1, 2, 2.3, 5, and 5.9.
This applies regardless of the breadth of the range. The upper and
lower limits of these intervening ranges may independently be
included in the smaller ranges, and are also encompassed within the
disclosure, subject to any specifically excluded limit in the
stated range. Where the stated range includes one or both of the
limits, ranges excluding either or both of those included limits
are also included in the disclosure, unless the context clearly
dictates otherwise.
[0066] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
any embodiment. As used herein, the singular forms "a," "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. It will be further understood
that the terms "comprises" and/or "comprising," when used in this
specification, specify the presence of stated features, integers,
steps, operations, elements, and/or components, but do not preclude
the presence or addition of one or more other features, integers,
steps, operations, elements, components, and/or groups thereof. As
used herein, the term "and/or" includes any and all combinations of
one or more of the associated listed items.
[0067] Unless specifically stated or obvious from context, as used
herein, the term "about" in reference to a number or range of
numbers is understood to mean the stated number and numbers +/-10%
thereof, or 10% below the lower listed limit and 10% above the
higher listed limit for the values listed for a range.
[0068] Unless specifically stated, as used herein, the term
"nucleic acid" encompasses double- or triple-stranded nucleic
acids, as well as single-stranded molecules. In double- or
triple-stranded nucleic acids, the nucleic acid strands need not be
coextensive (i.e., a double-stranded nucleic acid need not be
double-stranded along the entire length of both strands). Nucleic
acid sequences, when provided, are listed in the 5' to 3'
direction, unless stated otherwise. Methods described herein
provide for the generation of isolated nucleic acids. Methods
described herein additionally provide for the generation of
isolated and purified nucleic acids. A "nucleic acid" as referred
to herein can comprise at least 5, 10, 20, 30, 40, 50, 60, 70, 80,
90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375,
400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1100, 1200,
1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, or more bases in
length. Moreover, provided herein are methods for the synthesis of
any number of polypeptide-segments encoding nucleotide sequences,
including sequences encoding non-ribosomal peptides (NRPs),
sequences encoding non-ribosomal peptide-synthetase (NRPS) modules
and synthetic variants, polypeptide segments of other modular
proteins, such as antibodies, polypeptide segments from other
protein families, including non-coding DNA or RNA, such as
regulatory sequences e.g. promoters, transcription factors,
enhancers, siRNA, shRNA, RNAi, miRNA, small nucleolar RNA derived
from microRNA, or any functional or structural DNA or RNA unit of
interest. The following are non-limiting examples of
polynucleotides: coding or non-coding regions of a gene or gene
fragment, intergenic DNA, loci (locus) defined from linkage
analysis, exons, introns, messenger RNA (mRNA), transfer RNA,
ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA
(shRNA), micro-RNA (miRNA), small nucleolar RNA, ribozymes,
complementary DNA (cDNA), which is a DNA representation of mRNA,
usually obtained by reverse transcription of messenger RNA (mRNA)
or by amplification; DNA molecules produced synthetically or by
amplification, genomic DNA, recombinant polynucleotides, branched
polynucleotides, plasmids, vectors, isolated DNA of any sequence,
isolated RNA of any sequence, nucleic acid probes, and primers.
cDNA encoding for a gene or gene fragment referred herein may
comprise at least one region encoding for exon sequences without an
intervening intron sequence in the genomic equivalent sequence.
cDNA described herein may be generated by de novo synthesis.
[0069] Antibody Optimization Library for Coronavirus
[0070] Provided herein are methods, compositions, and systems for
the optimization of antibodies for coronavirus. In some
embodiments, the antibodies are optimized for SARS-CoV, MERS-CoV,
CoV-229E, HCoV-NL63, HCoV-OC43, or HCoV-HKU1. In some embodiments,
the antibodies are optimized for SARS-CoV-2. In some embodiments,
the antibodies are optimized for a receptor that binds to the
coronavirus. In some embodiments, the receptor of the coronavirus
is ACE2 or dipeptidyl peptidase 4 (DPP4). In some embodiments, the
antibodies are optimized based on interactions between the
coronavirus and the receptor that binds the coronavirus. In some
embodiments, the antibodies are optimized for
angiotensin-converting enzyme 2 (ACE2). In some embodiments, the
antibodies are optimized based on interactions between SARS-CoV-2
and ACE2.
[0071] Antibodies are in some instances optimized by the design of
in-silico libraries comprising variant sequences of an input
antibody sequence (FIG. 1). Input sequences 100 are in some
instances modified in-silico 102 with one or more mutations or
variants to generate libraries of optimized sequences 103. In some
instances, such libraries are synthesized, cloned into expression
vectors, and translation products (antibodies) evaluated for
activity. In some instances, fragments of sequences are synthesized
and subsequently assembled. In some instances, expression vectors
are used to display and enrich desired antibodies, such as phage
display. Selection pressures used during enrichment in some
instances includes, but is not limited to, binding affinity,
toxicity, immunological tolerance, stability, receptor-ligand
competition, or developability. Such expression vectors allow
antibodies with specific properties to be selected ("panning"), and
subsequent propagation or amplification of such sequences enriches
the library with these sequences Panning rounds can be repeated any
number of times, such as 1, 2, 3, 4, 5, 6, 7, or more than 7
rounds. Sequencing at one or more rounds is in some instances used
to identify which sequences 105 have been enriched in the
library.
[0072] Described herein are methods and systems of in-silico
library design. For example, an antibody or antibody fragment
sequence is used as input. In some instances, the antibody sequence
used as input is an antibody or antibody fragment sequence that
binds SARS-CoV-2. In some instances, the input is an antibody or
antibody fragment sequence that binds a protein of SARS-CoV-2. In
some instances, the protein is a spike glycoprotein, a membrane
protein, an envelope protein, a nucleocapsid protein, or
combinations thereof. In some instances, the protein is a spike
glycoprotein of SARS-CoV-2. In some instances, the protein is a
receptor binding domain of SARS-CoV-2. In some instances, the input
sequence is an antibody or antibody fragment sequence that binds
angiotensin-converting enzyme 2 (ACE2). In some instances, the
input sequence is an antibody or antibody fragment sequence that
binds an extracellular domain of the angiotensin-converting enzyme
2 (ACE2).
[0073] A database 102 comprising known mutations or variants of one
or more viruses is queried 101, and a library 103 of sequences
comprising combinations of these mutations or variants are
generated. In some instances, the database comprises known
mutations or variants of SARS-CoV-like coronaviruses, SARS-CoV-2,
SARS-CoV, or combinations thereof. In some instances, the database
comprises known mutations or variants of the spike protein of
SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations
thereof. In some instances, the database comprises known mutations
or variants of the receptor binding domain of SARS-CoV-like
coronaviruses, SARS-CoV-2, SARS-CoV, or combinations thereof. In
some instances, the database comprises mutations or variants of a
protein of SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or
combinations thereof that binds to ACE2.
[0074] In some instances, the input sequence is a heavy chain
sequence of an antibody or antibody fragment that binds
SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations
thereof. In some instances, the input sequence is a light chain
sequence of an antibody or antibody fragment that binds
SARS-CoV-like coronaviruses, SARS-CoV-2, SARS-CoV, or combinations
thereof. In some instances, the heavy chain sequence comprises
varied CDR regions. In some instances, the light chain sequence
comprises varied CDR regions. In some instances, known mutations or
variants from CDRs are used to build the sequence library. Filters
104, or exclusion criteria, are in some instances used to select
specific types of variants for members of the sequence library. For
example, sequences having a mutation or variant are added if a
minimum number of organisms in the database have the mutation or
variant. In some instances, additional CDRs are specified for
inclusion in the database. In some instances, specific mutations or
variants or combinations of mutations or variants are excluded from
the library (e.g., known immunogenic sites, structure sites, etc.).
In some instances, specific sites in the input sequence are
systematically replaced with histidine, aspartic acid, glutamic
acid, or combinations thereof. In some instances, the maximum or
minimum number of mutations or variants allowed for each region of
an antibody are specified. Mutations or variants in some instances
are described relative to the input sequence or the input
sequence's corresponding germline sequence. For example, sequences
generated by the optimization comprise at least 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16 mutations or
variants from the input sequence. In some instances, sequences
generated by the optimization comprise no more than 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or no more than 18
mutations or variants from the input sequence. In some instances,
sequences generated by the optimization comprise about 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or about 18 mutations or
variants relative to the input sequence. In some instances,
sequences generated by the optimization comprise about 1, 2, 3, 4,
5, 6, or 7 mutations or variants from the input sequence in a first
CDR region. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the input sequence in a second CDR region. In some
instances, sequences generated by the optimization comprise about
1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input
sequence in a third CDR region. In some instances, sequences
generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7
mutations or variants from the input sequence in a first CDR region
of a heavy chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the input sequence in a second CDR region of a heavy
chain. In some instances, sequences generated by the optimization
comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from
the input sequence in a third CDR region of a heavy chain. In some
instances, sequences generated by the optimization comprise about
1, 2, 3, 4, 5, 6, or 7 mutations or variants from the input
sequence in a first CDR region of a light chain. In some instances,
sequences generated by the optimization comprise about 1, 2, 3, 4,
5, 6, or 7 mutations or variants from the input sequence in a
second CDR region of a light chain. In some instances, sequences
generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7
mutations or variants from the input sequence in a third CDR region
of a light chain. In some instances, a first CDR region is CDR1. In
some instances, a second CDR region is CDR2. In some instances, a
third CDR region is CDR3. In-silico antibodies libraries are in
some instances synthesized, assembled, and enriched for desired
sequences.
[0075] The germline sequences corresponding to an input sequence
may also be modified to generate sequences in a library. For
example, sequences generated by the optimization methods described
herein comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, or more than 16 mutations or variants from the germline
sequence. In some instances, sequences generated by the
optimization comprise no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, or no more than 18 mutations or variants
from the germline sequence. In some instances, sequences generated
by the optimization comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, or about 18 mutations or variants relative
to the germline sequence.
[0076] Provided herein are methods, systems, and compositions for
antibody optimization, wherein the input sequence comprises
mutations or variants in an antibody region. Exemplary regions of
the antibody include, but are not limited to, a
complementarity-determining region (CDR), a variable domain, or a
constant domain. In some instances, the CDR is CDR1, CDR2, or CDR3.
In some instances, the CDR is a heavy domain including, but not
limited to, CDRH1, CDRH2, and CDRH3. In some instances, the CDR is
a light domain including, but not limited to, CDRL1, CDRL2, and
CDRL3. In some instances, the variable domain is variable domain,
light chain (VL) or variable domain, heavy chain (VH). In some
instances, the VL domain comprises kappa or lambda chains. In some
instances, the constant domain is constant domain, light chain (CL)
or constant domain, heavy chain (CH). In some instances, sequences
generated by the optimization comprise about 1, 2, 3, 4, 5, 6, or 7
mutations or variants from the germline sequence in a first CDR
region. In some instances, sequences generated by the optimization
comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or variants from
the germline sequence in a second CDR region. In some instances,
sequences generated by the optimization comprise about 1, 2, 3, 4,
5, 6, or 7 mutations or variants from the germline sequence in a
third CDR region. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a first CDR region of a
heavy chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a second CDR region of a
heavy chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a third CDR region of a
heavy chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a first CDR region of a
light chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a second CDR region of a
light chain. In some instances, sequences generated by the
optimization comprise about 1, 2, 3, 4, 5, 6, or 7 mutations or
variants from the germline sequence in a third CDR region of a
light chain. In some instances, a first CDR region is CDR1. In some
instances, a second CDR region is CDR2. In some instances, a third
CDR region is CDR3.
[0077] VHH Libraries
[0078] Provided herein are methods, compositions, and systems for
generation of antibodies or antibody fragments. In some instances,
the antibodies or antibody fragments are single domain antibodies.
Methods, compositions, and systems described herein for the
optimization of antibodies comprise a ratio-variant approach that
mirror the natural diversity of antibody sequences. In some
instances, libraries of optimized antibodies comprise variant
antibody sequences. In some instances, the variant antibody
sequences are designed comprising variant CDR regions. In some
instances, the variant antibody sequences comprising variant CDR
regions are generated by shuffling the natural CDR sequences in a
llama, humanized, or chimeric framework. In some instances, such
libraries are synthesized, cloned into expression vectors, and
translation products (antibodies) evaluated for activity. In some
instances, fragments of sequences are synthesized and subsequently
assembled. In some instances, expression vectors are used to
display and enrich desired antibodies, such as phage display. In
some instances, the phage vector is a Fab phagemid vector.
Selection pressures used during enrichment in some instances
includes, but is not limited to, binding affinity, toxicity,
immunological tolerance, stability, receptor-ligand competition, or
developability. Such expression vectors allow antibodies with
specific properties to be selected ("panning"), and subsequent
propagation or amplification of such sequences enriches the library
with these sequences. Panning rounds can be repeated any number of
times, such as 1, 2, 3, 4, 5, 6, 7, or more than 7 rounds. In some
instances, each round of panning involves a number of washes. In
some instances, each round of panning involves at least or about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more than 16
washes.
[0079] Described herein are methods and systems of in-silico
library design. Libraries as described herein, in some instances,
are designed based on a database comprising a variety of antibody
sequences. In some instances, the database comprises a plurality of
variant antibody sequences against various targets. In some
instances, the database comprises at least 100, 500, 1000, 1500,
2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000
antibody sequences. An exemplary database is an iCAN database. In
some instances, the database comprises naive and memory B-cell
receptor sequences. In some instances, the naive and memory B-cell
receptor sequences are human, mouse, or primate sequences. In some
instances, the naive and memory B-cell receptor sequences are human
sequences. In some instances, the database is analyzed for position
specific variation. In some instances, antibodies described herein
comprise position specific variations in CDR regions. In some
instances, the CDR regions comprise multiple sites for
variation.
[0080] Described herein are libraries comprising variation in a CDR
region. In some instances, the CDR is CDR1, CDR2, or CDR3 of a
variable heavy chain. In some instances, the CDR is CDR1, CDR2, or
CDR3 of a variable light chain. In some instances, the libraries
comprise multiple variants encoding for CDR1, CDR2, or CDR3. In
some instances, the libraries as described herein encode for at
least 50, 100, 200, 300, 400, 500, 1000, 1200, 1500, 1700, 2000,
2500, 3000, 3500, 4000, 4500, 5000, or more than 5000 CDR1
sequences. In some instances, the libraries as described herein
encode for at least 50, 100, 200, 300, 400, 500, 1000, 1200, 1500,
1700, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than 5000
CDR2 sequences. In some instances, the libraries as described
herein encode for at least 50, 100, 200, 300, 400, 500, 1000, 1200,
1500, 1700, 2000, 2500, 3000, 3500, 4000, 4500, 5000, or more than
5000 CDR3 sequences. In-silico antibodies libraries are in some
instances synthesized, assembled, and enriched for desired
sequences.
[0081] Following synthesis of CDR1 variants, CDR2 variants, and
CDR3 variants, in some instances, the CDR1 variants, the CDR2
variants, and the CDR3 variants are shuffled to generate a diverse
library. In some instances, the diversity of the libraries
generated by methods described herein have a theoretical diversity
of at least or about 10.sup.7, 10.sup.8, 10.sup.9, 10.sup.10,
10.sup.11, 10.sup.12, 10.sup.13, 10.sup.14, 10.sup.15, 10.sup.16,
10.sup.17, 10.sup.18, or more than 10.sup.18 sequences. In some
instances, the library has a final library diversity of at least or
about 10.sup.7, 10.sup.8, 10.sup.9, 10.sup.10, 10.sup.11,
10.sup.12, 10.sup.13, 10.sup.14, 10.sup.15, 10.sup.16, 10.sup.17,
10.sup.18, or more than 10.sup.18 sequences.
[0082] The germline sequences corresponding to a variant sequence
may also be modified to generate sequences in a library. For
example, sequences generated by methods described herein comprise
at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or
more than 16 mutations or variants from the germline sequence. In
some instances, sequences generated comprise no more than 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or no more than 18
mutations or variants from the germline sequence. In some
instances, sequences generated comprise about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, or about 18 mutations or variants
relative to the germline sequence.
[0083] Coronavirus Antibody Libraries
[0084] Provided herein are libraries generated from antibody
optimization methods described herein. Antibodies described herein
result in improved functional activity, structural stability,
expression, specificity, or a combination thereof.
[0085] Provided herein are methods and compositions relating to
SARS-CoV-2 binding libraries comprising nucleic acids encoding for
a SARS-CoV-2 antibody. Further provided herein are methods and
compositions relating to ACE2 binding libraries comprising nucleic
acids encoding for an ACE2 antibody. Such methods and compositions
in some instances are generated by the antibody optimization
methods and systems described herein. Libraries as described herein
may be further variegated to provide for variant libraries
comprising nucleic acids each encoding for a predetermined variant
of at least one predetermined reference nucleic acid sequence.
Further described herein are protein libraries that may be
generated when the nucleic acid libraries are translated. In some
instances, nucleic acid libraries as described herein are
transferred into cells to generate a cell library. Also provided
herein are downstream applications for the libraries synthesized
using methods described herein. Downstream applications include
identification of variant nucleic acids or protein sequences with
enhanced biologically relevant functions, e.g., improved stability,
affinity, binding, functional activity, and for the treatment or
prevention of an infection caused by a coronavirus such as
SARS-CoV-2.
[0086] In some instances, an antibody or antibody fragment
described herein comprises a sequence of any one of SEQ ID NOs:
1-716. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 80%
identical to a sequence of any one of SEQ ID NOs: 1-716. In some
instances, an antibody or antibody fragment described herein
comprises a sequence that is at least 85% identical to a sequence
of any one of SEQ ID NOs: 1-716. In some instances, an antibody or
antibody fragment described herein comprises a sequence that is at
least 90% identical to a sequence of any one of SEQ ID NOs: 1-716.
In some instances, an antibody or antibody fragment described
herein comprises a sequence that is at least 95% identical to a
sequence of any one of SEQ ID NOs: 1-716.
[0087] In some instances, an antibody or antibody fragment
described herein comprises a CDRH1 sequence of any one of SEQ ID
NOs: 1-36 or 217-282. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 80%
identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-36 or
217-282. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 85%
identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-36 or
217-282. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-36 or
217-282. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRH1 sequence of any one of SEQ ID NOs: 1-36 or
217-282. In some instances, an antibody or antibody fragment
described herein comprises a CDRH2 sequence of any one of SEQ ID
NOs: 37-72 or 283-348. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 80%
identical to a CDRH2 sequence of any one of SEQ ID NOs: 37-72 or
283-348. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 85%
identical to a CDRH2 sequence of any one of SEQ ID NOs: 37-72 or
283-348. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRH2 sequence of any one of SEQ ID NOs: 37-72 or
283-348. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRH2 sequence of any one of SEQ ID NOs: 37-72 or
283-348. In some instances, an antibody or antibody fragment
described herein comprises a CDRH3 sequence of any one of SEQ ID
NOs: 73-108 or 349-414. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 80%
identical to a CDRH3 sequence of any one of SEQ ID NOs: 73-108 or
349-414. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 85%
identical to a CDRH3 sequence of any one of SEQ ID NOs: 73-108 or
349-414. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRH3 sequence of any one of SEQ ID NOs: 73-108 or
349-414. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRH3 sequence of any one of SEQ ID NOs: 73-108 or
349-414.
[0088] In some instances, an antibody or antibody fragment
described herein comprises a CDRL1 sequence of any one of SEQ ID
NOs: 109-144 or 415-473. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 80%
identical to a CDRL1 sequence of any one of SEQ ID NOs: 109-144 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 85%
identical to a CDRL1 sequence of any one of SEQ ID NOs: 109-144 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRL1 sequence of any one of SEQ ID NOs: 109-144 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRL1 sequence of any one of SEQ ID NOs: 109-144 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a CDRL2 sequence of any one of SEQ ID
NOs: 145-180 or 415-473. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 80%
identical to a CDRL2 sequence of any one of SEQ ID NOs: 145-180 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 85%
identical to a CDRL2 sequence of any one of SEQ ID NOs: 145-180 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRL2 sequence of any one of SEQ ID NOs: 145-180 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRL2 sequence of any one of SEQ ID NOs: 145-180 or
415-473. In some instances, an antibody or antibody fragment
described herein comprises a CDRL3 sequence of any one of SEQ ID
NOs: 181-216, 442-456, or 532-546. In some instances, an antibody
or antibody fragment described herein comprises a sequence that is
at least 80% identical to a CDRL3 sequence of any one of SEQ ID
NOs: 181-216 or 533-591. In some instances, an antibody or antibody
fragment described herein comprises a sequence that is at least 85%
identical to a CDRL3 sequence of any one of SEQ ID NOs: 181-216 or
533-591. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 90%
identical to a CDRL3 sequence of any one of SEQ ID NOs: 181-216 or
533-591. In some instances, an antibody or antibody fragment
described herein comprises a sequence that is at least 95%
identical to a CDRL3 sequence of any one of SEQ ID NOs: 181-216 or
533-591.
[0089] In some embodiments, the antibody or antibody fragment
comprising a variable domain, heavy chain region (VH) and a
variable domain, light chain region (VL), wherein VH comprises
complementarity determining regions CDRH1, CDRH2, and CDRH3,
wherein VL comprises complementarity determining regions CDRL1,
CDRL2, and CDRL3, and wherein (a) an amino acid sequence of CDRH1
is as set forth in any one of SEQ ID NOs: 1-36 or 217-282; (b) an
amino acid sequence of CDRH2 is as set forth in any one of SEQ ID
NOs: 37-72 or 283-348; (c) an amino acid sequence of CDRH3 is as
set forth in any one of SEQ ID NOs: 73-108 or 349-414; (d) an amino
acid sequence of CDRL1 is as set forth in any one of SEQ ID NOs:
109-144 or 415-473; (e) an amino acid sequence of CDRL2 is as set
forth in any one of SEQ ID NOs: 145-180 or 415-473; and (f) an
amino acid sequence of CDRL3 is as set forth in any one of SEQ ID
NOs: 181-216 or 533-591. In some embodiments, the antibody or
antibody fragment comprising a variable domain, heavy chain region
(VH) and a variable domain, light chain region (VL), wherein VH
comprises complementarity determining regions CDRH1, CDRH2, and
CDRH3, wherein VL comprises complementarity determining regions
CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of
CDRH1 is at least or about 80%, 85%, 90%, or 95% identical to any
one of SEQ ID NOs: 1-36 or 217-282; (b) an amino acid sequence of
CDRH2 is at least or about 80%, 85%, 90%, or 95% identical to any
one of SEQ ID NOs: 37-72 or 283-348; (c) an amino acid sequence of
CDRH3 is at least or about 80%, 85%, 90%, or 95% identical to any
one of SEQ ID NOs: 73-108 or 349-414; (d) an amino acid sequence of
CDRL1 is at least or about 80%, 85%, 90%, or 95% identical to any
one of SEQ ID NOs: 109-144 or 415-473; (e) an amino acid sequence
of CDRL2 is at least or about 80%, 85%, 90%, or 95% identical to
any one of SEQ ID NOs: 145-180 or 415-473; and (f) an amino acid
sequence of CDRL3 is at least or about 80%, 85%, 90%, or 95%
identical to any one of SEQ ID NOs: 181-216 or 533-591.
[0090] Described herein, in some embodiments, are antibodies or
antibody fragments comprising a variable domain, heavy chain region
(VH) and a variable domain, light chain region (VL), wherein the VH
comprises an amino acid sequence at least about 90% identical to a
sequence as set forth in any one of SEQ ID NOs: 592-657, and
wherein the VL comprises an amino acid sequence at least about 90%
identical to a sequence as set forth in any one of SEQ ID NOs:
658-716. In some instances, the antibodies or antibody fragments
comprise VH comprising at least or about 70%, 80%, 85%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity
to any one of SEQ ID NOs: 592-657, and VL comprising at least or
about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
99%, or 100% sequence identity to any one of SEQ ID NOs:
658-716.
[0091] The term "sequence identity" means that two polynucleotide
sequences are identical (i.e., on a nucleotide-by-nucleotide basis)
over the window of comparison. The term "percentage of sequence
identity" is calculated by comparing two optimally aligned
sequences over the window of comparison, determining the number of
positions at which the identical nucleic acid base (e.g., A, T, C,
G, U, or I) occurs in both sequences to yield the number of matched
positions, dividing the number of matched positions by the total
number of positions in the window of comparison (i.e., the window
size), and multiplying the result by 100 to yield the percentage of
sequence identity.
[0092] The term "homology" or "similarity" between two proteins is
determined by comparing the amino acid sequence and its conserved
amino acid substitutes of one protein sequence to the second
protein sequence. Similarity may be determined by procedures which
are well-known in the art, for example, a BLAST program (Basic
Local Alignment Search Tool at the National Center for Biological
Information).
[0093] Provided herein are libraries comprising nucleic acids
encoding for SARS-CoV-2 antibodies. Antibodies described herein
allow for improved stability for a range of SARS-CoV-2 or ACE2
binding domain encoding sequences. In some instances, the binding
domain encoding sequences are determined by interactions between
SARS-CoV-2 and ACE2.
[0094] Sequences of binding domains based on surface interactions
between SARS-CoV-2 and ACE2 are analyzed using various methods. For
example, multispecies computational analysis is performed. In some
instances, a structure analysis is performed. In some instances, a
sequence analysis is performed. Sequence analysis can be performed
using a database known in the art. Non-limiting examples of
databases include, but are not limited to, NCBI BLAST
(blast.ncbi.nlm.nih.gov/Blast.cgi), UCSC Genome Browser
(genome.ucsc.edu/), UniProt (www.uniprot.org/), and IUPHAR/BPS
Guide to PHARMACOLOGY (guidetopharmacology.org/).
[0095] Described herein are SARS-CoV-2 or ACE2 binding domains
designed based on sequence analysis among various organisms. For
example, sequence analysis is performed to identify homologous
sequences in different organisms. Exemplary organisms include, but
are not limited to, mouse, rat, equine, sheep, cow, primate (e.g.,
chimpanzee, baboon, gorilla, orangutan, monkey), dog, cat, pig,
donkey, rabbit, fish, fly, and human. In some instances, homologous
sequences are identified in the same organism, across
individuals.
[0096] Following identification of SARS-CoV-2 or ACE2 binding
domains, libraries comprising nucleic acids encoding for the
SARS-CoV-2 or ACE2 binding domains may be generated. In some
instances, libraries of SARS-CoV-2 or ACE2 binding domains comprise
sequences of SARS-CoV-2 or ACE2 binding domains designed based on
conformational ligand interactions, peptide ligand interactions,
small molecule ligand interactions, extracellular domains of
SARS-CoV-2 or ACE2, or antibodies that target SARS-CoV-2 or ACE2.
Libraries of SARS-CoV-2 or ACE2 binding domains may be translated
to generate protein libraries. In some instances, libraries of
SARS-CoV-2 or ACE2 binding domains are translated to generate
peptide libraries, immunoglobulin libraries, derivatives thereof,
or combinations thereof. In some instances, libraries of SARS-CoV-2
or ACE2 binding domains are translated to generate protein
libraries that are further modified to generate peptidomimetic
libraries. In some instances, libraries of SARS-CoV-2 or ACE2
binding domains are translated to generate protein libraries that
are used to generate small molecules.
[0097] Methods described herein provide for synthesis of libraries
of SARS-CoV-2 or ACE2 binding domains comprising nucleic acids each
encoding for a predetermined variant of at least one predetermined
reference nucleic acid sequence. In some cases, the predetermined
reference sequence is a nucleic acid sequence encoding for a
protein, and the variant library comprises sequences encoding for
variation of at least a single codon such that a plurality of
different variants of a single residue in the subsequent protein
encoded by the synthesized nucleic acid are generated by standard
translation processes. In some instances, the libraries of
SARS-CoV-2 or ACE2 binding domains comprise varied nucleic acids
collectively encoding variations at multiple positions. In some
instances, the variant library comprises sequences encoding for
variation of at least a single codon in a SARS-CoV-2 or ACE2
binding domain. In some instances, the variant library comprises
sequences encoding for variation of multiple codons in a SARS-CoV-2
or ACE2 binding domain. An exemplary number of codons for variation
include, but are not limited to, at least or about 1, 5, 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 125, 150, 175, 225, 250, 275, 300, or more than 300
codons.
[0098] Methods described herein provide for synthesis of libraries
comprising nucleic acids encoding for the SARS-CoV-2 or ACE2
binding domains, wherein the libraries comprise sequences encoding
for variation of length of the SARS-CoV-2 or ACE2 binding domains.
In some instances, the library comprises sequences encoding for
variation of length of at least or about 1, 5, 10, 15, 20, 25, 30,
35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150,
175, 225, 250, 275, 300, or more than 300 codons less as compared
to a predetermined reference sequence. In some instances, the
library comprises sequences encoding for variation of length of at
least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275,
300, or more than 300 codons more as compared to a predetermined
reference sequence.
[0099] Following identification of SARS-CoV-2 or ACE2 binding
domains, antibodies may be designed and synthesized to comprise the
SARS-CoV-2 or ACE2 binding domains. Antibodies comprising
SARS-CoV-2 or ACE2 binding domains may be designed based on
binding, specificity, stability, expression, folding, or downstream
activity. In some instances, the antibodies comprising SARS-CoV-2
or ACE2 binding domains enable contact with the SARS-CoV-2 or ACE2.
In some instances, the antibodies comprising SARS-CoV-2 or ACE2
binding domains enables high affinity binding with the SARS-CoV-2
or ACE2. Exemplary amino acid sequences of SARS-CoV-2 or ACE2
binding domains comprise any one of SEQ ID NOs: 1-716.
[0100] In some instances, the SARS-CoV-2 antibody comprises a
binding affinity (e.g., K.sub.D) to SARS-CoV-2 of less than 1 nM,
less than 1.2 nM, less than 2 nM, less than 5 nM, less than 10 nM,
less than 11 nm, less than 13.5 nM, less than 15 nM, less than 20
nM, less than 25 nM, or less than 30 nM. In some instances, the
SARS-CoV-2 antibody comprises a K.sub.D of less than 1 nM. In some
instances, the SARS-CoV-2 antibody comprises a K.sub.D of less than
1.2 nM. In some instances, the SARS-CoV-2 antibody comprises a
K.sub.D of less than 2 nM. In some instances, the SARS-CoV-2
antibody comprises a K.sub.D of less than 5 nM. In some instances,
the SARS-CoV-2 antibody comprises a K.sub.D of less than 10 nM. In
some instances, the SARS-CoV-2 antibody comprises a K.sub.D of less
than 13.5 nM. In some instances, the SARS-CoV-2 antibody comprises
a K.sub.D of less than 15 nM. In some instances, the SARS-CoV-2
antibody comprises a K.sub.D of less than 20 nM. In some instances,
the SARS-CoV-2 antibody comprises a K.sub.D of less than 25 nM. In
some instances, the SARS-CoV-2 antibody comprises a K.sub.D of less
than 30 nM.
[0101] In some instances, the ACE2 antibody comprises a binding
affinity (e.g., K.sub.D) to ACE2 of less than 1 nM, less than 1.2
nM, less than 2 nM, less than 5 nM, less than 10 nM, less than 11
nm, less than 13.5 nM, less than 15 nM, less than 20 nM, less than
25 nM, or less than 30 nM. In some instances, the ACE2 antibody
comprises a K.sub.D of less than 1 nM. In some instances, the ACE2
antibody comprises a K.sub.D of less than 1.2 nM. In some
instances, the ACE2 antibody comprises a K.sub.D of less than 2 nM.
In some instances, the ACE2 antibody comprises a K.sub.D of less
than 5 nM. In some instances, the ACE2 antibody comprises a K.sub.D
of less than 10 nM. In some instances, the ACE2 antibody comprises
a K.sub.D of less than 13.5 nM. In some instances, the ACE2
antibody comprises a K.sub.D of less than 15 nM. In some instances,
the ACE2 antibody comprises a K.sub.D of less than 20 nM. In some
instances, the ACE2 antibody comprises a K.sub.D of less than 25
nM. In some instances, the ACE2 antibody comprises a K.sub.D of
less than 30 nM.
[0102] In some instances, the SARS-CoV-2 or ACE2 immunoglobulin is
an agonist. In some instances, the SARS-CoV-2 or ACE2
immunoglobulin is an antagonist. In some instances, the SARS-CoV-2
or ACE2 immunoglobulin is an allosteric modulator. In some
instances, the allosteric modulator is a negative allosteric
modulator. In some instances, the allosteric modulator is a
positive allosteric modulator. In some instances, the SARS-CoV-2 or
ACE2 immunoglobulin results in agonistic, antagonistic, or
allosteric effects at a concentration of at least or about 1 nM, 2
nM, 4 nM, 6 nM, 8 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70
nM, 80 nM, 90 nM, 100 nM, 120 nM, 140 nM, 160 nM, 180 nM, 200 nM,
300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1000 nM, or
more than 1000 nM. In some instances, the SARS-CoV-2 or ACE2
immunoglobulin is a negative allosteric modulator. In some
instances, the SARS-CoV-2 or ACE2 immunoglobulin is a negative
allosteric modulator at a concentration of at least or about 0.001,
0.005, 0.01, 0.05, 0.1, 0.5, 1 nM, 2 nM, 4 nM, 6 nM, 8 nM, 10 nM,
20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or
more than 100 nM. In some instances, the SARS-CoV-2 or ACE2
immunoglobulin is a negative allosteric modulator at a
concentration in a range of about 0.001 to about 100, 0.01 to about
90, about 0.1 to about 80, 1 to about 50, about 10 to about 40 nM,
or about 1 to about 10 nM. In some instances, the SARS-CoV-2 or
ACE2 immunoglobulin comprises an EC50 or IC50 of at least or about
0.001, 0.0025, 0.005, 0.01, 0.025, 0.05, 0.06, 0.07, 0.08, 0.9,
0.1, 0.5, 1, 2, 3, 4, 5, 6, or more than 6 nM. In some instances,
the SARS-CoV-2 or ACE2 immunoglobulin comprises an EC50 or IC50 of
at least or about 1 nM, 2 nM, 4 nM, 6 nM, 8 nM, 10 nM, 20 nM, 30
nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, or more than
100 nM.
[0103] In some instances, the affinity of the SARS-CoV-2 or ACE2
antibody generated by methods as described herein is at least or
about 1.5.times., 2.0.times., 5.times., 10.times., 20.times.,
30.times., 40.times., 50.times., 60.times., 70.times., 80.times.,
90.times., 100.times., 200.times., or more than 200.times. improved
binding affinity as compared to a comparator antibody. In some
instances, the SARS-CoV-2 or ACE2 antibody generated by methods as
described herein is at least or about 1.5.times., 2.0.times.,
5.times., 10.times., 20.times., 30.times., 40.times., 50.times.,
60.times., 70.times., 80.times., 90.times., 100.times., 200.times.,
or more than 200.times. improved function as compared to a
comparator antibody. In some instances, the comparator antibody is
an antibody with similar structure, sequence, or antigen
target.
[0104] Provided herein are SARS-CoV-2 or ACE2 binding libraries
comprising nucleic acids encoding for antibodies comprising
SARS-CoV-2 or ACE2 binding domains comprise variation in domain
type, domain length, or residue variation. In some instances, the
domain is a region in the antibody comprising the SARS-CoV-2 or
ACE2 binding domains. For example, the region is the VH, CDRH3, or
VL domain. In some instances, the domain is the SARS-CoV-2 or ACE2
binding domain.
[0105] Methods described herein provide for synthesis of a
SARS-CoV-2 or ACE21 binding library of nucleic acids each encoding
for a predetermined variant of at least one predetermined reference
nucleic acid sequence. In some cases, the predetermined reference
sequence is a nucleic acid sequence encoding for a protein, and the
variant library comprises sequences encoding for variation of at
least a single codon such that a plurality of different variants of
a single residue in the subsequent protein encoded by the
synthesized nucleic acid are generated by standard translation
processes. In some instances, the SARS-CoV-2 or ACE2 binding
library comprises varied nucleic acids collectively encoding
variations at multiple positions. In some instances, the variant
library comprises sequences encoding for variation of at least a
single codon of a VH or VL domain. In some instances, the variant
library comprises sequences encoding for variation of at least a
single codon in a SARS-CoV-2 or ACE2 binding domain. For example,
at least one single codon of a SARS-CoV-2 or ACE2 binding domain is
varied. In some instances, the variant library comprises sequences
encoding for variation of multiple codons of a VH or VL domain. In
some instances, the variant library comprises sequences encoding
for variation of multiple codons in a SARS-CoV-2 or ACE2 binding
domain. An exemplary number of codons for variation include, but
are not limited to, at least or about 1, 5, 10, 15, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175,
225, 250, 275, 300, or more than 300 codons.
[0106] Methods described herein provide for synthesis of a
SARS-CoV-2 or ACE2 binding library of nucleic acids each encoding
for a predetermined variant of at least one predetermined reference
nucleic acid sequence, wherein the SARS-CoV-2 or ACE2 binding
library comprises sequences encoding for variation of length of a
domain. In some instances, the domain is VH or VL domain. In some
instances, the domain is the SARS-CoV-2 or ACE2binding domain. In
some instances, the library comprises sequences encoding for
variation of length of at least or about 1, 5, 10, 15, 20, 25, 30,
35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150,
175, 225, 250, 275, 300, or more than 300 codons less as compared
to a predetermined reference sequence. In some instances, the
library comprises sequences encoding for variation of length of at
least or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275,
300, or more than 300 codons more as compared to a predetermined
reference sequence.
[0107] Provided herein are SARS-CoV-2 or ACE2 binding libraries
comprising nucleic acids encoding for antibodies comprising
SARS-CoV-2 or ACE2 binding domains, wherein the SARS-CoV-2 or ACE2
binding libraries are synthesized with various numbers of
fragments. In some instances, the fragments comprise the VH or VL
domain. In some instances, the SARS-CoV-2 or ACE2 binding libraries
are synthesized with at least or about 2 fragments, 3 fragments, 4
fragments, 5 fragments, or more than 5 fragments. The length of
each of the nucleic acid fragments or average length of the nucleic
acids synthesized may be at least or about 50, 75, 100, 125, 150,
175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475,
500, 525, 550, 575, 600, or more than 600 base pairs. In some
instances, the length is about 50 to 600, 75 to 575, 100 to 550,
125 to 525, 150 to 500, 175 to 475, 200 to 450, 225 to 425, 250 to
400, 275 to 375, or 300 to 350 base pairs.
[0108] SARS-CoV-2 or ACE2 binding libraries comprising nucleic
acids encoding for antibodies comprising SARS-CoV-2 or ACE2 binding
domains as described herein comprise various lengths of amino acids
when translated. In some instances, the length of each of the amino
acid fragments or average length of the amino acid synthesized may
be at least or about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135,
140, 145, 150, or more than 150 amino acids. In some instances, the
length of the amino acid is about 15 to 150, 20 to 145, 25 to 140,
30 to 135, 35 to 130, 40 to 125, 45 to 120, 50 to 115, 55 to 110,
60 to 110, 65 to 105, 70 to 100, or 75 to 95 amino acids. In some
instances, the length of the amino acid is about 22 to about 75
amino acids.
[0109] SARS-CoV-2 or ACE2 binding libraries comprising de novo
synthesized variant sequences encoding for antibodies comprising
SARS-CoV-2 or ACE2 binding domains comprise a number of variant
sequences. In some instances, a number of variant sequences is de
novo synthesized for a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3,
VL, VH, or a combination thereof. In some instances, a number of
variant sequences is de novo synthesized for framework element 1
(FW1), framework element 2 (FW2), framework element 3 (FW3), or
framework element 4 (FW4). In some instances, a number of variant
sequences are de novo synthesized for a SARS-CoV-2 or ACE2 binding
domain. The number of variant sequences may be at least or about 5,
10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375,
400, 425, 450, 475, 500, or more than 500 sequences. In some
instances, the number of variant sequences is about 10 to 300, 25
to 275, 50 to 250, 75 to 225, 100 to 200, or 125 to 150
sequences.
[0110] SARS-CoV-2 or ACE2 binding libraries comprising de novo
synthesized variant sequences encoding for antibodies comprising
SARS-CoV-2 or ACE2 binding domains comprise improved diversity. In
some instances, variants include affinity maturation variants.
Alternatively or in combination, variants include variants in other
regions of the antibody including, but not limited to, CDRH1,
CDRH2, CDRL1, CDRL2, and CDRL3. In some instances, the number of
variants of the SARS-CoV-2 or ACE2 binding libraries is least or
about 10.sup.4, 10.sup.5, 10.sup.6, 10.sup.7, 10.sup.8, 10.sup.9,
10.sup.10, 10.sup.11, 10.sup.12, 10.sup.13, 10.sup.14 or more than
10.sup.14 non-identical sequences.
[0111] Following synthesis of SARS-CoV-2 or ACE2 binding libraries
comprising nucleic acids encoding antibodies comprising SARS-CoV-2
or ACE2 binding domains, libraries may be used for screening and
analysis. For example, libraries are assayed for library
displayability and panning. In some instances, displayability is
assayed using a selectable tag. Exemplary tags include, but are not
limited to, a radioactive label, a fluorescent label, an enzyme, a
chemiluminescent tag, a colorimetric tag, an affinity tag or other
labels or tags that are known in the art. In some instances, the
tag is histidine, polyhistidine, myc, hemagglutinin (HA), or FLAG.
For example, SARS-CoV-2 or ACE2 binding libraries comprise nucleic
acids encoding antibodies comprising SARS-CoV-2 or ACE2 binding
domains with multiple tags such as GFP, FLAG, and Lucy as well as a
DNA barcode. In some instances, libraries are assayed by sequencing
using various methods including, but not limited to,
single-molecule real-time (SMRT) sequencing, Polony sequencing,
sequencing by ligation, reversible terminator sequencing, proton
detection sequencing, ion semiconductor sequencing, nanopore
sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert
sequencing, chain termination (e.g., Sanger) sequencing, +S
sequencing, or sequencing by synthesis.
[0112] As used herein, the term antibody will be understood to
include proteins having the characteristic two-armed, Y-shape of a
typical antibody molecule as well as one or more fragments of an
antibody that retain the ability to specifically bind to an
antigen. Exemplary antibodies include, but are not limited to, a
monoclonal antibody, a polyclonal antibody, a bi-specific antibody,
a multispecific antibody, a grafted antibody, a human antibody, a
humanized antibody, a synthetic antibody, a chimeric antibody, a
camelized antibody, a single-chain Fvs (scFv) (including fragments
in which the VL and VH are joined using recombinant methods by a
synthetic or natural linker that enables them to be made as a
single protein chain in which the VL and VH regions pair to form
monovalent molecules, including single chain Fab and scFab), a
single chain antibody, a Fab fragment (including monovalent
fragments comprising the VL, VH, CL, and CH1 domains), a F(ab')2
fragment (including bivalent fragments comprising two Fab fragments
linked by a disulfide bridge at the hinge region), a Fd fragment
(including fragments comprising the VH and CH1 fragment), a Fv
fragment (including fragments comprising the VL and VH domains of a
single arm of an antibody), a single-domain antibody (dAb or sdAb)
(including fragments comprising a VH domain), an isolated
complementarity determining region (CDR), a diabody (including
fragments comprising bivalent dimers such as two VL and VH domains
bound to each other and recognizing two different antigens), a
fragment comprised of only a single monomeric variable domain,
disulfide-linked Fvs (sdFv), an intrabody, an anti-idiotypic
(anti-Id) antibody, or ab antigen-binding fragments thereof. In
some instances, the libraries disclosed herein comprise nucleic
acids encoding for an antibody, wherein the antibody is a Fv
antibody, including Fv antibodies comprised of the minimum antibody
fragment which contains a complete antigen-recognition and
antigen-binding site. In some embodiments, the Fv antibody consists
of a dimer of one heavy chain and one light chain variable domain
in tight, non-covalent association, and the three hypervariable
regions of each variable domain interact to define an
antigen-binding site on the surface of the VH-VL dimer. In some
embodiments, the six hypervariable regions confer antigen-binding
specificity to the antibody. In some embodiments, a single variable
domain (or half of an Fv comprising only three hypervariable
regions specific for an antigen, including single domain antibodies
isolated from camelid animals comprising one heavy chain variable
domain such as VHH antibodies or nanobodies) has the ability to
recognize and bind antigen. In some instances, the libraries
disclosed herein comprise nucleic acids encoding for an antibody,
wherein the antibody is a single-chain Fv or scFv, including
antibody fragments comprising a VH, a VL, or both a VH and VL
domain, wherein both domains are present in a single polypeptide
chain. In some embodiments, the Fv polypeptide further comprises a
polypeptide linker between the VH and VL domains allowing the scFv
to form the desired structure for antigen binding. In some
instances, a scFv is linked to the Fc fragment or a VHH is linked
to the Fc fragment (including minibodies). In some instances, the
antibody comprises immunoglobulin molecules and immunologically
active fragments of immunoglobulin molecules, e.g., molecules that
contain an antigen binding site. Immunoglobulin molecules are of
any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG
1, IgG 2, IgG 3, IgG 4, IgA 1 and IgA 2) or subclass.
[0113] In some embodiments, the antibody is a multivalent antibody.
In some embodiments, the antibody is a monovalent, bivalent, or
multivalent antibody. In some instances, the antibody is
monospecific, bispecific, or multispecific. In some embodiments,
the antibody is monovalent monospecific, monovalent bispecific,
monovalent multispecific, bivalent monospecific, bivalent
bispecific, bivalent multispecific, multivalent monospecific,
multivalent bispecific, multivalent multispecific. In some
instances, the antibody is homodimeric, heterodimeric, or
heterotrimeric.
[0114] In some embodiments, libraries comprise immunoglobulins that
are adapted to the species of an intended therapeutic target.
Generally, these methods include "mammalization" and comprises
methods for transferring donor antigen-binding information to a
less immunogenic mammal antibody acceptor to generate useful
therapeutic treatments. In some instances, the mammal is mouse,
rat, equine, sheep, cow, primate (e.g., chimpanzee, baboon,
gorilla, orangutan, monkey), dog, cat, pig, donkey, rabbit, and
human. In some instances, provided herein are libraries and methods
for felinization and caninization of antibodies.
[0115] "Humanized" forms of non-human antibodies can be chimeric
antibodies that contain minimal sequence derived from the non-human
antibody. A humanized antibody is generally a human antibody
(recipient antibody) in which residues from one or more CDRs are
replaced by residues from one or more CDRs of a non-human antibody
(donor antibody). The donor antibody can be any suitable non-human
antibody, such as a mouse, rat, rabbit, chicken, or non-human
primate antibody having a desired specificity, affinity, or
biological effect. In some instances, selected framework region
residues of the recipient antibody are replaced by the
corresponding framework region residues from the donor antibody
Humanized antibodies may also comprise residues that are not found
in either the recipient antibody or the donor antibody. In some
instances, these modifications are made to further refine antibody
performance.
[0116] "Caninization" can comprise a method for transferring
non-canine antigen-binding information from a donor antibody to a
less immunogenic canine antibody acceptor to generate treatments
useful as therapeutics in dogs. In some instances, caninized forms
of non-canine antibodies provided herein are chimeric antibodies
that contain minimal sequence derived from non-canine antibodies.
In some instances, caninized antibodies are canine antibody
sequences ("acceptor" or "recipient" antibody) in which
hypervariable region residues of the recipient are replaced by
hypervariable region residues from a non-canine species ("donor"
antibody) such as mouse, rat, rabbit, cat, dogs, goat, chicken,
bovine, horse, llama, camel, dromedaries, sharks, non-human
primates, human, humanized, recombinant sequence, or an engineered
sequence having the desired properties. In some instances,
framework region (FR) residues of the canine antibody are replaced
by corresponding non-canine FR residues. In some instances,
caninized antibodies include residues that are not found in the
recipient antibody or in the donor antibody. In some instances,
these modifications are made to further refine antibody
performance. The caninized antibody may also comprise at least a
portion of an immunoglobulin constant region (Fc) of a canine
antibody.
[0117] "Felinization" can comprise a method for transferring
non-feline antigen-binding information from a donor antibody to a
less immunogenic feline antibody acceptor to generate treatments
useful as therapeutics in cats. In some instances, felinized forms
of non-feline antibodies provided herein are chimeric antibodies
that contain minimal sequence derived from non-feline antibodies.
In some instances, felinized antibodies are feline antibody
sequences ("acceptor" or "recipient" antibody) in which
hypervariable region residues of the recipient are replaced by
hypervariable region residues from a non-feline species ("donor"
antibody) such as mouse, rat, rabbit, cat, dogs, goat, chicken,
bovine, horse, llama, camel, dromedaries, sharks, non-human
primates, human, humanized, recombinant sequence, or an engineered
sequence having the desired properties. In some instances,
framework region (FR) residues of the feline antibody are replaced
by corresponding non-feline FR residues. In some instances,
felinized antibodies include residues that are not found in the
recipient antibody or in the donor antibody. In some instances,
these modifications are made to further refine antibody
performance. The felinized antibody may also comprise at least a
portion of an immunoglobulin constant region (Fc) of a felinize
antibody.
[0118] Methods as described herein may be used for optimization of
libraries encoding a non-immunoglobulin. In some instances, the
libraries comprise antibody mimetics. Exemplary antibody mimetics
include, but are not limited to, anticalins, affilins, affibody
molecules, affimers, affitins, alphabodies, avimers, atrimers,
DARPins, fynomers, Kunitz domain-based proteins, monobodies,
anticalins, knottins, armadillo repeat protein-based proteins, and
bicyclic peptides.
[0119] Libraries described herein comprising nucleic acids encoding
for an antibody comprise variations in at least one region of the
antibody. Exemplary regions of the antibody for variation include,
but are not limited to, a complementarity-determining region (CDR),
a variable domain, or a constant domain. In some instances, the CDR
is CDR1, CDR2, or CDR3. In some instances, the CDR is a heavy
domain including, but not limited to, CDRH1, CDRH2, and CDRH3. In
some instances, the CDR is a light domain including, but not
limited to, CDRL1, CDRL2, and CDRL3. In some instances, the
variable domain is variable domain, light chain (VL) or variable
domain, heavy chain (VH). In some instances, the VL domain
comprises kappa or lambda chains. In some instances, the constant
domain is constant domain, light chain (CL) or constant domain,
heavy chain (CH).
[0120] Methods described herein provide for synthesis of libraries
comprising nucleic acids encoding an antibody, wherein each nucleic
acid encodes for a predetermined variant of at least one
predetermined reference nucleic acid sequence. In some cases, the
predetermined reference sequence is a nucleic acid sequence
encoding for a protein, and the variant library comprises sequences
encoding for variation of at least a single codon such that a
plurality of different variants of a single residue in the
subsequent protein encoded by the synthesized nucleic acid are
generated by standard translation processes. In some instances, the
antibody library comprises varied nucleic acids collectively
encoding variations at multiple positions. In some instances, the
variant library comprises sequences encoding for variation of at
least a single codon of a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3,
VL, or VH domain. In some instances, the variant library comprises
sequences encoding for variation of multiple codons of a CDRH1,
CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, or VH domain. In some
instances, the variant library comprises sequences encoding for
variation of multiple codons of framework element 1 (FW1),
framework element 2 (FW2), framework element 3 (FW3), or framework
element 4 (FW4). An exemplary number of codons for variation
include, but are not limited to, at least or about 1, 5, 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 125, 150, 175, 225, 250, 275, 300, or more than 300
codons.
[0121] In some instances, the at least one region of the antibody
for variation is from heavy chain V-gene family, heavy chain D-gene
family, heavy chain J-gene family, light chain V-gene family, or
light chain J-gene family. In some instances, the light chain
V-gene family comprises immunoglobulin kappa (IGK) gene or
immunoglobulin lambda (IGL). Exemplary regions of the antibody for
variation include, but are not limited to, IGHV1-18, IGHV1-69,
IGHV1-8, IGHV3-21, IGHV3-23, IGHV3-30/33rn, IGHV3-28, IGHV1-69,
IGHV3-74, IGHV4-39, IGHV4-59/61, IGKV1-39, IGKV1-9, IGKV2-28,
IGKV3-11, IGKV3-15, IGKV3-20, IGKV4-1, IGLV1-51, IGLV2-14,
IGLV1-40, and IGLV3-1. In some instances, the gene is IGHV1-69,
IGHV3-30, IGHV3-23, IGHV3, IGHV1-46, IGHV3-7, IGHV1, or IGHV1-8. In
some instances, the gene is IGHV1-69 and IGHV3-30. In some
instances, the region of the antibody for variation is IGHJ3,
IGHJ6, IGHJ, IGHJ4, IGHJ5, IGHJ2, or IGH1. In some instances, the
region of the antibody for variation is IGHJ3, IGHJ6, IGHJ, or
IGHJ4. In some instances, the at least one region of the antibody
for variation is IGHV1-69, IGHV3-23, IGKV3-20, IGKV1-39, or
combinations thereof. In some instances, the at least one region of
the antibody for variation is IGHV1-69 and IGKV3-20, In some
instances, the at least one region of the antibody for variation is
IGHV1-69 and IGKV1-39. In some instances, the at least one region
of the antibody for variation is IGHV3-23 and IGKV3-20. In some
instances, the at least one region of the antibody for variation is
IGHV3-23 and IGKV1-39.
[0122] Provided herein are libraries comprising nucleic acids
encoding for antibodies, wherein the libraries are synthesized with
various numbers of fragments. In some instances, the fragments
comprise the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, or VH
domain. In some instances, the fragments comprise framework element
1 (FW1), framework element 2 (FW2), framework element 3 (FW3), or
framework element 4 (FW4). In some instances, the antibody
libraries are synthesized with at least or about 2 fragments, 3
fragments, 4 fragments, 5 fragments, or more than 5 fragments. The
length of each of the nucleic acid fragments or average length of
the nucleic acids synthesized may be at least or about 50, 75, 100,
125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425,
450, 475, 500, 525, 550, 575, 600, or more than 600 base pairs. In
some instances, the length is about 50 to 600, 75 to 575, 100 to
550, 125 to 525, 150 to 500, 175 to 475, 200 to 450, 225 to 425,
250 to 400, 275 to 375, or 300 to 350 base pairs.
[0123] Libraries comprising nucleic acids encoding for antibodies
as described herein comprise various lengths of amino acids when
translated. In some instances, the length of each of the amino acid
fragments or average length of the amino acid synthesized may be at
least or about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145,
150, or more than 150 amino acids. In some instances, the length of
the amino acid is about 15 to 150, 20 to 145, 25 to 140, 30 to 135,
35 to 130, 40 to 125, 45 to 120, 50 to 115, 55 to 110, 60 to 110,
65 to 105, 70 to 100, or 75 to 95 amino acids. In some instances,
the length of the amino acid is about 22 amino acids to about 75
amino acids. In some instances, the antibodies comprise at least or
about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000,
3000, 4000, 5000, or more than 5000 amino acids.
[0124] A number of variant sequences for the at least one region of
the antibody for variation are de novo synthesized using methods as
described herein. In some instances, a number of variant sequences
is de novo synthesized for CDRH1, CDRH2, CDRH3, CDRL1, CDRL2,
CDRL3, VL, VH, or combinations thereof. In some instances, a number
of variant sequences is de novo synthesized for framework element 1
(FW1), framework element 2 (FW2), framework element 3 (FW3), or
framework element 4 (FW4). The number of variant sequences may be
at least or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275,
300, 325, 350, 375, 400, 425, 450, 475, 500, or more than 500
sequences. In some instances, the number of variant sequences is at
least or about 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000,
5000, 6000, 7000, 8000, or more than 8000 sequences. In some
instances, the number of variant sequences is about 10 to 500, 25
to 475, 50 to 450, 75 to 425, 100 to 400, 125 to 375, 150 to 350,
175 to 325, 200 to 300, 225 to 375, 250 to 350, or 275 to 325
sequences.
[0125] Variant sequences for the at least one region of the
antibody, in some instances, vary in length or sequence. In some
instances, the at least one region that is de novo synthesized is
for CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3, VL, VH, or
combinations thereof. In some instances, the at least one region
that is de novo synthesized is for framework element 1 (FW1),
framework element 2 (FW2), framework element 3 (FW3), or framework
element 4 (FW4). In some instances, the variant sequence comprises
at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30,
35, 40, 45, 50, or more than 50 variant nucleotides or amino acids
as compared to wild-type. In some instances, the variant sequence
comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,
25, 30, 35, 40, 45, or 50 additional nucleotides or amino acids as
compared to wild-type. In some instances, the variant sequence
comprises at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20,
25, 30, 35, 40, 45, or 50 less nucleotides or amino acids as
compared to wild-type. In some instances, the libraries comprise at
least or about 10.sup.1, 10.sup.2, 10.sup.3, 10.sup.4, 10.sup.5,
10.sup.6, 10.sup.7, 10.sup.8, 10.sup.9, 10.sup.10, or more than
10.sup.10 variants.
[0126] Following synthesis of antibody libraries, antibody
libraries may be used for screening and analysis. For example,
antibody libraries are assayed for library displayability and
panning. In some instances, displayability is assayed using a
selectable tag. Exemplary tags include, but are not limited to, a
radioactive label, a fluorescent label, an enzyme, a
chemiluminescent tag, a colorimetric tag, an affinity tag or other
labels or tags that are known in the art. In some instances, the
tag is histidine, polyhistidine, myc, hemagglutinin (HA), or FLAG.
In some instances, antibody libraries are assayed by sequencing
using various methods including, but not limited to,
single-molecule real-time (SMRT) sequencing, Polony sequencing,
sequencing by ligation, reversible terminator sequencing, proton
detection sequencing, ion semiconductor sequencing, nanopore
sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert
sequencing, chain termination (e.g., Sanger) sequencing, +S
sequencing, or sequencing by synthesis. In some instances, antibody
libraries are displayed on the surface of a cell or phage. In some
instances, antibody libraries are enriched for sequences with a
desired activity using phage display.
[0127] In some instances, the antibody libraries are assayed for
functional activity, structural stability (e.g., thermal stable or
pH stable), expression, specificity, or a combination thereof. In
some instances, the antibody libraries are assayed for antibody
capable of folding. In some instances, a region of the antibody is
assayed for functional activity, structural stability, expression,
specificity, folding, or a combination thereof. For example, a VH
region or VL region is assayed for functional activity, structural
stability, expression, specificity, folding, or a combination
thereof.
[0128] In some instances, the affinity of antibodies or IgGs
generated by methods as described herein is at least or about
1.5.times., 2.0.times., 5.times., 10.times., 20.times., 30.times.,
40.times., 50.times., 60.times., 70.times., 80.times., 90.times.,
100.times., 200.times., or more than 200.times. improved binding
affinity as compared to a comparator antibody. In some instances,
the affinity of antibodies or IgGs generated by methods as
described herein is at least or about 1.5.times., 2.0.times.,
5.times., 10.times., 20.times., 30.times., 40.times., 50.times.,
60.times., 70.times., 80.times., 90.times., 100.times., 200.times.,
or more than 200.times. improved function as compared to a
comparator antibody. In some instances, the comparator antibody is
an antibody with similar structure, sequence, or antigen
target.
[0129] Expression Systems
[0130] Provided herein are libraries comprising nucleic acids
encoding for antibody comprising binding domains, wherein the
libraries have improved specificity, stability, expression,
folding, or downstream activity. In some instances, libraries
described herein are used for screening and analysis.
[0131] Provided herein are libraries comprising nucleic acids
encoding for antibody comprising binding domains, wherein the
nucleic acid libraries are used for screening and analysis. In some
instances, screening and analysis comprises in vitro, in vivo, or
ex vivo assays. Cells for screening include primary cells taken
from living subjects or cell lines. Cells may be from prokaryotes
(e.g., bacteria and fungi) or eukaryotes (e.g., animals and
plants). Exemplary animal cells include, without limitation, those
from a mouse, rabbit, primate, and insect. In some instances, cells
for screening include a cell line including, but not limited to,
Chinese Hamster Ovary (CHO) cell line, human embryonic kidney (HEK)
cell line, or baby hamster kidney (BHK) cell line. In some
instances, nucleic acid libraries described herein may also be
delivered to a multicellular organism. Exemplary multicellular
organisms include, without limitation, a plant, a mouse, rabbit,
primate, and insect.
[0132] Nucleic acid libraries described herein may be screened for
various pharmacological or pharmacokinetic properties. In some
instances, the libraries are screened using in vitro assays, in
vivo assays, or ex vivo assays. For example, in vitro
pharmacological or pharmacokinetic properties that are screened
include, but are not limited to, binding affinity, binding
specificity, and binding avidity. Exemplary in vivo pharmacological
or pharmacokinetic properties of libraries described herein that
are screened include, but are not limited to, therapeutic efficacy,
activity, preclinical toxicity properties, clinical efficacy
properties, clinical toxicity properties, immunogenicity, potency,
and clinical safety properties.
[0133] Provided herein are nucleic acid libraries, wherein the
nucleic acid libraries may be expressed in a vector. Expression
vectors for inserting nucleic acid libraries disclosed herein may
comprise eukaryotic or prokaryotic expression vectors. Exemplary
expression vectors include, without limitation, mammalian
expression vectors: pSF-CMV-NEO-NH2-PPT-3XFLAG,
pSF-CMV-NEO-COOH-3XFLAG, pSF-CMV-PURO-NH2-GST-TEV,
pSF-OXB20-COOH-TEV-FLAG(R)-6His, pCEP4 pDEST27, pSF-CMV-Ub-KrYFP,
pSF-CMV-FMDV-daGFP, pEF1a-mCherry-N1 Vector, pEF1a-tdTomato Vector,
pSF-CMV-FMDV-Hygro, pSF-CMV-PGK-Puro, pMCP-tag(m), and
pSF-CMV-PURO-NH2-CMYC; bacterial expression vectors:
pSF-OXB20-BetaGal,pSF-OXB20-Fluc, pSF-OXB20, and pSF-Tac; plant
expression vectors: pRI 101-AN DNA and pCambia2301; and yeast
expression vectors: pTYB21 and pKLAC2, and insect vectors:
pAc5.1/V5-His A and pDEST8. In some instances, the vector is pcDNA3
or pcDNA3.1.
[0134] Described herein are nucleic acid libraries that are
expressed in a vector to generate a construct comprising an
antibody. In some instances, a size of the construct varies. In
some instances, the construct comprises at least or about 500, 600,
700, 800, 900, 1000, 1100, 1300, 1400, 1500, 1600, 1700, 1800,
2000, 2400, 2600, 2800, 3000, 3200, 3400, 3600, 3800, 4000, 4200,
4400, 4600, 4800, 5000, 6000, 7000, 8000, 9000, 10000, or more than
10000 bases. In some instances, a the construct comprises a range
of about 300 to 1,000, 300 to 2,000, 300 to 3,000, 300 to 4,000,
300 to 5,000, 300 to 6,000, 300 to 7,000, 300 to 8,000, 300 to
9,000, 300 to 10,000, 1,000 to 2,000, 1,000 to 3,000, 1,000 to
4,000, 1,000 to 5,000, 1,000 to 6,000, 1,000 to 7,000, 1,000 to
8,000, 1,000 to 9,000, 1,000 to 10,000, 2,000 to 3,000, 2,000 to
4,000, 2,000 to 5,000, 2,000 to 6,000, 2,000 to 7,000, 2,000 to
8,000, 2,000 to 9,000, 2,000 to 10,000, 3,000 to 4,000, 3,000 to
5,000, 3,000 to 6,000, 3,000 to 7,000, 3,000 to 8,000, 3,000 to
9,000, 3,000 to 10,000, 4,000 to 5,000, 4,000 to 6,000, 4,000 to
7,000, 4,000 to 8,000, 4,000 to 9,000, 4,000 to 10,000, 5,000 to
6,000, 5,000 to 7,000, 5,000 to 8,000, 5,000 to 9,000, 5,000 to
10,000, 6,000 to 7,000, 6,000 to 8,000, 6,000 to 9,000, 6,000 to
10,000, 7,000 to 8,000, 7,000 to 9,000, 7,000 to 10,000, 8,000 to
9,000, 8,000 to 10,000, or 9,000 to 10,000 bases.
[0135] Provided herein are libraries comprising nucleic acids
encoding for antibodies, wherein the nucleic acid libraries are
expressed in a cell. In some instances, the libraries are
synthesized to express a reporter gene. Exemplary reporter genes
include, but are not limited to, acetohydroxyacid synthase (AHAS),
alkaline phosphatase (AP), beta galactosidase (LacZ), beta
glucuronidase (GUS), chloramphenicol acetyltransferase (CAT), green
fluorescent protein (GFP), red fluorescent protein (RFP), yellow
fluorescent protein (YFP), cyan fluorescent protein (CFP), cerulean
fluorescent protein, citrine fluorescent protein, orange
fluorescent protein, cherry fluorescent protein, turquoise
fluorescent protein, blue fluorescent protein, horseradish
peroxidase (HRP), luciferase (Luc), nopaline synthase (NOS),
octopine synthase (OCS), luciferase, and derivatives thereof.
Methods to determine modulation of a reporter gene are well known
in the art, and include, but are not limited to, fluorometric
methods (e.g. fluorescence spectroscopy, Fluorescence Activated
Cell Sorting (FACS), fluorescence microscopy), and antibiotic
resistance determination.
[0136] Diseases and Disorders
[0137] Provided herein are SARS-CoV-2 or ACE2 binding libraries
comprising nucleic acids encoding for antibodies comprising
SARS-CoV-2 or ACE2 binding domains may have therapeutic effects. In
some instances, the SARS-CoV-2 or ACE2 binding libraries result in
protein when translated that is used to treat a disease or
disorder. In some instances, the protein is an immunoglobulin. In
some instances, the protein is a peptidomimetic. In some instances,
the disease or disorder is a viral infection caused by SARS-CoV-2.
In some instances, the disease or disorder is a respiratory disease
or disorder caused by SARS-CoV-2.
[0138] SARS-CoV-2 or ACE2 variant antibody libraries as described
herein may be used to treat SARS-CoV-2. In some embodiments, the
SARS-CoV-2 or ACE2 variant antibody libraries are used to treat or
prevent symptoms of SARS-CoV-2. These symptoms include, but are not
limited to, fever, chills, cough, fatigue, headaches, loss of
taste, loss of smell, nausea, vomiting, muscle weakness, sleep
difficulties, anxiety, and depression. In some embodiments, the
SARS-CoV-2 or ACE2 variant antibody libraries are used to treat a
subject who has symptoms for an extended period of time. In some
embodiments, the subject has symptoms for an extended period of
time after testing negative for SARS-CoV-2. In some embodiments,
the subject has symptoms for an extended period of time including
at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4
months, 5 months, 6 months, 7 months, 8 months, 9 months, 10
months, 11 months, 1 year, or more than 1 year.
[0139] In some instances, the subject is a mammal. In some
instances, the subject is a mouse, rabbit, dog, or human. Subjects
treated by methods described herein may be infants, adults, or
children. Pharmaceutical compositions comprising antibodies or
antibody fragments as described herein may be administered
intravenously or subcutaneously. In some instances, a
pharmaceutical composition comprises an antibody or antibody
fragment described herein comprising a CDRH1 sequence of any one of
SEQ ID NOs: 217-266, 1495-1635, or 2059-2238. In some instances, a
pharmaceutical composition comprises an antibody or antibody
fragment described herein comprising a CDRH2 sequence of any one of
SEQ ID NOs: 267-316, 1636-1776, or 2239-2418 In some instances, a
pharmaceutical composition comprises an antibody or antibody
fragment described herein comprising a CDRH3 sequence of any one of
SEQ ID NOs: 317-366, 1777-1917, or 2419-2598. In some instances, a
pharmaceutical composition comprises an antibody or antibody
fragment described herein comprising a variable domain, heavy chain
region (VH) and a variable domain, light chain region (VL), wherein
VH comprises complementarity determining regions CDRH1, CDRH2, and
CDRH3, wherein VL comprises complementarity determining regions
CDRL1, CDRL2, and CDRL3, and wherein (a) an amino acid sequence of
CDRH1 is as set forth in any one of SEQ ID NOs: 1-36 or 217-282;
(b) an amino acid sequence of CDRH2 is as set forth in any one of
SEQ ID NOs: 37-72 or 283-348; (c) an amino acid sequence of CDRH3
is as set forth in any one of SEQ ID NOs: 73-108 or 349-414; (d) an
amino acid sequence of CDRL1 is as set forth in any one of SEQ ID
NOs: 109-144 or 415-473; (e) an amino acid sequence of CDRL2 is as
set forth in any one of SEQ ID NOs: 145-180 or 415-473; and (f) an
amino acid sequence of CDRL3 is as set forth in any one of SEQ ID
NOs: 181-216 or 533-591. In some instances, a pharmaceutical
composition comprises an antibody or antibody fragment described
herein comprising a VH comprising at least or about 70%, 80%, 85%,
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence
identity to any one of SEQ ID NOs: 592-657, and VL comprising at
least or about 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, 99%, or 100% sequence identity to any one of SEQ ID NOs:
658-716. In some instances, a pharmaceutical composition comprises
an antibody or antibody fragment described herein comprising a
heavy chain variable domain comprising at least or about 70%, 80%,
85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%
sequence identity to any one of SEQ ID NOs: 1918-2058, 2599-2778,
and 3095-3173.
[0140] SARS-CoV-2 or ACE2 antibodies as described herein may confer
immunity after exposure to SARS-CoV-2 or ACE2 antibodies. In some
embodiments, the SARS-CoV-2 or ACE2 antibodies described herein are
used for passive immunization of a subject. In some instances, the
subject is actively immunized after exposure to SARS-CoV-2 or ACE2
antibodies followed by exposure to SARS-CoV-2. In some embodiments,
SARS-CoV-2 or ACE2 antibodies are derived from a subject who has
recovered from SARS-CoV-2.
[0141] In some embodiments, the immunity occurs at least about 30
minutes, 1 hour, 5 hours, 10 hours, 16 hours, 20 hours, 24 hours, 2
days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or more than
2 weeks after exposure to SARS-CoV-2 or ACE2 antibodies. In some
instances, the immunity lasts for at least about 1 day, 2 days, 3
days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, or more than 5 years after exposure to SARS-CoV-2 or ACE2
antibodies.
[0142] In some embodiments, the subject receives the SARS-CoV-2 or
ACE2 antibodies prior to exposure to SARS-CoV-2. In some
embodiments, the subject receives the SARS-CoV-2 or ACE2 antibodies
at least about 30 minutes, 1 hour, 4 hours, 8 hours, 12 hours, 16
hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1
week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5
months, 6 months, 7 months, 8 months, 9 months, 10 months, 11
months, 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5
years prior to exposure to SARS-CoV-2. In some embodiments, the
subject receives the SARS-CoV-2 or ACE2 antibodies after exposure
to SARS-CoV-2. In some embodiments, the subject receives the
SARS-CoV-2 or ACE2 antibodies at least about 30 minutes, 1 hour, 4
hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3
days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, or more than 5 years after exposure to SARS-CoV-2.
[0143] SARS-CoV-2 or ACE2 antibodies described herein may be
administered through various routes. The administration may,
depending on the composition being administered, for example, be
oral, pulmonary, intravenous, intraperitoneal, intramuscular,
intracavity, subcutaneous, or transdermal.
[0144] Described herein are compositions or pharmaceutical
compositions comprising SARS-CoV-2 or ACE2 antibodies or antibody
fragment thereof that comprise various dosages of the antibodies or
antibody fragment. In some instances, the dosage is ranging from
about 1 to 25 mg/kg, from about 1 to 50 mg/kg, from about 1 to 80
mg/kg, from about 1 to about 100 mg/kg, from about 5 to about 100
mg/kg, from about 5 to about 80 mg/kg, from about 5 to about 60
mg/kg, from about 5 to about 50 mg/kg or from about 5 to about 500
mg/kg which can be administered in single or multiple doses. In
some instances, the dosage is administered in an amount of about
0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.25 mg/kg,
about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg,
about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg,
about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,
about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg,
about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg,
about 95 mg/kg, about 100 mg/kg, about 105 mg/kg, about 110 mg/kg,
about 115 mg/kg, about 120, about 125, about 130, about 135, about
140, about 145, about 150, about 155, about 160, about 165, about
170, about 175, about 180, about 185, about 190, about 195, about
200, about 205, about 210, about 215, about 220, about 225, about
230, about 240, about 250, about 260, about 270, about 275, about
280, about 290, about 300, about 310, about 320, about 330, about
340, about 350, about 360 mg/kg, about 370 mg/kg, about 380 mg/kg,
about 390 mg/kg, about 400 mg/kg, 410 mg/kg, about 420 mg/kg, about
430 mg/kg, about 440 mg/kg, about 450 mg/kg, about 460 mg/kg, about
470 mg/kg, about 480 mg/kg, about 490 mg/kg, or about 500
mg/kg.
[0145] SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof
described herein, in some embodiments, improve disease severity. In
some embodiments, the SARS-CoV-2 or ACE2 antibodies or antibody
fragment thereof improve disease severity at a dose level of about
0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.25 mg/kg,
about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg,
about 15 mg/kg, or about 20 mg/kg. In some embodiments, the
SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof improve
disease severity at a dose level of about 1 mg/kg, about 5 mg/kg,
or about 10 mg/kg. In some embodiments, disease severity is
determined by percent weight loss. In some embodiments, the
SARS-CoV-2 or ACE2 antibodies or antibody fragment thereof protects
against weight loss at a dose level of about 0.01 mg/kg, about 0.05
mg/kg, about 0.10 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 1
mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, or about 20
mg/kg. In some embodiments, the SARS-CoV-2 or ACE2 antibodies or
antibody fragment thereof protects against weight loss at a dose
level of about 1 mg/kg, about 5 mg/kg, or about 10 mg/kg. In some
embodiments, SARS-CoV-2 or ACE2 antibodies or antibody fragment
thereof
[0146] Variant Libraries
[0147] Codon Variation
[0148] Variant nucleic acid libraries described herein may comprise
a plurality of nucleic acids, wherein each nucleic acid encodes for
a variant codon sequence compared to a reference nucleic acid
sequence. In some instances, each nucleic acid of a first nucleic
acid population contains a variant at a single variant site. In
some instances, the first nucleic acid population contains a
plurality of variants at a single variant site such that the first
nucleic acid population contains more than one variant at the same
variant site. The first nucleic acid population may comprise
nucleic acids collectively encoding multiple codon variants at the
same variant site. The first nucleic acid population may comprise
nucleic acids collectively encoding up to 19 or more codons at the
same position. The first nucleic acid population may comprise
nucleic acids collectively encoding up to 60 variant triplets at
the same position, or the first nucleic acid population may
comprise nucleic acids collectively encoding up to 61 different
triplets of codons at the same position. Each variant may encode
for a codon that results in a different amino acid during
translation. Table 1 provides a listing of each codon possible (and
the representative amino acid) for a variant site.
TABLE-US-00001 TABLE 1 List of codons and amino acids One Three
letter letter Amino Acids code code Codons Alanine A Ala GCA GCC
GCG GCT Cysteine C Cys TGC TGT Aspartic D Asp GAC GAT acid Glutamic
E Glu GAA GAG acid Phenylalanine F Phe TTC TTT Glycine G Gly GGA
GGC GGG GGT Histidine H His CAC CAT Isoleucine I Iso ATA ATC ATT
Lysine K Lys AAA AAG Leucine L Leu TTA TTG CTA CTC CTG CTT
Methionine M Met ATG Asparagine N Asn AAC AAT Proline P Pro CCA CCC
CCG CCT Glutamine Q Gln CAA CAG Arginine R Arg AGA AGG CGA CGC CGG
CGT Serine S Ser AGC AGT TCA TCC TCG TCT Threonine T Thr ACA ACC
ACG ACT Valine V Val GTA GTC GTG GTT Tryptophan W Trp TGG Tyrosine
Y Tyr TAC TAT
[0149] A nucleic acid population may comprise varied nucleic acids
collectively encoding up to 20 codon variations at multiple
positions. In such cases, each nucleic acid in the population
comprises variation for codons at more than one position in the
same nucleic acid. In some instances, each nucleic acid in the
population comprises variation for codons at 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more codons in
a single nucleic acid. In some instances, each variant long nucleic
acid comprises variation for codons at 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30 or more codons in a single long nucleic acid. In
some instances, the variant nucleic acid population comprises
variation for codons at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30
or more codons in a single nucleic acid. In some instances, the
variant nucleic acid population comprises variation for codons in
at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more
codons in a single long nucleic acid.
[0150] Highly Parallel Nucleic Acid Synthesis
[0151] Provided herein is a platform approach utilizing
miniaturization, parallelization, and vertical integration of the
end-to-end process from polynucleotide synthesis to gene assembly
within nanowells on silicon to create a revolutionary synthesis
platform. Devices described herein provide, with the same footprint
as a 96-well plate, a silicon synthesis platform is capable of
increasing throughput by a factor of up to 1,000 or more compared
to traditional synthesis methods, with production of up to
approximately 1,000,000 or more polynucleotides, or 10,000 or more
genes in a single highly-parallelized run.
[0152] With the advent of next-generation sequencing, high
resolution genomic data has become an important factor for studies
that delve into the biological roles of various genes in both
normal biology and disease pathogenesis. At the core of this
research is the central dogma of molecular biology and the concept
of "residue-by-residue transfer of sequential information." Genomic
information encoded in the DNA is transcribed into a message that
is then translated into the protein that is the active product
within a given biological pathway.
[0153] Another exciting area of study is on the discovery,
development and manufacturing of therapeutic molecules focused on a
highly-specific cellular target. High diversity DNA sequence
libraries are at the core of development pipelines for targeted
therapeutics. Gene variants are used to express proteins in a
design, build, and test protein engineering cycle that ideally
culminates in an optimized gene for high expression of a protein
with high affinity for its therapeutic target. As an example,
consider the binding pocket of a receptor. The ability to test all
sequence permutations of all residues within the binding pocket
simultaneously will allow for a thorough exploration, increasing
chances of success. Saturation mutagenesis, in which a researcher
attempts to generate all possible mutations or variants at a
specific site within the receptor, represents one approach to this
development challenge. Though costly and time and labor-intensive,
it enables each variant to be introduced into each position. In
contrast, combinatorial mutagenesis, where a few selected positions
or short stretch of DNA may be modified extensively, generates an
incomplete repertoire of variants with biased representation.
[0154] To accelerate the drug development pipeline, a library with
the desired variants available at the intended frequency in the
right position available for testing--in other words, a precision
library, enables reduced costs as well as turnaround time for
screening. Provided herein are methods for synthesizing nucleic
acid synthetic variant libraries which provide for precise
introduction of each intended variant at the desired frequency. To
the end user, this translates to the ability to not only thoroughly
sample sequence space but also be able to query these hypotheses in
an efficient manner, reducing cost and screening time. Genome-wide
editing can elucidate important pathways, libraries where each
variant and sequence permutation can be tested for optimal
functionality, and thousands of genes can be used to reconstruct
entire pathways and genomes to re-engineer biological systems for
drug discovery.
[0155] In a first example, a drug itself can be optimized using
methods described herein. For example, to improve a specified
function of an antibody, a variant polynucleotide library encoding
for a portion of the antibody is designed and synthesized. A
variant nucleic acid library for the antibody can then be generated
by processes described herein (e.g., PCR mutagenesis followed by
insertion into a vector). The antibody is then expressed in a
production cell line and screened for enhanced activity. Example
screens include examining modulation in binding affinity to an
antigen, stability, or effector function (e.g., ADCC, complement,
or apoptosis). Exemplary regions to optimize the antibody include,
without limitation, the Fc region, Fab region, variable region of
the Fab region, constant region of the Fab region, variable domain
of the heavy chain or light chain (V.sub.H or V.sub.L), and
specific complementarity-determining regions (CDRs) of V.sub.H or
V.sub.L.
[0156] Nucleic acid libraries synthesized by methods described
herein may be expressed in various cells associated with a disease
state. Cells associated with a disease state include cell lines,
tissue samples, primary cells from a subject, cultured cells
expanded from a subject, or cells in a model system. Exemplary
model systems include, without limitation, plant and animal models
of a disease state.
[0157] To identify a variant molecule associated with prevention,
reduction or treatment of a disease state, a variant nucleic acid
library described herein is expressed in a cell associated with a
disease state, or one in which a cell a disease state can be
induced. In some instances, an agent is used to induce a disease
state in cells. Exemplary tools for disease state induction
include, without limitation, a Cre/Lox recombination system, LPS
inflammation induction, and streptozotocin to induce hypoglycemia.
The cells associated with a disease state may be cells from a model
system or cultured cells, as well as cells from a subject having a
particular disease condition. Exemplary disease conditions include
a bacterial, fungal, viral, autoimmune, or proliferative disorder
(e.g., cancer). In some instances, the variant nucleic acid library
is expressed in the model system, cell line, or primary cells
derived from a subject, and screened for changes in at least one
cellular activity. Exemplary cellular activities include, without
limitation, proliferation, cycle progression, cell death, adhesion,
migration, reproduction, cell signaling, energy production, oxygen
utilization, metabolic activity, and aging, response to free
radical damage, or any combination thereof
[0158] Substrates
[0159] Devices used as a surface for polynucleotide synthesis may
be in the form of substrates which include, without limitation,
homogenous array surfaces, patterned array surfaces, channels,
beads, gels, and the like. Provided herein are substrates
comprising a plurality of clusters, wherein each cluster comprises
a plurality of loci that support the attachment and synthesis of
polynucleotides. In some instances, substrates comprise a
homogenous array surface. For example, the homogenous array surface
is a homogenous plate. The term "locus" as used herein refers to a
discrete region on a structure which provides support for
polynucleotides encoding for a single predetermined sequence to
extend from the surface. In some instances, a locus is on a two
dimensional surface, e.g., a substantially planar surface. In some
instances, a locus is on a three-dimensional surface, e.g., a well,
microwell, channel, or post. In some instances, a surface of a
locus comprises a material that is actively functionalized to
attach to at least one nucleotide for polynucleotide synthesis, or
preferably, a population of identical nucleotides for synthesis of
a population of polynucleotides. In some instances, polynucleotide
refers to a population of polynucleotides encoding for the same
nucleic acid sequence. In some cases, a surface of a substrate is
inclusive of one or a plurality of surfaces of a substrate. The
average error rates for polynucleotides synthesized within a
library described here using the systems and methods provided are
often less than 1 in 1000, less than about 1 in 2000, less than
about 1 in 3000 or less often without error correction.
[0160] Provided herein are surfaces that support the parallel
synthesis of a plurality of polynucleotides having different
predetermined sequences at addressable locations on a common
support. In some instances, a substrate provides support for the
synthesis of more than 50, 100, 200, 400, 600, 800, 1000, 1200,
1400, 1600, 1800, 2,000; 5,000; 10,000; 20,000; 50,000; 100,000;
200,000; 300,000; 400,000; 500,000; 600,000; 700,000; 800,000;
900,000; 1,000,000; 1,200,000; 1,400,000; 1,600,000; 1,800,000;
2,000,000; 2,500,000; 3,000,000; 3,500,000; 4,000,000; 4,500,000;
5,000,000; 10,000,000 or more non-identical polynucleotides. In
some cases, the surfaces provide support for the synthesis of more
than 50, 100, 200, 400, 600, 800, 1000, 1200, 1400, 1600, 1800,
2,000; 5,000; 10,000; 20,000; 50,000; 100,000; 200,000; 300,000;
400,000; 500,000; 600,000; 700,000; 800,000; 900,000; 1,000,000;
1,200,000; 1,400,000; 1,600,000; 1,800,000; 2,000,000; 2,500,000;
3,000,000; 3,500,000; 4,000,000; 4,500,000; 5,000,000; 10,000,000
or more polynucleotides encoding for distinct sequences. In some
instances, at least a portion of the polynucleotides have an
identical sequence or are configured to be synthesized with an
identical sequence. In some instances, the substrate provides a
surface environment for the growth of polynucleotides having at
least 80, 90, 100, 120, 150, 175, 200, 225, 250, 275, 300, 325,
350, 375, 400, 425, 450, 475, 500 bases or more.
[0161] Provided herein are methods for polynucleotide synthesis on
distinct loci of a substrate, wherein each locus supports the
synthesis of a population of polynucleotides. In some cases, each
locus supports the synthesis of a population of polynucleotides
having a different sequence than a population of polynucleotides
grown on another locus. In some instances, each polynucleotide
sequence is synthesized with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more
redundancy across different loci within the same cluster of loci on
a surface for polynucleotide synthesis. In some instances, the loci
of a substrate are located within a plurality of clusters. In some
instances, a substrate comprises at least 10, 500, 1000, 2000,
3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000,
13000, 14000, 15000, 20000, 30000, 40000, 50000 or more clusters.
In some instances, a substrate comprises more than 2,000; 5,000;
10,000; 100,000; 200,000; 300,000; 400,000; 500,000; 600,000;
700,000; 800,000; 900,000; 1,000,000; 1,100,000; 1,200,000;
1,300,000; 1,400,000; 1,500,000; 1,600,000; 1,700,000; 1,800,000;
1,900,000; 2,000,000; 300,000; 400,000; 500,000; 600,000; 700,000;
800,000; 900,000; 1,000,000; 1,200,000; 1,400,000; 1,600,000;
1,800,000; 2,000,000; 2,500,000; 3,000,000; 3,500,000; 4,000,000;
4,500,000; 5,000,000; or 10,000,000 or more distinct loci. In some
instances, a substrate comprises about 10,000 distinct loci. The
amount of loci within a single cluster is varied in different
instances. In some cases, each cluster includes 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 130, 150,
200, 300, 400, 500 or more loci. In some instances, each cluster
includes about 50-500 loci. In some instances, each cluster
includes about 100-200 loci. In some instances, each cluster
includes about 100-150 loci. In some instances, each cluster
includes about 109, 121, 130 or 137 loci. In some instances, each
cluster includes about 19, 20, 61, 64 or more loci. Alternatively
or in combination, polynucleotide synthesis occurs on a homogenous
array surface.
[0162] In some instances, the number of distinct polynucleotides
synthesized on a substrate is dependent on the number of distinct
loci available in the substrate. In some instances, the density of
loci within a cluster or surface of a substrate is at least or
about 1, 10, 25, 50, 65, 75, 100, 130, 150, 175, 200, 300, 400,
500, 1,000 or more loci per mm.sup.2. In some cases, a substrate
comprises 10-500, 25-400, 50-500, 100-500, 150-500, 10-250, 50-250,
10-200, or 50-200 mm.sup.2. In some instances, the distance between
the centers of two adjacent loci within a cluster or surface is
from about 10-500, from about 10-200, or from about 10-100 um. In
some instances, the distance between two centers of adjacent loci
is greater than about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 um.
In some instances, the distance between the centers of two adjacent
loci is less than about 200, 150, 100, 80, 70, 60, 50, 40, 30, 20
or 10 um. In some instances, each locus has a width of about 0.5,
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or
100 um. In some cases, each locus has a width of about 0.5-100,
0.5-50, 10-75, or 0.5-50 um.
[0163] In some instances, the density of clusters within a
substrate is at least or about 1 cluster per 100 mm.sup.2, 1
cluster per 10 mm.sup.2, 1 cluster per 5 mm.sup.2, 1 cluster per 4
mm.sup.2, 1 cluster per 3 mm.sup.2, 1 cluster per 2 mm.sup.2, 1
cluster per 1 mm.sup.2, 2 clusters per 1 mm.sup.2, 3 clusters per 1
mm.sup.2, 4 clusters per 1 mm.sup.2, 5 clusters per 1 mm.sup.2, 10
clusters per 1 mm.sup.2, 50 clusters per 1 mm.sup.2 or more. In
some instances, a substrate comprises from about 1 cluster per 10
mm.sup.2 to about 10 clusters per 1 mm.sup.2. In some instances,
the distance between the centers of two adjacent clusters is at
least or about 50, 100, 200, 500, 1000, 2000, or 5000 um. In some
cases, the distance between the centers of two adjacent clusters is
between about 50-100, 50-200, 50-300, 50-500, and 100-2000 um. In
some cases, the distance between the centers of two adjacent
clusters is between about 0.05-50, 0.05-10, 0.05-5, 0.05-4, 0.05-3,
0.05-2, 0.1-10, 0.2-10, 0.3-10, 0.4-10, 0.5-10, 0.5-5, or 0.5-2 mm.
In some cases, each cluster has a cross section of about 0.5 to
about 2, about 0.5 to about 1, or about 1 to about 2 mm. In some
cases, each cluster has a cross section of about 0.5, 0.6, 0.7,
0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 mm.
In some cases, each cluster has an interior cross section of about
0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.15, 1.2, 1.3, 1.4, 1.5, 1.6,
1.7, 1.8, 1.9 or 2 mm.
[0164] In some instances, a substrate is about the size of a
standard 96 well plate, for example between about 100 and about 200
mm by between about 50 and about 150 mm. In some instances, a
substrate has a diameter less than or equal to about 1000, 500,
450, 400, 300, 250, 200, 150, 100 or 50 mm. In some instances, the
diameter of a substrate is between about 25-1000, 25-800, 25-600,
25-500, 25-400, 25-300, or 25-200 mm. In some instances, a
substrate has a planar surface area of at least about 100; 200;
500; 1,000; 2,000; 5,000; 10,000; 12,000; 15,000; 20,000; 30,000;
40,000; 50,000 mm.sup.2 or more. In some instances, the thickness
of a substrate is between about 50-2000, 50-1000, 100-1000,
200-1000, or 250-1000 mm.
[0165] Surface Materials
[0166] Substrates, devices, and reactors provided herein are
fabricated from any variety of materials suitable for the methods,
compositions, and systems described herein. In certain instances,
substrate materials are fabricated to exhibit a low level of
nucleotide binding. In some instances, substrate materials are
modified to generate distinct surfaces that exhibit a high level of
nucleotide binding. In some instances, substrate materials are
transparent to visible and/or UV light. In some instances,
substrate materials are sufficiently conductive, e.g., are able to
form uniform electric fields across all or a portion of a
substrate. In some instances, conductive materials are connected to
an electric ground. In some instances, the substrate is heat
conductive or insulated. In some instances, the materials are
chemical resistant and heat resistant to support chemical or
biochemical reactions, for example polynucleotide synthesis
reaction processes. In some instances, a substrate comprises
flexible materials. For flexible materials, materials can include,
without limitation: nylon, both modified and unmodified,
nitrocellulose, polypropylene, and the like. In some instances, a
substrate comprises rigid materials. For rigid materials, materials
can include, without limitation: glass; fuse silica; silicon,
plastics (for example polytetrafluoroethylene, polypropylene,
polystyrene, polycarbonate, and blends thereof, and the like);
metals (for example, gold, platinum, and the like). The substrate,
solid support or reactors can be fabricated from a material
selected from the group consisting of silicon, polystyrene,
agarose, dextran, cellulosic polymers, polyacrylamides,
polydimethylsiloxane (PDMS), and glass. The substrates/solid
supports or the microstructures, reactors therein may be
manufactured with a combination of materials listed herein or any
other suitable material known in the art.
[0167] Surface Architecture
[0168] Provided herein are substrates for the methods,
compositions, and systems described herein, wherein the substrates
have a surface architecture suitable for the methods, compositions,
and systems described herein. In some instances, a substrate
comprises raised and/or lowered features. One benefit of having
such features is an increase in surface area to support
polynucleotide synthesis. In some instances, a substrate having
raised and/or lowered features is referred to as a
three-dimensional substrate. In some cases, a three-dimensional
substrate comprises one or more channels. In some cases, one or
more loci comprise a channel. In some cases, the channels are
accessible to reagent deposition via a deposition device such as a
material deposition device. In some cases, reagents and/or fluids
collect in a larger well in fluid communication one or more
channels. For example, a substrate comprises a plurality of
channels corresponding to a plurality of loci with a cluster, and
the plurality of channels are in fluid communication with one well
of the cluster. In some methods, a library of polynucleotides is
synthesized in a plurality of loci of a cluster.
[0169] Provided herein are substrates for the methods,
compositions, and systems described herein, wherein the substrates
are configured for polynucleotide synthesis. In some instances, the
structure is configured to allow for controlled flow and mass
transfer paths for polynucleotide synthesis on a surface. In some
instances, the configuration of a substrate allows for the
controlled and even distribution of mass transfer paths, chemical
exposure times, and/or wash efficacy during polynucleotide
synthesis. In some instances, the configuration of a substrate
allows for increased sweep efficiency, for example by providing
sufficient volume for a growing polynucleotide such that the
excluded volume by the growing polynucleotide does not take up more
than 50, 45, 40, 35, 30, 25, 20, 15, 14, 13, 12, 11, 10, 9, 8, 7,
6, 5, 4, 3, 2, 1%, or less of the initially available volume that
is available or suitable for growing the polynucleotide. In some
instances, a three-dimensional structure allows for managed flow of
fluid to allow for the rapid exchange of chemical exposure.
[0170] Provided herein are substrates for the methods,
compositions, and systems described herein, wherein the substrates
comprise structures suitable for the methods, compositions, and
systems described herein. In some instances, segregation is
achieved by physical structure. In some instances, segregation is
achieved by differential functionalization of the surface
generating active and passive regions for polynucleotide synthesis.
In some instances, differential functionalization is achieved by
alternating the hydrophobicity across the substrate surface,
thereby creating water contact angle effects that cause beading or
wetting of the deposited reagents. Employing larger structures can
decrease splashing and cross-contamination of distinct
polynucleotide synthesis locations with reagents of the neighboring
spots. In some cases, a device, such as a material deposition
device, is used to deposit reagents to distinct polynucleotide
synthesis locations. Substrates having three-dimensional features
are configured in a manner that allows for the synthesis of a large
number of polynucleotides (e.g., more than about 10,000) with a low
error rate (e.g., less than about 1:500, 1:1000, 1:1500, 1:2,000,
1:3,000, 1:5,000, or 1:10,000). In some cases, a substrate
comprises features with a density of about or greater than about 1,
5, 10, 20, 30, 40, 50, 60, 70, 80, 100, 110, 120, 130, 140, 150,
160, 170, 180, 190, 200, 300, 400 or 500 features per mm.sup.2.
[0171] A well of a substrate may have the same or different width,
height, and/or volume as another well of the substrate. A channel
of a substrate may have the same or different width, height, and/or
volume as another channel of the substrate. In some instances, the
diameter of a cluster or the diameter of a well comprising a
cluster, or both, is between about 0.05-50, 0.05-10, 0.05-5,
0.05-4, 0.05-3, 0.05-2, 0.05-1, 0.05-0.5, 0.05-0.1, 0.1-10, 0.2-10,
0.3-10, 0.4-10, 0.5-10, 0.5-5, or 0.5-2 mm. In some instances, the
diameter of a cluster or well or both is less than or about 5, 4,
3, 2, 1, 0.5, 0.1, 0.09, 0.08, 0.07, 0.06, or 0.05 mm. In some
instances, the diameter of a cluster or well or both is between
about 1.0 and 1.3 mm. In some instances, the diameter of a cluster
or well, or both is about 1.150 mm. In some instances, the diameter
of a cluster or well, or both is about 0.08 mm. The diameter of a
cluster refers to clusters within a two-dimensional or
three-dimensional substrate.
[0172] In some instances, the height of a well is from about
20-1000, 50-1000, 100-1000, 200-1000, 300-1000, 400-1000, or
500-1000 um. In some cases, the height of a well is less than about
1000, 900, 800, 700, or 600 um.
[0173] In some instances, a substrate comprises a plurality of
channels corresponding to a plurality of loci within a cluster,
wherein the height or depth of a channel is 5-500, 5-400, 5-300,
5-200, 5-100, 5-50, or 10-50 um. In some cases, the height of a
channel is less than 100, 80, 60, 40, or 20 um.
[0174] In some instances, the diameter of a channel, locus (e.g.,
in a substantially planar substrate) or both channel and locus
(e.g., in a three-dimensional substrate wherein a locus corresponds
to a channel) is from about 1-1000, 1-500, 1-200, 1-100, 5-100, or
10-100 um, for example, about 90, 80, 70, 60, 50, 40, 30, 20 or 10
um. In some instances, the diameter of a channel, locus, or both
channel and locus is less than about 100, 90, 80, 70, 60, 50, 40,
30, 20 or 10 um. In some instances, the distance between the center
of two adjacent channels, loci, or channels and loci is from about
1-500, 1-200, 1-100, 5-200, 5-100, 5-50, or 5-30, for example,
about 20 um.
[0175] Surface Modifications
[0176] Provided herein are methods for polynucleotide synthesis on
a surface, wherein the surface comprises various surface
modifications. In some instances, the surface modifications are
employed for the chemical and/or physical alteration of a surface
by an additive or subtractive process to change one or more
chemical and/or physical properties of a substrate surface or a
selected site or region of a substrate surface. For example,
surface modifications include, without limitation, (1) changing the
wetting properties of a surface, (2) functionalizing a surface,
i.e., providing, modifying or substituting surface functional
groups, (3) defunctionalizing a surface, i.e., removing surface
functional groups, (4) otherwise altering the chemical composition
of a surface, e.g., through etching, (5) increasing or decreasing
surface roughness, (6) providing a coating on a surface, e.g., a
coating that exhibits wetting properties that are different from
the wetting properties of the surface, and/or (7) depositing
particulates on a surface.
[0177] In some cases, the addition of a chemical layer on top of a
surface (referred to as adhesion promoter) facilitates structured
patterning of loci on a surface of a substrate. Exemplary surfaces
for application of adhesion promotion include, without limitation,
glass, silicon, silicon dioxide and silicon nitride. In some cases,
the adhesion promoter is a chemical with a high surface energy. In
some instances, a second chemical layer is deposited on a surface
of a substrate. In some cases, the second chemical layer has a low
surface energy. In some cases, surface energy of a chemical layer
coated on a surface supports localization of droplets on the
surface. Depending on the patterning arrangement selected, the
proximity of loci and/or area of fluid contact at the loci are
alterable.
[0178] In some instances, a substrate surface, or resolved loci,
onto which nucleic acids or other moieties are deposited, e.g., for
polynucleotide synthesis, are smooth or substantially planar (e.g.,
two-dimensional) or have irregularities, such as raised or lowered
features (e.g., three-dimensional features). In some instances, a
substrate surface is modified with one or more different layers of
compounds. Such modification layers of interest include, without
limitation, inorganic and organic layers such as metals, metal
oxides, polymers, small organic molecules and the like.
[0179] In some instances, resolved loci of a substrate are
functionalized with one or more moieties that increase and/or
decrease surface energy. In some cases, a moiety is chemically
inert. In some cases, a moiety is configured to support a desired
chemical reaction, for example, one or more processes in a
polynucleotide synthesis reaction. The surface energy, or
hydrophobicity, of a surface is a factor for determining the
affinity of a nucleotide to attach onto the surface. In some
instances, a method for substrate functionalization comprises: (a)
providing a substrate having a surface that comprises silicon
dioxide; and (b) silanizing the surface using, a suitable
silanizing agent described herein or otherwise known in the art,
for example, an organofunctional alkoxysilane molecule. Methods and
functionalizing agents are described in U.S. Pat. No. 5,474,796,
which is herein incorporated by reference in its entirety.
[0180] In some instances, a substrate surface is functionalized by
contact with a derivatizing composition that contains a mixture of
silanes, under reaction conditions effective to couple the silanes
to the substrate surface, typically via reactive hydrophilic
moieties present on the substrate surface. Silanization generally
covers a surface through self-assembly with organofunctional
alkoxysilane molecules. A variety of siloxane functionalizing
reagents can further be used as currently known in the art, e.g.,
for lowering or increasing surface energy. The organofunctional
alkoxysilanes are classified according to their organic
functions.
[0181] Polynucleotide Synthesis
[0182] Methods of the current disclosure for polynucleotide
synthesis may include processes involving phosphoramidite
chemistry. In some instances, polynucleotide synthesis comprises
coupling a base with phosphoramidite. Polynucleotide synthesis may
comprise coupling a base by deposition of phosphoramidite under
coupling conditions, wherein the same base is optionally deposited
with phosphoramidite more than once, i.e., double coupling.
Polynucleotide synthesis may comprise capping of unreacted sites.
In some instances, capping is optional. Polynucleotide synthesis
may also comprise oxidation or an oxidation step or oxidation
steps. Polynucleotide synthesis may comprise deblocking,
detritylation, and sulfurization. In some instances, polynucleotide
synthesis comprises either oxidation or sulfurization. In some
instances, between one or each step during a polynucleotide
synthesis reaction, the device is washed, for example, using
tetrazole or acetonitrile. Time frames for any one step in a
phosphoramidite synthesis method may be less than about 2 min, 1
min, 50 sec, 40 sec, 30 sec, 20 sec and 10 sec.
[0183] Polynucleotide synthesis using a phosphoramidite method may
comprise a subsequent addition of a phosphoramidite building block
(e.g., nucleoside phosphoramidite) to a growing polynucleotide
chain for the formation of a phosphite triester linkage.
Phosphoramidite polynucleotide synthesis proceeds in the 3' to 5'
direction. Phosphoramidite polynucleotide synthesis allows for the
controlled addition of one nucleotide to a growing nucleic acid
chain per synthesis cycle. In some instances, each synthesis cycle
comprises a coupling step. Phosphoramidite coupling involves the
formation of a phosphite triester linkage between an activated
nucleoside phosphoramidite and a nucleoside bound to the substrate,
for example, via a linker. In some instances, the nucleoside
phosphoramidite is provided to the device activated. In some
instances, the nucleoside phosphoramidite is provided to the device
with an activator. In some instances, nucleoside phosphoramidites
are provided to the device in a 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70,
80, 90, 100-fold excess or more over the substrate-bound
nucleosides. In some instances, the addition of nucleoside
phosphoramidite is performed in an anhydrous environment, for
example, in anhydrous acetonitrile. Following addition of a
nucleoside phosphoramidite, the device is optionally washed. In
some instances, the coupling step is repeated one or more
additional times, optionally with a wash step between nucleoside
phosphoramidite additions to the substrate. In some instances, a
polynucleotide synthesis method used herein comprises 1, 2, 3 or
more sequential coupling steps. Prior to coupling, in many cases,
the nucleoside bound to the device is de-protected by removal of a
protecting group, where the protecting group functions to prevent
polymerization. A common protecting group is 4,4'-dimethoxytrityl
(DMT).
[0184] Following coupling, phosphoramidite polynucleotide synthesis
methods optionally comprise a capping step. In a capping step, the
growing polynucleotide is treated with a capping agent. A capping
step is useful to block unreacted substrate-bound 5'-OH groups
after coupling from further chain elongation, preventing the
formation of polynucleotides with internal base deletions. Further,
phosphoramidites activated with 1H-tetrazole may react, to a small
extent, with the O6 position of guanosine. Without being bound by
theory, upon oxidation with I.sub.2/water, this side product,
possibly via O6-N7 migration, may undergo depurination. The
apurinic sites may end up being cleaved in the course of the final
deprotection of the polynucleotide thus reducing the yield of the
full-length product. The O6 modifications may be removed by
treatment with the capping reagent prior to oxidation with
I.sub.2/water. In some instances, inclusion of a capping step
during polynucleotide synthesis decreases the error rate as
compared to synthesis without capping. As an example, the capping
step comprises treating the substrate-bound polynucleotide with a
mixture of acetic anhydride and 1-methylimidazole. Following a
capping step, the device is optionally washed.
[0185] In some instances, following addition of a nucleoside
phosphoramidite, and optionally after capping and one or more wash
steps, the device bound growing nucleic acid is oxidized. The
oxidation step comprises the phosphite triester is oxidized into a
tetracoordinated phosphate triester, a protected precursor of the
naturally occurring phosphate diester internucleoside linkage. In
some instances, oxidation of the growing polynucleotide is achieved
by treatment with iodine and water, optionally in the presence of a
weak base (e.g., pyridine, lutidine, collidine). Oxidation may be
carried out under anhydrous conditions using, e.g. tert-Butyl
hydroperoxide or (1S)-(+)-(10-camphorsulfonyl)-oxaziridine (CSO).
In some methods, a capping step is performed following oxidation. A
second capping step allows for device drying, as residual water
from oxidation that may persist can inhibit subsequent coupling.
Following oxidation, the device and growing polynucleotide is
optionally washed. In some instances, the step of oxidation is
substituted with a sulfurization step to obtain polynucleotide
phosphorothioates, wherein any capping steps can be performed after
the sulfurization. Many reagents are capable of the efficient
sulfur transfer, including but not limited to
3-(Dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-3-thione,
DDTT, 3H-1,2-benzodithiol-3-one 1,1-dioxide, also known as Beaucage
reagent, and N,N,N'N'-Tetraethylthiuram disulfide (TETD).
[0186] In order for a subsequent cycle of nucleoside incorporation
to occur through coupling, the protected 5' end of the device bound
growing polynucleotide is removed so that the primary hydroxyl
group is reactive with a next nucleoside phosphoramidite. In some
instances, the protecting group is DMT and deblocking occurs with
trichloroacetic acid in dichloromethane. Conducting detritylation
for an extended time or with stronger than recommended solutions of
acids may lead to increased depurination of solid support-bound
polynucleotide and thus reduces the yield of the desired
full-length product. Methods and compositions of the disclosure
described herein provide for controlled deblocking conditions
limiting undesired depurination reactions. In some instances, the
device bound polynucleotide is washed after deblocking. In some
instances, efficient washing after deblocking contributes to
synthesized polynucleotides having a low error rate.
[0187] Methods for the synthesis of polynucleotides typically
involve an iterating sequence of the following steps: application
of a protected monomer to an actively functionalized surface (e.g.,
locus) to link with either the activated surface, a linker or with
a previously deprotected monomer; deprotection of the applied
monomer so that it is reactive with a subsequently applied
protected monomer; and application of another protected monomer for
linking. One or more intermediate steps include oxidation or
sulfurization. In some instances, one or more wash steps precede or
follow one or all of the steps.
[0188] Methods for phosphoramidite-based polynucleotide synthesis
comprise a series of chemical steps. In some instances, one or more
steps of a synthesis method involve reagent cycling, where one or
more steps of the method comprise application to the device of a
reagent useful for the step. For example, reagents are cycled by a
series of liquid deposition and vacuum drying steps. For substrates
comprising three-dimensional features such as wells, microwells,
channels and the like, reagents are optionally passed through one
or more regions of the device via the wells and/or channels.
[0189] Methods and systems described herein relate to
polynucleotide synthesis devices for the synthesis of
polynucleotides. The synthesis may be in parallel. For example, at
least or about at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50,
100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,
750, 800, 850, 900, 1000, 10000, 50000, 75000, 100000 or more
polynucleotides can be synthesized in parallel. The total number
polynucleotides that may be synthesized in parallel may be from
2-100000, 3-50000, 4-10000, 5-1000, 6-900, 7-850, 8-800, 9-750,
10-700, 11-650, 12-600, 13-550, 14-500, 15-450, 16-400, 17-350,
18-300, 19-250, 20-200, 21-150, 22-100, 23-50, 24-45, 25-40, 30-35.
Those of skill in the art appreciate that the total number of
polynucleotides synthesized in parallel may fall within any range
bound by any of these values, for example 25-100. The total number
of polynucleotides synthesized in parallel may fall within any
range defined by any of the values serving as endpoints of the
range. Total molar mass of polynucleotides synthesized within the
device or the molar mass of each of the polynucleotides may be at
least or at least about 10, 20, 30, 40, 50, 100, 250, 500, 750,
1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 25000,
50000, 75000, 100000 picomoles, or more. The length of each of the
polynucleotides or average length of the polynucleotides within the
device may be at least or about at least 10, 15, 20, 25, 30, 35,
40, 45, 50, 100, 150, 200, 300, 400, 500 nucleotides, or more. The
length of each of the polynucleotides or average length of the
polynucleotides within the device may be at most or about at most
500, 400, 300, 200, 150, 100, 50, 45, 35, 30, 25, 20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10 nucleotides, or less. The length of each
of the polynucleotides or average length of the polynucleotides
within the device may fall from 10-500, 9-400, 11-300, 12-200,
13-150, 14-100, 15-50, 16-45, 17-40, 18-35, 19-25. Those of skill
in the art appreciate that the length of each of the
polynucleotides or average length of the polynucleotides within the
device may fall within any range bound by any of these values, for
example 100-300. The length of each of the polynucleotides or
average length of the polynucleotides within the device may fall
within any range defined by any of the values serving as endpoints
of the range.
[0190] Methods for polynucleotide synthesis on a surface provided
herein allow for synthesis at a fast rate. As an example, at least
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 70,
80, 90, 100, 125, 150, 175, 200 nucleotides per hour, or more are
synthesized. Nucleotides include adenine, guanine, thymine,
cytosine, uridine building blocks, or analogs/modified versions
thereof. In some instances, libraries of polynucleotides are
synthesized in parallel on substrate. For example, a device
comprising about or at least about 100; 1,000; 10,000; 30,000;
75,000; 100,000; 1,000,000; 2,000,000; 3,000,000; 4,000,000; or
5,000,000 resolved loci is able to support the synthesis of at
least the same number of distinct polynucleotides, wherein
polynucleotide encoding a distinct sequence is synthesized on a
resolved locus. In some instances, a library of polynucleotides is
synthesized on a device with low error rates described herein in
less than about three months, two months, one month, three weeks,
15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 days, 24 hours or
less. In some instances, larger nucleic acids assembled from a
polynucleotide library synthesized with low error rate using the
substrates and methods described herein are prepared in less than
about three months, two months, one month, three weeks, 15, 14, 13,
12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 days, 24 hours or less.
[0191] In some instances, methods described herein provide for
generation of a library of nucleic acids comprising variant nucleic
acids differing at a plurality of codon sites. In some instances, a
nucleic acid may have 1 site, 2 sites, 3 sites, 4 sites, 5 sites, 6
sites, 7 sites, 8 sites, 9 sites, 10 sites, 11 sites, 12 sites, 13
sites, 14 sites, 15 sites, 16 sites, 17 sites 18 sites, 19 sites,
20 sites, 30 sites, 40 sites, 50 sites, or more of variant codon
sites.
[0192] In some instances, the one or more sites of variant codon
sites may be adjacent. In some instances, the one or more sites of
variant codon sites may not be adjacent and separated by 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more codons.
[0193] In some instances, a nucleic acid may comprise multiple
sites of variant codon sites, wherein all the variant codon sites
are adjacent to one another, forming a stretch of variant codon
sites. In some instances, a nucleic acid may comprise multiple
sites of variant codon sites, wherein none the variant codon sites
are adjacent to one another. In some instances, a nucleic acid may
comprise multiple sites of variant codon sites, wherein some the
variant codon sites are adjacent to one another, forming a stretch
of variant codon sites, and some of the variant codon sites are not
adjacent to one another.
[0194] Referring to the Figures, FIG. 2 illustrates an exemplary
process workflow for synthesis of nucleic acids (e.g., genes) from
shorter nucleic acids. The workflow is divided generally into
phases: (1) de novo synthesis of a single stranded nucleic acid
library, (2) joining nucleic acids to form larger fragments, (3)
error correction, (4) quality control, and (5) shipment. Prior to
de novo synthesis, an intended nucleic acid sequence or group of
nucleic acid sequences is preselected. For example, a group of
genes is preselected for generation.
[0195] Once large nucleic acids for generation are selected, a
predetermined library of nucleic acids is designed for de novo
synthesis. Various suitable methods are known for generating high
density polynucleotide arrays. In the workflow example, a device
surface layer is provided. In the example, chemistry of the surface
is altered in order to improve the polynucleotide synthesis
process. Areas of low surface energy are generated to repel liquid
while areas of high surface energy are generated to attract
liquids. The surface itself may be in the form of a planar surface
or contain variations in shape, such as protrusions or microwells
which increase surface area. In the workflow example, high surface
energy molecules selected serve a dual function of supporting DNA
chemistry, as disclosed in International Patent Application
Publication WO/2015/021080, which is herein incorporated by
reference in its entirety.
[0196] In situ preparation of polynucleotide arrays is generated on
a solid support and utilizes single nucleotide extension process to
extend multiple oligomers in parallel. A deposition device, such as
a material deposition device 201, is designed to release reagents
in a step wise fashion such that multiple polynucleotides extend,
in parallel, one residue at a time to generate oligomers with a
predetermined nucleic acid sequence 202. In some instances,
polynucleotides are cleaved from the surface at this stage.
Cleavage includes gas cleavage, e.g., with ammonia or
methylamine.
[0197] The generated polynucleotide libraries are placed in a
reaction chamber. In this exemplary workflow, the reaction chamber
(also referred to as "nanoreactor") is a silicon coated well,
containing PCR reagents and lowered onto the polynucleotide library
203. Prior to or after the sealing 204 of the polynucleotides, a
reagent is added to release the polynucleotides from the substrate.
In the exemplary workflow, the polynucleotides are released
subsequent to sealing of the nanoreactor 205. Once released,
fragments of single stranded polynucleotides hybridize in order to
span an entire long range sequence of DNA. Partial hybridization
205 is possible because each synthesized polynucleotide is designed
to have a small portion overlapping with at least one other
polynucleotide in the pool.
[0198] After hybridization, a PCA reaction is commenced. During the
polymerase cycles, the polynucleotides anneal to complementary
fragments and gaps are filled in by a polymerase. Each cycle
increases the length of various fragments randomly depending on
which polynucleotides find each other. Complementarity amongst the
fragments allows for forming a complete large span of double
stranded DNA 206.
[0199] After PCA is complete, the nanoreactor is separated from the
device 207 and positioned for interaction with a device having
primers for PCR 208. After sealing, the nanoreactor is subject to
PCR 209 and the larger nucleic acids are amplified. After PCR 210,
the nanochamber is opened 211, error correction reagents are added
212, the chamber is sealed 213 and an error correction reaction
occurs to remove mismatched base pairs and/or strands with poor
complementarity from the double stranded PCR amplification products
214. The nanoreactor is opened and separated 215. Error corrected
product is next subject to additional processing steps, such as PCR
and molecular bar coding, and then packaged 222 for shipment
223.
[0200] In some instances, quality control measures are taken. After
error correction, quality control steps include for example
interaction with a wafer having sequencing primers for
amplification of the error corrected product 216, sealing the wafer
to a chamber containing error corrected amplification product 217,
and performing an additional round of amplification 218. The
nanoreactor is opened 219 and the products are pooled 220 and
sequenced 221. After an acceptable quality control determination is
made, the packaged product 222 is approved for shipment 223.
[0201] In some instances, a nucleic acid generate by a workflow
such as that in FIG. 2 is subject to mutagenesis using overlapping
primers disclosed herein. In some instances, a library of primers
are generated by in situ preparation on a solid support and utilize
single nucleotide extension process to extend multiple oligomers in
parallel. A deposition device, such as a material deposition
device, is designed to release reagents in a step wise fashion such
that multiple polynucleotides extend, in parallel, one residue at a
time to generate oligomers with a predetermined nucleic acid
sequence 202.
[0202] Computer Systems
[0203] Any of the systems described herein, may be operably linked
to a computer and may be automated through a computer either
locally or remotely. In various instances, the methods and systems
of the disclosure may further comprise software programs on
computer systems and use thereof. Accordingly, computerized control
for the synchronization of the dispense/vacuum/refill functions
such as orchestrating and synchronizing the material deposition
device movement, dispense action and vacuum actuation are within
the bounds of the disclosure. The computer systems may be
programmed to interface between the user specified base sequence
and the position of a material deposition device to deliver the
correct reagents to specified regions of the substrate.
[0204] The computer system 300 illustrated in FIG. 3 may be
understood as a logical apparatus that can read instructions from
media 311 and/or a network port 305, which can optionally be
connected to server 309 having fixed media 312. The system, such as
shown in FIG. 3 can include a CPU 301, disk drives 303, optional
input devices such as keyboard 315 and/or mouse 316 and optional
monitor 307. Data communication can be achieved through the
indicated communication medium to a server at a local or a remote
location. The communication medium can include any means of
transmitting and/or receiving data. For example, the communication
medium can be a network connection, a wireless connection or an
internet connection. Such a connection can provide for
communication over the World Wide Web. It is envisioned that data
relating to the present disclosure can be transmitted over such
networks or connections for reception and/or review by a party 322
as illustrated in FIG. 3.
[0205] FIG. 4 is a block diagram illustrating a first example
architecture of a computer system 400 that can be used in
connection with example instances of the present disclosure. As
depicted in FIG. 4, the example computer system can include a
processor 402 for processing instructions. Non-limiting examples of
processors include: Intel Xeon.TM. processor, AMD Opteron.TM.
processor, Samsung 32-bit RISC ARM 1176JZ(F)-S v1.0.TM. processor,
ARM Cortex-A8 Samsung S5PC100.TM. processor, ARM Cortex-A8 Apple
A4.TM. processor, Marvell PXA 930.TM. processor, or a
functionally-equivalent processor. Multiple threads of execution
can be used for parallel processing. In some instances, multiple
processors or processors with multiple cores can also be used,
whether in a single computer system, in a cluster, or distributed
across systems over a network comprising a plurality of computers,
cell phones, and/or personal data assistant devices.
[0206] As illustrated in FIG. 4, a high speed cache 404 can be
connected to, or incorporated in, the processor 402 to provide a
high speed memory for instructions or data that have been recently,
or are frequently, used by processor 402. The processor 402 is
connected to a north bridge 406 by a processor bus 408. The north
bridge 406 is connected to random access memory (RAM) 410 by a
memory bus 412 and manages access to the RAM 410 by the processor
402. The north bridge 406 is also connected to a south bridge 414
by a chipset bus 416. The south bridge 414 is, in turn, connected
to a peripheral bus 418. The peripheral bus can be, for example,
PCI, PCI-X, PCI Express, or other peripheral bus. The north bridge
and south bridge are often referred to as a processor chipset and
manage data transfer between the processor, RAM, and peripheral
components on the peripheral bus 418. In some alternative
architectures, the functionality of the north bridge can be
incorporated into the processor instead of using a separate north
bridge chip. In some instances, system 400 can include an
accelerator card 422 attached to the peripheral bus 418. The
accelerator can include field programmable gate arrays (FPGAs) or
other hardware for accelerating certain processing. For example, an
accelerator can be used for adaptive data restructuring or to
evaluate algebraic expressions used in extended set processing.
[0207] Software and data are stored in external storage 424 and can
be loaded into RAM 410 and/or cache 404 for use by the processor.
The system 400 includes an operating system for managing system
resources; non-limiting examples of operating systems include:
Linux, Windows.TM., MACOS.TM., BlackBerry OS.TM., iOS.TM., and
other functionally-equivalent operating systems, as well as
application software running on top of the operating system for
managing data storage and optimization in accordance with example
instances of the present disclosure. In this example, system 400
also includes network interface cards (NICs) 420 and 421 connected
to the peripheral bus for providing network interfaces to external
storage, such as Network Attached Storage (NAS) and other computer
systems that can be used for distributed parallel processing.
[0208] FIG. 5 is a diagram showing a network 500 with a plurality
of computer systems 502a, and 502b, a plurality of cell phones and
personal data assistants 502c, and Network Attached Storage (NAS)
504a, and 504b. In example instances, systems 502a, 502b, and 502c
can manage data storage and optimize data access for data stored in
Network Attached Storage (NAS) 504a and 504b. A mathematical model
can be used for the data and be evaluated using distributed
parallel processing across computer systems 502a, and 502b, and
cell phone and personal data assistant systems 502c. Computer
systems 502a, and 502b, and cell phone and personal data assistant
systems 502c can also provide parallel processing for adaptive data
restructuring of the data stored in Network Attached Storage (NAS)
504a and 504b. FIG. 5 illustrates an example only, and a wide
variety of other computer architectures and systems can be used in
conjunction with the various instances of the present disclosure.
For example, a blade server can be used to provide parallel
processing. Processor blades can be connected through a back plane
to provide parallel processing. Storage can also be connected to
the back plane or as Network Attached Storage (NAS) through a
separate network interface. In some example instances, processors
can maintain separate memory spaces and transmit data through
network interfaces, back plane or other connectors for parallel
processing by other processors. In other instances, some or all of
the processors can use a shared virtual address memory space.
[0209] FIG. 6 is a block diagram of a multiprocessor computer
system using a shared virtual address memory space in accordance
with an example instance. The system includes a plurality of
processors 602a-f that can access a shared memory subsystem 604.
The system incorporates a plurality of programmable hardware memory
algorithm processors (MAPs) 606a-f in the memory subsystem 604.
Each MAP 606a-f can comprise a memory 608a-f and one or more field
programmable gate arrays (FPGAs) 610a-f. The MAP provides a
configurable functional unit and particular algorithms or portions
of algorithms can be provided to the FPGAs 610a-f for processing in
close coordination with a respective processor. For example, the
MAPs can be used to evaluate algebraic expressions regarding the
data model and to perform adaptive data restructuring in example
instances. In this example, each MAP is globally accessible by all
of the processors for these purposes. In one configuration, each
MAP can use Direct Memory Access (DMA) to access an associated
memory 608a-f, allowing it to execute tasks independently of, and
asynchronously from the respective microprocessor 602a-f. In this
configuration, a MAP can feed results directly to another MAP for
pipelining and parallel execution of algorithms.
[0210] The above computer architectures and systems are examples
only, and a wide variety of other computer, cell phone, and
personal data assistant architectures and systems can be used in
connection with example instances, including systems using any
combination of general processors, co-processors, FPGAs and other
programmable logic devices, system on chips (SOCs), application
specific integrated circuits (ASICs), and other processing and
logic elements. In some instances, all or part of the computer
system can be implemented in software or hardware. Any variety of
data storage media can be used in connection with example
instances, including random access memory, hard drives, flash
memory, tape drives, disk arrays, Network Attached Storage (NAS)
and other local or distributed data storage devices and
systems.
[0211] In example instances, the computer system can be implemented
using software modules executing on any of the above or other
computer architectures and systems. In other instances, the
functions of the system can be implemented partially or completely
in firmware, programmable logic devices such as field programmable
gate arrays (FPGAs) as referenced in FIG. 4, system on chips
(SOCs), application specific integrated circuits (ASICs), or other
processing and logic elements. For example, the Set Processor and
Optimizer can be implemented with hardware acceleration through the
use of a hardware accelerator card, such as accelerator card 422
illustrated in FIG. 4.
[0212] The following examples are set forth to illustrate more
clearly the principle and practice of embodiments disclosed herein
to those skilled in the art and are not to be construed as limiting
the scope of any claimed embodiments. Unless otherwise stated, all
parts and percentages are on a weight basis.
EXAMPLES
[0213] The following examples are given for the purpose of
illustrating various embodiments of the disclosure and are not
meant to limit the present disclosure in any fashion. The present
examples, along with the methods described herein are presently
representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the disclosure. Changes
therein and other uses which are encompassed within the spirit of
the disclosure as defined by the scope of the claims will occur to
those skilled in the art.
Example 1: Functionalization of a Device Surface
[0214] A device was functionalized to support the attachment and
synthesis of a library of polynucleotides. The device surface was
first wet cleaned using a piranha solution comprising 90%
H.sub.2SO.sub.4 and 10% H.sub.2O.sub.2 for 20 minutes. The device
was rinsed in several beakers with DI water, held under a DI water
gooseneck faucet for 5 min, and dried with N2. The device was
subsequently soaked in NH.sub.4OH (1:100; 3 mL:300 mL) for 5 min,
rinsed with DI water using a handgun, soaked in three successive
beakers with DI water for 1 min each, and then rinsed again with DI
water using the handgun. The device was then plasma cleaned by
exposing the device surface to O.sub.2. A SAMCO PC-300 instrument
was used to plasma etch O.sub.2 at 250 watts for 1 min in
downstream mode.
[0215] The cleaned device surface was actively functionalized with
a solution comprising
N-(3-triethoxysilylpropyl)-4-hydroxybutyramide using a YES-1224P
vapor deposition oven system with the following parameters: 0.5 to
1 torr, 60 min, 70.degree. C., 135.degree. C. vaporizer. The device
surface was resist coated using a Brewer Science 200.times. spin
coater. SPR.TM. 3612 photoresist was spin coated on the device at
2500 rpm for 40 sec. The device was pre-baked for 30 min at
90.degree. C. on a Brewer hot plate. The device was subjected to
photolithography using a Karl Suss MA6 mask aligner instrument. The
device was exposed for 2.2 sec and developed for 1 min in MSF 26A.
Remaining developer was rinsed with the handgun and the device
soaked in water for 5 min. The device was baked for 30 min at
100.degree. C. in the oven, followed by visual inspection for
lithography defects using a Nikon L200. A descum process was used
to remove residual resist using the SAMCO PC-300 instrument to O2
plasma etch at 250 watts for 1 min.
[0216] The device surface was passively functionalized with a 100
.mu.L solution of perfluorooctyltrichlorosilane mixed with 10 .mu.L
light mineral oil. The device was placed in a chamber, pumped for
10 min, and then the valve was closed to the pump and left to stand
for 10 min. The chamber was vented to air. The device was resist
stripped by performing two soaks for 5 min in 500 mL NMP at
70.degree. C. with ultrasonication at maximum power (9 on Crest
system). The device was then soaked for 5 min in 500 mL isopropanol
at room temperature with ultrasonication at maximum power. The
device was dipped in 300 mL of 200 proof ethanol and blown dry with
N.sub.2. The functionalized surface was activated to serve as a
support for polynucleotide synthesis.
Example 2: Synthesis of a 50-Mer Sequence on an Oligonucleotide
Synthesis Device
[0217] A two dimensional oligonucleotide synthesis device was
assembled into a flowcell, which was connected to a flowcell
(Applied Biosystems (ABI394 DNA Synthesizer"). The two-dimensional
oligonucleotide synthesis device was uniformly functionalized with
N-(3-TRIETHOXYSILYLPROPYL)-4-HYDROXYBUTYRAMIDE (Gelest) was used to
synthesize an exemplary polynucleotide of 50 bp ("50-mer
polynucleotide") using polynucleotide synthesis methods described
herein.
[0218] The sequence of the 50-mer was as described.
TABLE-US-00002 5'AGACAATCAACCATTTGGGGTGGACAGCCTTGAC
CTCTAGACTTCGGCAT##TTTTTTTTTT3',
where # denotes Thymidine-succinyl hexamide CED phosphoramidite
(CLP-2244 from ChemGenes), which is a cleavable linker enabling the
release of oligos from the surface during deprotection.
[0219] The synthesis was done using standard DNA synthesis
chemistry (coupling, capping, oxidation, and deblocking) according
to the protocol in Table 2 and an ABI synthesizer.
TABLE-US-00003 TABLE 2 Synthesis protocols General DNA Synthesis
Table 2 Process Name Process Step Time (sec) WASH (Acetonitrile
Wash Acetonitrile System Flush 4 Flow) Acetonitrile to Flowcell 23
N2 System Flush 4 Acetonitrile System Flush 4 DNA BASE ADDITION
Activator Manifold Flush 2 (Phosphoramidite + Activator Activator
to Flowcell 6 Flow) Activator + Phosphoramidite 6 to Flowcell
Activator to Flowcell 0.5 Activator + Phosphoramidite 5 to Flowcell
Activator to Flowcell 0.5 Activator + Phosphoramidite 5 to Flowcell
Activator to Flowcell 0.5 Activator + Phosphoramidite 5 to Flowcell
Incubate for 25 sec 25 WASH (Acetonitrile Wash Acetonitrile System
Flush 4 Flow) Acetonitrile to Flowcell 15 N2 System Flush 4
Acetonitrile System Flush 4 DNA BASE ADDITION Activator Manifold
Flush 2 (Phosphoramidite + Activator Activator to Flowcell 5 Flow)
Activator + Phosphoramidite 18 to Flowcell Incubate for 25 sec 25
WASH (Acetonitrile Wash Acetonitrile System Flush 4 Flow)
Acetonitrile to Flowcell 15 N2 System Flush 4 Acetonitrile System
Flush 4 CAPPING (CapA + B, 1:1, CapA + B to Flowcell 15 Flow) WASH
(Acetonitrile Wash Acetonitrile System Flush 4 Flow) Acetonitrile
to Flowcell 15 Acetonitrile System Flush 4 OXIDATION (Oxidizer
Oxidizer to Flowcell 18 Flow) WASH (Acetonitrile Wash Acetonitrile
System Flush 4 Flow) N2 System Flush 4 Acetonitrile System Flush 4
Acetonitrile to Flowcell 15 Acetonitrile System Flush 4
Acetonitrile to Flowcell 15 N2 System Flush 4 Acetonitrile System
Flush 4 Acetonitrile to Flowcell 23 N2 System Flush 4 Acetonitrile
System Flush 4 DEBLOCKING (Deblock Deblock to Flowcell 36 Flow)
WASH (Acetonitrile Wash Acetonitrile System Flush 4 Flow) N2 System
Flush 4 Acetonitrile System Flush 4 Acetonitrile to Flowcell 18 N2
System Flush 4.13 Acetonitrile System Flush 4.13 Acetonitrile to
Flowcell 15
[0220] The phosphoramidite/activator combination was delivered
similar to the delivery of bulk reagents through the flowcell. No
drying steps were performed as the environment stays "wet" with
reagent the entire time.
[0221] The flow restrictor was removed from the ABI 394 synthesizer
to enable faster flow. Without flow restrictor, flow rates for
amidites (0.1M in ACN), Activator, (0.25M Benzoylthiotetrazole
("BTT"; 30-3070-xx from GlenResearch) in ACN), and Ox (0.02M I2 in
20% pyridine, 10% water, and 70% THF) were roughly .about.100
uL/sec, for acetonitrile ("ACN") and capping reagents (1:1 mix of
CapA and CapB, wherein CapA is acetic anhydride in THF/Pyridine and
CapB is 16% 1-methylimidizole in THF), roughly .about.200 uL/sec,
and for Deblock (3% dichloroacetic acid in toluene), roughly
.about.300 uL/sec (compared to .about.50 uL/sec for all reagents
with flow restrictor). The time to completely push out Oxidizer was
observed, the timing for chemical flow times was adjusted
accordingly and an extra ACN wash was introduced between different
chemicals. After polynucleotide synthesis, the chip was deprotected
in gaseous ammonia overnight at 75 psi. Five drops of water were
applied to the surface to recover polynucleotides. The recovered
polynucleotides were then analyzed on a BioAnalyzer small RNA
chip.
Example 3: Synthesis of a 100-Mer Sequence on an Oligonucleotide
Synthesis Device
[0222] The same process as described in Example 2 for the synthesis
of the 50-mer sequence was used for the synthesis of a 100-mer
polynucleotide ("100-mer polynucleotide"; 5'
CGGGATCCTTATCGTCATCGTCGTACAGATCCCGACCCATTTGCTGTCCACCAGTCATGCTAGC
CATACCATGATGATGATGATGATGAGAACCCCGCAT##TTTTTTTTTT3', where # denotes
Thymidine-succinyl hexamide CED phosphoramidite (CLP-2244 from
ChemGenes) on two different silicon chips, the first one uniformly
functionalized with N-(3-TRIETHOXYSILYLPROPYL)-4-HYDROXYBUTYRAMIDE
and the second one functionalized with 5/95 mix of
11-acetoxyundecyltriethoxysilane and n-decyltriethoxysilane, and
the polynucleotides extracted from the surface were analyzed on a
BioAnalyzer instrument.
[0223] All ten samples from the two chips were further PCR
amplified using a forward (5'ATGCGGGGTTCTCATCATC3') and a reverse
(5'CGGGATCCTTATCGTCATCG3') primer in a 50 uL PCR mix (25 uL NEB Q5
mastermix, 2.5 uL 10 uM Forward primer, 2.5 uL 10 uM Reverse
primer, 1uL polynucleotide extracted from the surface, and water up
to 50 uL) using the following thermalcycling program:
[0224] 98.degree. C., 30 sec
[0225] 98.degree. C., 10 sec; 63.degree. C., 10 sec; 72.degree. C.,
10 sec; repeat 12 cycles
[0226] 72.degree. C., 2 min
[0227] The PCR products were also run on a BioAnalyzer,
demonstrating sharp peaks at the 100-mer position. Next, the PCR
amplified samples were cloned, and Sanger sequenced. Table 3
summarizes the results from the Sanger sequencing for samples taken
from spots 1-5 from chip 1 and for samples taken from spots 6-10
from chip 2.
TABLE-US-00004 TABLE 3 Sequencing results Spot Error rate Cycle
efficiency 1 1/763 bp 99.87% 2 1/824 bp 99.88% 3 1/780 bp 99.87% 4
1/429 bp 99.77% 5 1/1525 bp 99.93% 6 1/1615 bp 99.94% 7 1/531 bp
99.81% 8 1/1769 bp 99.94% 9 1/854 bp 99.88% 10 1/1451 bp 99.93%
[0228] Thus, the high quality and uniformity of the synthesized
polynucleotides were repeated on two chips with different surface
chemistries. Overall, 89% of the 100-mers that were sequenced were
perfect sequences with no errors, corresponding to 233 out of
262.
[0229] Table 4 summarizes error characteristics for the sequences
obtained from the polynucleotides samples from spots 1-10.
TABLE-US-00005 TABLE 4 Error characteristics Spot no. Sample ID
OSA_0046/1 OSA_0047/2 OSA_0048/3 OSA_0049/4 OSA_0050/5 Total
Sequences 32 32 32 32 32 Sequencing Quality 25 of 28 27 of 27 26 of
30 21 of 23 25 of 26 Oligo Quality 23 of 25 25 of 27 22 of 26 18 of
21 24 of 25 ROI Match Count 2500 2698 2561 2122 2499 ROI Mutation 2
2 1 3 1 ROI Multi Base 0 0 0 0 0 Deletion ROI Small Insertion 1 0 0
0 0 ROI Single Base 0 0 0 0 0 Deletion Large Deletion 0 0 1 0 0
Count Mutation: G > A 2 2 1 2 1 Mutation: T > C 0 0 0 1 0 ROI
Error Count 3 2 2 3 1 ROI Error Rate Err: ~1 Err: ~1 Err: ~1 Err:
~1 Err: ~1 in 834 in 1350 in 1282 in 708 in 2500 ROI Minus Primer
MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 Error Rate
in 763 in 824 in 780 in 429 in 1525 Spot no. Sample ID OSA_0051/6
OSA_0052/7 OSA_0053/8 OSA_0054/9 OSA_0055/10 Total Sequences 32 32
32 32 32 Sequencing Quality 29 of 30 27 of 31 29 of 31 28 of 29 25
of 28 Oligo Quality 25 of 29 22 of 27 28 of 29 26 of 28 20 of 25
ROI Match Count 2666 2625 2899 2798 2348 ROI Mutation 0 2 1 2 1 ROI
Multi Base 0 0 0 0 0 Deletion ROI Small Insertion 0 0 0 0 0 ROI
Single Base 0 0 0 0 0 Deletion Large Deletion 1 1 0 0 0 Count
Mutation: G > A 0 2 1 2 1 Mutation: T > C 0 0 0 0 0 ROI Error
Count 1 3 1 2 1 ROI Error Rate Err: ~1 Err: ~1 Err: ~1 Err: ~1 Err:
~1 in 2667 in 876 in 2900 in 1400 in 2349 ROI Minus Primer MP Err:
~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 MP Err: ~1 Error Rate in 1615
in 531 in 1769 in 854 in 1451
Example 4: Panning and Screening for Identification of Antibodies
for SARS-CoV-2 and ACE2
[0230] This example describes identification of antibodies for
SARS-CoV-2 and ACE2.
[0231] Phage displayed scFv, VHH, and Fab libraries were panned for
binding to biotinylated SARS-CoV-2 S1 and human ACE2. FIG. 7 shows
a schema of the panning strategy. Biotinylated antigen was bound to
streptavidin coated magnetic beads at a density of 100 pmol antigen
per mg of beads (Thermo Fisher #11206D). Phage libraries were
blocked with 5% BSA in PBS. Following magnetic bead depletion for 1
hour at room temperature (RT), the beads were removed, and phage
supernatant was transferred to 1 mg of antigen-bound beads in 1 ml
PBS and incubated at RT with rotation for 1 hour. Non-binding
clones were washed away by addition of 1 ml PBST, increasing the
number of washes with each panning round. Trypsin was used to elute
the phage bound to the antigen-bead complex. Phage were amplified
in TG1 E. coli for the next round of selection. This selection
strategy was repeated for four rounds, with successively lower
amounts of antigen per round. Following all four selection rounds,
400 clones from each of round 2, 3, and 4 were selected for phage
expression and phage ELISA screening. Data from the panning is seen
in Table 5.
TABLE-US-00006 TABLE 5 Panning Data Antibody Titer Round 1 Round 2
Round 3 Round 4 Round 5 1 Input titer 1.5 .times. 10.sup.12 1.2
.times. 10.sup.13 4.4 .times. 10.sup.13 1.8 .times. 10.sup.13 --
Output titer 1.2 .times. 10.sup.6 1.5 .times. 10.sup.6 2.0 .times.
10.sup.6 1.4 .times. 10.sup.8 -- 2 Input titer 1.4 .times.
10.sup.12 2.6 .times. 10.sup.13 3.0 .times. 10.sup.13 1.0 .times.
10.sup.13 -- Output titer 9.5 .times. 10.sup.5 1.2 .times. 10.sup.6
2.2 .times. 10.sup.6 1.2 .times. 10.sup.8 -- 3 Input titer 1.7
.times. 10.sup.12 2.0 .times. 10.sup.13 2.8 .times. 10.sup.13 3.2
.times. 10.sup.13 -- Output titer 1.5 .times. 10.sup.5 1.7 .times.
10.sup.6 1.5 .times. 10.sup.6 1.1 .times. 10.sup.8 -- 4 Input titer
1.2 .times. 10.sup.12 1.6 .times. 10.sup.13 3.6 .times. 10.sup.13
1.5 .times. 10.sup.13 -- Output titer 1.3 .times. 10.sup.5 2.2
.times. 10.sup.7 2.6 .times. 10.sup.7 2.5 .times. 10.sup.8 --
[0232] To test for binding to SARS-CoV-2 S1 and ACE2, phage were
expressed from each picked colony by KO7 superinfection in 384 well
microtiter plates. Phage containing supernatant was blocked by 1:1
addition of 4% non-fat milk (NFM). Assay plates were prepared by
passive immobilization of 0.4 .mu.g antigen in 384-well Maxisorp
plates (Thermo Fisher #464718) and then blocked with 4% NFM.
Following 3.times. wash in PBST, blocked phage supernatant was
incubated for 1 hour at RT. After 3.times. wash in PBST, 0.3
.mu.g/ml anti-M13-HRP (Sino Biological #11973-MM05T-H) was
aliquoted for 1 hour incubation at room temperature. Binding of
phage-displayed antibody was determined by absorbance at 450 nm
with 3,3',5,5'-tetramethylbenzidine (Thermo Fisher #34029). Phage
that bound to antigen with 3.times. over background of human Fc
protein were identified as potential binders for sequencing
analysis. DNA was amplified by rolling circle amplification from
glycerol stocks of each clone and submitted for Sanger sequencing
(Genewiz) to capture the VH and VL domains. FIGS. 8A-8D shows phage
ELISA data from round 4 of SARS-CoV-2 S1 (subunit 1) protein
panning for antibody 1 (FIGS. 8A-8B) and antibody 2 (FIGS. 8C-8D).
FIGS. 9A-9D shows phage ELISA data from round 4 of ACE2 protein
panning for antibody 3 (FIGS. 9A-9B) and antibody 4 (FIGS.
9C-9D).
[0233] SARS-CoV-2 variants were tested for specificity using a
phage ELISA as described above. The antigens used included Acro
COVID S1 (S1N-C82E8), COVID S1 RBD Fc fusion (Antigen 1), and COVID
S1 RBM Fc fusion (Antigen 2). Data from the phage ELISA is seen in
Table 6A. Table 6A shows screening ELISA mean, fold over background
(column A), specificity ELISA, fold over background (column B), and
specificity ELISA, percent binding relative to binding to Acro S1
(column C). As seen in Table 6A, nearly all receptor binding domain
(RBD) specific clones show good binding to full length subunit 1
(S1) and produced S1 RBD Fc. None of the S1 RBD variants were found
to bind to S1 RBM Fc.
TABLE-US-00007 TABLE 6A SARS-CoV-2 Phage ELISA Column A Column B
Column C ELISA S1- S1- S1- S1- Variant (Avg) Acro S1 RBD-Fc S1-Fc
RBM-Fc RBD-Fc S1-Fc RBM-Fc 1-21 47.6 19.5 14.8 1.4 1.4 75.7% 7.2%
7.0% 1-22 40.6 32.7 26.5 2.5 1.5 81.2% 7.6% 4.7% 1-30 29.5 16.8 1.7
5.6 1.4 9.8% 33.3% 8.5% 1-35 28.6 21.6 1.8 1.4 1.6 8.2% 6.5% 7.3%
1-17 27.4 25.1 20.1 1.6 1.3 79.8% 6.2% 5.2% 1-27 27.2 1.5 1.9 1.3
1.6 124.5% 84.8% 108.8% 1-37 27.0 11.6 2.0 5.4 1.4 17.7% 46.7%
12.3% 1-12 25.7 1.7 1.7 1.3 1.7 104.0% 79.6% 102.5% 1-2 24.2 1.8
1.9 1.7 1.7 103.3% 95.4% 93.5% 1-3 23.9 1.6 1.8 1.5 1.5 109.3%
91.2% 91.9% 1-23 23.1 5.1 3.6 1.6 1.6 70.9% 31.1% 32.0% 1-7 22.5
6.8 3.3 1.7 1.6 48.7% 24.8% 23.0% 1-31 20.7 30.4 1.3 15.7 1.2 4.3%
51.6% 3.8% 1-4 20.6 1.0 1.4 0.9 1.1 137.5% 90.8% 105.3% 1-38 20.2
1.1 1.5 0.9 1.2 127.9% 82.8% 100.9% 1-8 19.3 12.0 11.2 1.1 1.2
92.9% 8.8% 10.3% 1-9 18.5 10.7 9.8 0.9 1.0 91.1% 8.7% 9.3% 1-32
17.9 11.5 1.5 4.0 1.1 13.1% 35.3% 9.5% 1-33 17.6 7.1 1.5 3.0 1.0
21.1% 42.1% 14.6% 1-24 32.9 12.9 11.0 1.1 1.3 85.4% 8.9% 10.3% 1-39
24.4 18.6 11.6 2.5 1.3 62.5% 13.2% 6.7% 1-40 22.9 18.7 14.3 1.3 1.1
76.7% 7.1% 6.0% 1-5 20.6 1.5 1.6 1.2 1.4 107.8% 82.9% 92.0% 1-41
18.1 4.5 2.7 1.3 1.2 58.8% 28.9% 26.3% 1-28 17.7 1.0 1.1 1.1 1.2
112.9% 109.7% 124.1% 1-10 16.9 17.4 17.4 1.3 1.1 100.5% 7.3% 6.2%
2-1 45.3 39.3 36.8 20.2 1.5 93.7% 51.3% 3.9% 2-10 43.8 38.9 39.9
9.4 1.2 102.7% 24.1% 3.1% 2-5 30.8 38.3 35.9 24.3 1.1 93.7% 63.3%
3.0% 2-2 23.4 39.4 39.6 4.7 1.1 100.4% 12.0% 2.8% 3-10 17.4 1.2 1.2
1.2 1.1 97.2% 99.6% 93.3% 1-26 19.5 1.4 1.1 1.3 1.0 76.8% 98.0%
74.7% 1-42 34.5 22.7 20.8 1.4 1.0 91.4% 6.4% 4.2% 1-13 28.2 4.8 4.3
0.9 1.2 89.3% 18.4% 24.2% 1-43 21.9 6.7 5.8 3.9 1.0 87.3% 58.3%
14.5% 1-44 24.6 10.4 8.2 1.0 0.8 78.6% 9.6% 7.6% 1-14 21.7 16.8
13.5 1.1 0.9 80.6% 6.7% 5.4% 1-6 20.8 1.8 1.3 1.1 0.8 69.6% 60.5%
45.4% 1-45 24.0 12.1 10.3 1.2 1.0 85.3% 9.6% 8.3% 1-46 21.7 4.6 3.1
1.1 0.9 66.6% 24.5% 19.8% 1-20 26.0 5.7 3.9 1.0 0.8 67.3% 17.0%
14.5% 1-47 22.6 8.1 5.5 1.2 0.9 68.9% 14.6% 11.1% 1-29 23.8 1.1 0.9
1.0 0.9 81.4% 94.0% 78.3% 1-1 32.5 4.5 4.0 1.6 1.1 90.7% 35.3%
24.5% 1-19 22.3 24.2 23.9 1.5 1.2 98.7% 6.4% 4.9% 1-16 22.1 3.4 3.1
1.0 0.9 89.7% 29.5% 27.3% 1-34 28.7 7.5 3.1 1.8 1.0 41.3% 24.5%
13.3% 1-48 22.6 2.5 2.1 0.8 0.8 84.7% 31.5% 30.3% 1-49 27.6 1.0 1.0
0.8 0.8 99.3% 85.6% 78.8% 1-18 22.7 9.8 7.0 1.1 0.8 71.0% 11.0%
8.0% 1-11 33.2 4.8 4.8 0.9 1.0 99.5% 18.7% 20.6% 1-50 21.1 13.9
12.4 1.2 0.8 88.9% 8.8% 5.9% 1-25 27.9 3.6 2.7 1.0 0.8 75.4% 28.1%
22.3% 1-36 23.6 10.1 1.2 1.1 0.8 11.5% 10.6% 8.4% 1-15 24.8 2.5 1.4
1.0 0.8 55.4% 41.5% 32.1% 2-4 15.5 37.7 38.8 7.2 1.2 102.7% 19.0%
3.1% 2-6 22.1 11.1 12.8 1.8 1.1 115.8% 16.4% 9.5% 2-11 28.1 1.1 1.0
1.2 0.9 86.3% 103.4% 76.1% 2-12 18.2 39.8 40.3 14.7 1.1 101.3%
37.0% 2.9% 2-13 19.1 27.3 32.1 3.7 0.9 117.5% 13.4% 3.1% 2-14 17.2
31.7 32.9 4.2 0.9 103.9% 13.3% 2.8% 2-7 25.3 37.2 37.3 7.7 0.9
100.3% 20.6% 2.4% 2-8 32.4 35.9 36.5 5.4 1.1 101.8% 15.0% 3.1% 2-15
13.7 31.0 28.1 3.8 0.9 90.6% 12.4% 3.0% 2-9 14.1 24.1 24.3 3.0 0.8
100.7% 12.2% 3.5%
[0234] Tables 6B-6C show Carterra SPR kinetics for SARS-CoV-2
variant antibodies ranked by off-rate (Table 6B) and by K.sub.D
(Table 6C). FIG. 10 shows that ACE2 binds to S1-RBD-Fc and S1-Fc
variants.
TABLE-US-00008 TABLE 6B SARS-CoV-2 Carterra SPR Kinetics Ranked by
Off-Rate S1- S1- ka K.sub.D IgG Acro S1 RBD-Fc S1-Fc RBM-Fc (M-1
s-1) (s-1) 2-10 38.9 39.9 9.4 1.2 2.08E+05 1.15E-04 2-5 38.3 35.9
24.3 1.1 9.39E+04 2.59E-04 1-31 30.4 1.3 15.7 1.2 2.05E+04 7.62E-04
2-2 39.4 39.6 4.7 1.1 7.74E+04 9.06E-04 1-13 4.8 4.3 0.9 1.2
2.17E+05 1.38E-03 1-30 16.8 1.7 5.6 1.4 4.39E+04 1.64E-03 1-29 1.1
0.9 1.0 0.9 5.35E+02 1.97E-03 1-27 1.5 1.9 1.3 1.6 2.27E+05
2.85E-03 1-35 21.6 1.8 1.4 1.6 5.90E+04 5.43E-03 1-36 10.1 1.2 1.1
0.8 1.14E+05 7.85E-03 1-67 18.6 11.6 2.5 1.3 7.36E+04 8.86E-03 1-2
1.8 1.9 1.7 1.7 1.58E+03 2.72E-02 1-5 1.5 1.6 1.2 1.4 2.15E+03
5.40E-02 1-68 6.7 5.8 3.9 1.0 2.46E+06 8.75E-02 1-69 1.1 1.5 0.9
1.2 3.08E+05 1.23E-01 1-4 1.0 1.4 0.9 1.1 4.20E+04 1.24E-01 1-12
1.7 1.7 1.3 1.7 3.59E+05 1.34E-01 1-11 4.8 4.8 0.9 1.0 5.92E+05
1.43E-01 1-10 17.4 17.4 1.3 1.1 1.04E+06 1.47E-01 1-7 4.5 2.7 1.3
1.2 2.09E+05 1.55E-01 1-15 2.5 1.4 1.0 0.8 4.49E+05 1.56E-01 1-25
3.6 2.7 1.0 0.8 1.98E+06 1.56E-01 1-23 5.1 3.6 1.6 1.6 5.06E+05
1.59E-01 1-7 6.8 3.3 1.7 1.6 1.34E+06 1.70E-01 1-47 8.1 5.5 1.2 0.9
6.32E+03 2.40E-01 1-3 1.6 1.8 1.5 1.5 1.42E+06 3.04E-01 1-32 11.5
1.5 4.0 1.1 5.49E+06 3.17E-01 1-20 5.7 3.9 1.0 0.8 5.17E+02
6.95E-01 1-28 1.0 1.1 1.1 1.2 1.23E+08 9.05E+00 1-48 2.5 2.1 0.8
0.8 5.56E+07 9.11E+00 1-24 12.9 11.0 1.1 1.3 1.94E+08 1.46E+01 1-6
1.8 1.3 1.1 0.8 4.49E+08 2.08E+01 1-17 25.1 20.1 1.6 1.3 3.92E+08
2.63E+01 1-49 1.0 1.0 0.8 0.8 6.00E+08 3.22E+01 1-71 11.6 2.0 5.4
1.4 3.69E+08 4.03E+01 1-42 22.7 20.8 1.4 1.0 9.10E+08 1.03E+02
TABLE-US-00009 TABLE 6C SARS-CoV-2 Carterra SPR Kinetics Ranked by
K.sub.D S1- S1- ka kd K.sub.D Rmax IgG Acro S1 RBD-Fc S1-Fc RBM-Fc
(M-1 s-1) (s-1) (nM) (RU) 2-10 38.9 39.9 9.4 1.2 2.08E+05 1.15E-04
0.6 20 2-5 38.3 35.9 24.3 1.1 9.39E+04 2.59E-04 2.8 39 1-13 4.8 4.3
0.9 1.2 2.17E+05 1.38E-03 6.4 23 2-2 39.4 39.6 4.7 1.1 7.74E+04
9.06E-04 11.7 131 1-27 1.5 1.9 1.3 1.6 2.27E+05 2.85E-03 12.5 39
1-68 6.7 5.8 3.9 1.0 2.46E+06 8.75E-02 35.6 73 1-30 16.8 1.7 5.6
1.4 4.39E+04 1.64E-03 37.2 98 1-31 30.4 1.3 15.7 1.2 2.05E+04
7.62E-04 37.2 256 1-6 1.8 1.3 1.1 0.8 4.49E+08 2.08E+01 46.3 87
1-49 1.0 1.0 0.8 0.8 6.00E+08 3.22E+01 53.6 72 1-32 11.5 1.5 4.0
1.1 5.49E+06 3.17E-01 57.8 112 1-17 25.1 20.1 1.6 1.3 3.92E+08
2.63E+01 67.1 46 1-36 10.1 1.2 1.1 0.8 1.14E+05 7.85E-03 68.9 150
1-28 1.0 1.1 1.1 1.2 1.23E+08 9.05E+00 73.5 58 1-24 12.9 11.0 1.1
1.3 1.94E+08 1.46E+01 75.5 48 1-25 3.6 2.7 1.0 0.8 1.98E+06
1.56E-01 78.9 46 1-35 21.6 1.8 1.4 1.6 5.90E+04 5.43E-03 91.9 341
1-71 11.6 2.0 5.4 1.4 3.69E+08 4.03E+01 109.3 113 1-42 22.7 20.8
1.4 1.0 9.10E+08 1.03E+02 113.4 68 1-67 18.6 11.6 2.5 1.3 7.36E+04
8.86E-03 120.4 22 1-7 6.8 3.3 1.7 1.6 1.34E+06 1.70E-01 127.1 31
1-10 17.4 17.4 1.3 1.1 1.04E+06 1.47E-01 141.7 27 1-48 2.5 2.1 0.8
0.8 5.56E+07 9.11E+00 163.8 64 1-3 1.6 1.8 1.5 1.5 1.42E+06
3.04E-01 214.6 87 1-11 4.8 4.8 0.9 1.0 5.92E+05 1.43E-01 240.9 53
1-23 5.1 3.6 1.6 1.6 5.06E+05 1.59E-01 314.6 128 1-15 2.5 1.4 1.0
0.8 4.49E+05 1.56E-01 346.9 79 1-12 1.7 1.7 1.3 1.7 3.59E+05
1.34E-01 372.5 112 1-69 1.1 1.5 0.9 1.2 3.08E+05 1.23E-01 398.4 66
1-7 4.5 2.7 1.3 1.2 2.09E+05 1.55E-01 742.5 160 1-4 1.0 1.4 0.9 1.1
4.20E+04 1.24E-01 2946.4 385 1-29 1.1 0.9 1.0 0.9 5.35E+02 1.97E-03
3684.3 1206 1-2 1.8 1.9 1.7 1.7 1.58E+03 2.72E-02 17228.5 1652 1-5
1.5 1.6 1.2 1.4 2.15E+03 5.40E-02 25170.1 4457 1-47 8.1 5.5 1.2 0.9
6.32E+03 2.40E-01 37971.0 5497 1-20 5.7 3.9 1.0 0.8 5.17E+02
6.95E-01 1344113.2 64406
Example 5. SARS-CoV-2 and ACE Variants
[0235] SARS-CoV-2 and ACE variant antibodies were tested for
specificity and affinity.
[0236] Recombinant S1 Protein (Acros Biosystems Cat. No. S1N-S52H5)
was passively immobilized on a 384 well ELISA plate and blocked
with BSA. The S1 Panel antibodies were diluted from 50 nM to 0.0076
nM and incubated with the blocked plate. Antibody binding was
detected using Goat-anti-Human-HRP secondary and developed with HRP
substrate (list here). The absorbance signal was plotted as % of
maximal binding and fitted to determine the EC50 of each antibody
using GraphPad Prism.
[0237] Exemplary data for affinity of SARS-CoV-2 variant 2-6 is
seen in FIGS. 11A-11B. The binding of SARS-CoV-2 panel of
antibodies was measured as seen in FIG. 12 and Tables 7A-7F
below.
TABLE-US-00010 TABLE 7A SARS-CoV-2 Variants EC50 Antibody EC50 (nM)
1-31 0.03139 2-6 0.03364 ACRO 0.04831 1-34 0.06522 2-2 0.07992 1-27
0.09283 2-8 0.1029 1-22 0.1248 1-32 0.1406 1-16 0.1435 1-12 0.1585
2-5 0.1615 CR3022 0.1657 1-53 0.1691 1-30 0.2084 1-28 0.2224 1-71
0.2673 1-20 0.3236 1-4 0.4216 1-35 0.4922 1-47 0.5893 1-5 0.774 2-4
0.8792 1-3 0.9724 1-21 1.003 2-19 1.257 1-51 1.465 1-19 1.706 1-42
1.742 2-2 1.789 2-1 1.894 1-33 3.006 2-13 5.139 2-11 6.921 2-15
8.509 2-7 10.09 1-26 11.93 1-24 12.86 1-49 13.04 1-10 18.31 1-1
21.87 1-8 25.09 1-7 26.94 1-72 29.13 1-17 33.17 1-36 34.86 1-73
43.58 2-10 46.43 1-9 46.88 2-17 51.86 1-52 57.88 2-18 74.71 1-29
83.41 2-12 95.94 1-25 107 2-9 118.3 1-23 123.9 1-48 296 2-14
854.7
TABLE-US-00011 TABLE 7B SARS-CoV-2 Variants Frequency and ELISA
Data IgG Freq. ELISA (Avg) 1-21 1 47.6 1-22 3 40.6 1-30 1 29.5 1-35
3 28.6 1-17 79 27.4 1-27 1 27.2 1-12 2 25.7 1-2 14 24.2 1-3 2 23.9
1-23 1 23.1 1-7 4 22.5 1-31 1 20.7 1-4 1 20.6 1-8 2 19.3 1-9 2 18.5
1-32 1 17.9 1-33 1 17.6 1-24 1 32.9 1-5 1 20.6 1-28 2 17.7 1-10 1
16.9 1-26 1 19.5 1-13 1 28.2 1-14 1 21.7 1-6 1 20.8 1-20 3 26.0
1-29 1 23.8 1-1 1 32.5 1-19 1 22.3 1-16 1 22.1 1-34 1 28.7 1-18 1
22.7 1-11 1 33.2 1-25 1 27.9 1-36 1 23.6 1-15 1 24.8 1-51 1 7.1
1-52 1 3.5 1-53 1 21.7
TABLE-US-00012 TABLE 7C SARS-CoV-2 S1 Variants DB/S1 DB/S-T DC/S1
DC/S-T Inhibitor Fc/S1 Fc/S-T ELISA K.sub.D K.sub.D K.sub.D K.sub.D
IC50 K.sub.D K.sub.D IgG Freq (Avg) (nM) (nM) (nM) (nM) (nM) (nM)
(nM)f 1-21 1 47.6 6.7 1-22 3 40.6 73.2 1-30 1 29.5 37.2 4.7
475861.6 25.3 1-35 3 28.6 91.9 569.8 47.5 16.7 209.2 139.4 0.5 1-17
79 27.4 67.1 6649.2 10.0 1-27 1 27.2 12.5 5519.6 9.6 9.6 1-12 2
25.7 372.5 10.6 33.0 6.1 14.0 1-2 14 24.2 17228.5 304.3 1-3 2 23.9
214.6 423.0 252.8 5306.9 15.7 10.0 1-23 1 23.1 314.6 1-7 4 22.5
127.1 1-31 1 20.7 37.2 14.4 9.2 17.5 1-4 1 20.6 2946.4 6.6 659.2
129.2 25.5 12.3 1-8 2 19.3 97.3 1-9 2 18.5 282.4 1-32 1 17.9 57.8
14.8 2979.8 1-33 1 17.6 8.1 1739312.4 1-24 1 32.9 75.5 2043.7 1-40
2 22.9 1-5 1 20.6 25170.1 1155.7 1-28 2 17.7 73.5 13.4 520.3 96.6
3236.7 8.6 1-10 1 16.9 141.7 17.7 1-26 1 19.5 8.0 1-13 1 28.2 6.4
1-14 1 21.7 8.1 1-6 1 20.8 46.3 684.2 1-20 3 26.0 1344113.2 34.4
145.0 10.3 17.3 1-29 1 23.8 3684.3 36.1 19.3 1-1 1 32.5 1-19 1 22.3
85.4 0.0 14.3 18.6 1-16 1 22.1 2282.0 4487.3 1.7 178.8 2.2 1-34 1
28.7 8.2 623.6 13.4 1.4 1-18 1 22.7 1-11 1 33.2 240.9 30.2 1-25 1
27.9 78.9 3.0 6.1 1-36 1 23.6 68.9 3.9 9.3 33.2 1-15 1 24.8 346.9
1-51 1 7.1 1-52 1 3.5 739.8 1-53 1 21.7 1426.0 2-16 1 7.1 433.4
2-17 1 3.5 2-18 1 43.0 2-19 1 21.7 2-2 1 12.8
TABLE-US-00013 TABLE 7D SARS-CoV-2 S1 Variants Frequency and ELISA
Data IgG Freq. ELISA(Avg) 2-1 1 45.3 2-10 1 43.8 2-5 46 30.8 2-2 2
23.4 2-4 1 15.5 2-6 5 22.1 2-11 3 28.1 2-12 1 18.2 2-13 1 19.1 2-14
1 17.2 2-7 1 25.3 2-8 1 32.4 2-15 1 13.7 2-9 1 14.1 2-16 1 7.1 2-17
1 3.5 2-18 1 43.0 2-19 1 21.7 2-2 1 12.8
TABLE-US-00014 TABLE 7E SARS-CoV-2 S1 Variants DB/S1 DB/S-T DC/S1
DC/S-T Inhibitor Fc/S1 Fc/S-T ELISA K.sub.D K.sub.D K.sub.D K.sub.D
IC50 K.sub.D K.sub.D IgG Freq (Avg) (nM) (nM) (nM) (nM) (nM) (nM)
(nM) 2-10 1 43.8 0.6 125.6 2-5 46 30.8 2.8 17.3 4.2 1.9 90.2 2-2 2
23.4 11.7 1.2 1.4 3.6 58.3 0.8 2-4 1 15.5 4337.7 2-6 5 22.1 3.0
563.8 0.4 32.3 0.01 2-11 3 28.1 3.1 90.0 284.5 2-12 1 18.2 6.4 63.8
1.0 3.2 2-13 1 19.1 45.0 2-14 1 17.2 2.5 34.8 2-7 1 25.3 252.5 2-8
1 32.4 115.1 33.4 47.4 12.2 52.8 2-15 1 13.7 3.5 4.7 2-9 1 14.1
23.2 23582.5
TABLE-US-00015 TABLE 7F Antibody Panel ELISA Binding Titrations
(EC50) ANTIBODY EC50 (nM) 2-8 0.08001 1-35 0.09604 1-3 0.133 2-5
0.1332 1-27 0.1479 1-31 0.2035 2-6 0.283 1-2 0.523 1-34 0.5584 2-2
0.612 1-67 0.9402 1-16 1.409 1-12 2.15 1-28 2.284 1-4 2.559 1-1
4.157 1-19 4.413 1-22 6.548 1-5 7.833 1-42 7.92 2-15 7.92 1-49
8.669 1-53 10.25 2-9 12.58 1-33 17.5 1-26 48.46 2-29 63.43 1-7
95.66 1-25 95.66 1-51 98.17 2-17 100 2-2 100
[0238] Data for competition ELISA for a first set of SARS-CoV-2 S1
RBD and ACE2 variant antibodies is seen in FIGS. 13A-13B and FIG.
14A. SARS-CoV-2 variant antibodies with high potency in order of
potency included variant 2-2, Acro mAb (1.5333), variant 2-5,
variant 1-12, and variant 2-9. ACE variant antibodies with high
potency in order of potency included variant 4-52, variant 4-17,
variant 4-39, Acro mAb (1.533), variant 4-54, and variant 3.5. Data
for competition ELISA for a second set of ACE2 variant antibodies
is seen in FIG. 14B. Variant antibodies with high potency in order
of potency included variant 4-101, variant 4-140, variant 4-121,
variant 4-118, and Acro mAb (2.76 nM). FIGS. 14C-14D show the
SARS-CoV-2 variant antibodies show potent neutralization.
[0239] Inhibition assays were also performed as seen in FIG.
15.
[0240] SARS-CoV-2 variant antibodies were assayed for Vero
inhibition using FACS. Briefly, Vero cells stripped with Cell
Stripper (.about.20 minutes with 90% viability after removal).
Cells were plated at 0.1.times.10.sup.6 cells per well. Stock
solution of the variant antibodies were at 200 nM titrated 1:3.
SARS-CoV-2 S protein RBD, SPD-C5259 were made up at 6 ug/mL.
Variant antibody titrations were mixed 1:1 with 6 ug/mL S protein
(50 uL IgG: 50 uL S protein). 100 uL of the mixture were added to
cells and then incubated on ice for 1 hour. The cells were washed
1.times. followed by addition of 50 uL of goat anti-mouse secondary
made up at 1:200. The cells were then incubated on ice for 1 hour
in the dark, washed three times, and the plates were then read.
Data for SARS-CoV-2 variant antibodies is seen in FIGS. 16A-16D,
FIGS. 17A-17D, and Tables 8 and 9. As seen in the data, several
variant antibodies blocked labeled S1 RBD from binding to ACE2 on
the Vero cells including variants 2-8, 2-5, 2-2, 2-4, and 1-63.
TABLE-US-00016 TABLE 8 Antibody IC50 (nM) Acro Anti-S1 2.7 1-30 NC
1-35 NC 1-12 NC 1-31 NC 1-63 106.6 2-5 4.4 2-2 3.0 2-4 46.3 2-6 NC
2-8 19.5
TABLE-US-00017 TABLE 9 S1 Monomer (nM) S Trimer (nM) 1-31 0.22 0.80
1-30 0.67 4.02 1-35 0.15 0.76 1-12 2.08 0.61 1-63 1.40 14.39 2-8
1.52 7.08 2-5 0.17 0.59 2-2 0.13 0.64 2-4 1.58 10.18 2-6 0.07
0.43
[0241] A summary of epitope binning for SARS-CoV-2 variant
antibodies is seen in Table 10 below.
TABLE-US-00018 TABLE 10 SARS-CoV-2 Epitope Binning Acro Abcam ID
mAb 2-2 CR3022 2-5 2-8 2-11 1-32 1-16 2-6 1-35 *Acro 0 0 2 1 1 1 1
1 1 1 mAb *2-2 0 0 0 0 0 0 2 0 2 1 Abcam 2 0 0 0 0 1 1 2 2 2 CR3022
*2-5 1 0 0 0 0 1 1 1 1 1 *2-8 1 0 0 0 0 1 1 1 1 1 2-11 1 0 0 0 0 0
1 2 1 1 **1-32 2 1 3 1 2 1 0 0 1 1 1-16 1 1 2 2 1 1 1 0 0 0 2-6 2 2
3 2 2 2 1 0 0 0 1-35 1 1 2 2 1 1 1 0 0 0 *Anti-S1 inhibiting IgG in
FACS (Vero E6) **Anti-S1 inhibiting IgG in ELISA (soluble ACE2)
[0242] The variant antibodies were also measured in binding against
other coronaviruses. Data shows that the variant antibodies do not
bind significantly to S1 HCoV-229E (Sino), S1 HCoV-HKU1 (Sino), S1
HCoV-NL63 (Sino), or S1 HCoV-OC43 (Sino) (data not shown).
[0243] The data shows that the SARS-CoV-2 and ACE2 variant
antibodies have high specificity and affinity to their antigen
targets with affinities in the picomolar to nanomolar range.
Example 6. SARS-CoV-2 S1 Variants
[0244] VHH-Fc antibodies targeting S1 were titrated 1:3 starting at
200 nM and mixed 1:1 with SARS-COV2-S1 RBD (mouse IgG2Fc tag). The
RBD/VHH-Fc complex was added to Vero E6 cells expressing endogenous
ACE2 receptor and incubated. Cells were subsequently washed and an
anti-mouse secondary was used to measure binding of S1 RBD to ACE2,
thus assessing the inhibition of S1. Over 60 clones demonstrated
potent inhibition. Data is seen in FIGS. 18A-18C and Tables 11 and
12.
TABLE-US-00019 TABLE 11 Sample IC.sub.50 [nM] 2-2 0.56 5-56 0.68
5-1 0.75 5-67 0.76 5-47 0.80 5-8 0.94 5-38 0.96 5-37 1.01 5-34 1.21
5-20 1.23 5-55 1.45 5-46 1.52 5-50 1.61 5-5 1.79 2-5 2.146 5-60
2.15 5-15 2.19 5-29 2.19 Acro Anti S1 3.80 5-49 5.61 5-44 11.73
TABLE-US-00020 TABLE 12 Sample IC.sub.50 [nM] 6-85 0.2044 2-2 0.56
6-63 0.74 6-3 0.74 6-78 0.7427 6-20 0.76 6-91 0.89 6-44 0.97 6-55
0.97 6-73 1.01 6-26 1.07 6-76 1.11 6-45 1.16 6-60 1.31 6-40 1.36
6-81 1.383 6-10 1.44 6-7 1.53 6-39 1.53 6-109 1.60 6-38 1.94 2-5
2.146 6-30 2.94 6-57 3.13 Acro Anti S1 3.49 6-67 3.80 6-77 4.041
6-100 5.07 6-47 5.86 6-41 6.60 6-88 7.118 6-105 7.82 6-34 8.24 6-54
8.90 6-18 12.29 6-1 15.76 6-65 37.47
[0245] Antibody kinetics were measured for variants 2-5, 2-2, and
2-6 (FIG. 19A) and variants 1-12, 1-42, 1-20, and 1-19 (FIG. 19B).
Data is seen in FIGS. 19A-19B. The data shows that the antibodies
bind with nanomolar affinities. FIG. 19C shows percent
neutralization for variants 1-12, 1-42 and 1-20. FIG. 19D shows
percent neutralization for variants 1-12, 1-42 and 1-20 using live
virus.
Example 7. Neutralization of Live Virus
[0246] VHH-Fc antibodies targeting S1 were titrated 1:3 starting at
200 nM and mixed 1:1 with SARS-COV2-S1 RBD (mouse IgG2Fc tag). The
RBD/VHH-Fc complex was added to Vero E6 cells expressing endogenous
ACE2 receptor and incubated. Cells were subsequently washed and an
anti-mouse secondary was used to measure binding of S1 RBD to ACE2,
thus assessing the inhibition of S1. Over 60 clones demonstrated
potent inhibition. The data is seen in FIGS. 20A-20B and Table
13.
TABLE-US-00021 TABLE 13 Antibody EC50 (ug/mL) 6-63 0.06 6-3 0.06
2165mAb* 0.08 5-1 0.10 6-60 0.15 6-55 0.21 5-20 0.27 1-20 0.37 5-34
0.54 6-85 0.84 6-76 1.08 6-73 1.46 1-42 2.03 1-12 2.10 6-26 2.97
6-20 5.03 6-78 8.26 2-6 11.77 2-5 18.31 2-2 67.57 1-63 106.90
[0247] FIG. 20B shows that variant 6-2 showed higher neutralization
versus IgG in live virus. Variants 6-63, 6-3, and 5-1 showed
comparable neutralization versus 2165 mAb derived from a COVID-19
subject. FIGS. 20C-20E and Table 14 show data from VHH single
domain antibodies in VSV-pseudotype SARS-CoV-2 neutralization
assays. Variants 5-1, 6-3, and 6-63 showed improved neutralization
in pseudovirus testing including in live virus FRNT (FIG. 20E).
Variants 6-3, 6-60, 6-63, and 6-76 showed potent neutralization in
live virus PRNT as seen in Table 15 and FIG. 20F. Data as seen in
Table 16 and FIGS. 20G-20H show that variants 6-3, 6-63, and 1-20
exhibited potent neutralization in live virus PRNT.
TABLE-US-00022 TABLE 14 Antibody NC50 (ug/mL) 6-63 0.06 6-3 0.06
5-1 0.10 6-60 0.15 6-55 0.21 5-20 0.27 1-20 0.37 5-34 0.54 6-85
0.84 6-76 1.08 6-73 1.46 1-42 2.03 1-12 2.10 6-26 2.97 6-20 5.03
6-78 8.26 2-6 11.77 2-5 18.31 2-2 67.57 1-63 106.90
TABLE-US-00023 TABLE 15 Antibody PRNT90 (ng/mL) 5-1 15.6 5-20 3.9
5-34 15.6 6-26 62.5 6-60 <0.98 6-63 3.9 6-3 <0.98 6-55 62.5
6-76 3.9 6-78 250 6-20 15.6 6-73 250 6-85 62.5
TABLE-US-00024 TABLE 16 Antibody EC80 (ug/mL) 6-63 0.057861 6-3
0.115234 1-20 0.171875 6-60 0.236816 5-20 0.376 6-76 0.425781 6-55
0.445313 5-34 0.570313 6-42 0.734375 5-1 0.810547 1-12 0.855469
6-85 1.0625 5-38 1.5 5-67 1.566406 1-42 1.78125 6-73 2.015625 6-20
2.3125 5-47 2.457031 1-19 2.78125 6-44 3.15625 6-26 3.609375 6-45
4.015625 5-37 12.4375 6-78 13.75 5-63 14.1875 5-8 15.8125 6-6
24.375 6-13 25.6875 6-24 31.375 1-63 50.5 6-32 60.625 2-6 72.34043
6-22 103.25 5-56 104.75 2-5 106.5 6-82 107.75 5-32 180.1418 6-91
240.5 2-2 354.6099 5-51 387.9433
[0248] The variants were also tested in pseudovirus neutralization
and live virus PRNT studies. Variants 5-20, 6-60, 6-63, and 6-3
showed potent neutralization in live virus PRNT as seen in FIG.
20I.
Example 8. In Vivo Evaluation of Variant Coronavirus
Immunoglobulins
[0249] This Example assesses the variant coronavirus
immunoglobulins in a Syrian hamster model (immunosuppressed) of
COVID-19 disease.
[0250] 8-10 week-old female Syrian hamsters were immunosuppressed
using cyclophosphamide (140 mg/kg day 3 days before challenge and
then 100 mg/kg every 4 days by i.p. route). Eleven groups of six
hamsters per group were injected with antibody on day -1 relative
to challenge by the intraperitoneal route (i.p.). On Day 0 all
hamster were challenged with 1,000 PFU SARS CoV-2 Washington
isolate by the intranasal route and weighed daily. % Weight change
relative to starting weight was calculated. Pharyngeal swabs were
collected on Days -1, 1, 4, 7, 9. Day 9 lungs were collected and
homogenized for viral load. Groups are shown in Table 17.
TABLE-US-00025 TABLE 17 Groups Diluent/volume Group injected i.p.
Convalescent plasma NA/2.5 mL Negative control MAb c7d11 PBS/2.5 mL
6-63 PBS/2.5 mL 6-3 PBS/2.5 mL 6-36 PBS/2.5 mL NA = not
applicable
[0251] Animals injected intraperitonealy (i.p.) with the Negative
Control antibody lost weight starting losing significant amounts of
weight between Days 5 and 6 and continued to decline until the end
of the experiment on Day 9. The maximum mean weight loss of the
group was -11.7%. In contrast, animals injected with positive
control human convalescent plasma maintained weight within -3.2% of
their weight on Day 0 indicating this plasma protected against
disease manifested by weight loss (FIG. 21A).
[0252] Groups of six animals were injected i.p. with 10, 5, or 1
mg/kg of monoclonal antibody 6-63 diluted in PBS. All groups
maintained their weight at or above starting weight indicating the
antibody protected against disease resulting weight loss (FIG.
21B).
[0253] Groups of six animals were injected i.p. with 10, 5, or 1
mg/kg of monoclonal antibody 6-3 diluted in PBS. The 1 and 10 mg/kg
groups maintained their weight at or above starting weight at all
time points. The 5 mg/kg group weight dipped slightly below the
convalescent control on Days 7-9 but clearly was different from the
Negative Control antibody. Together, these data indicate the
antibody decreased weight loss associated with disease (FIG.
21C).
[0254] Groups of six animals were injected i.p. with 10, 5, or 1
mg/kg of monoclonal antibody 6-36 diluted in PBS. The 10 and 5
mg/kg groups maintained their weight at levels similar to the
positive control at all time points. The 1 mg/kg group weight
dropped significantly similar to the Negative Control. These data
indicate antibody 6-36 at 1 mg/kg is insufficient to provide
benefit, but a 5-fold or greater dose is adequate to reduce disease
as determined by weight loss (FIG. 21D).
[0255] FIG. 3421E shows data from the variant antibodies grouped by
dose. FIG. 21F shows graphs of percent weight change for antibodies
6-3, 6-63, and 1-20.
[0256] In wild type hamsters, virus is typically cleared by Day 7.
However, in the cyclophosphamide model, viral levels are not
suppressed unless there is intervention (e.g. protective antibodies
administered) or the cyclophosphamide is discontinued to allow
immune response and clearance. In this experiment the positive
control human convalescent serum eliminated virus from the lungs
from all except one hamster. In contrast, all but one of the
hamsters injected with negative control antibody still had
infectious virus in the lungs. Interestingly, hamsters
prophylactically treated (24 hour previous to exposure) with any of
the three antibodies at the highest dose (10 mg/kg) had infectious
virus in the lungs of at least half the animals assessed 9 days
later. Paradoxically, 6-63 and 6-3 at the lower doses (5 and 1
mg/kg) had animals with relatively less infectious virus in the
lungs. 4 of 6 animals injected with 1-20 at 5 mg/kg dose animals
had no detectable virus in the lungs. When the doses of that
antibody was reduced to 1 mg/kg, all but one animal had infectious
virus. Data is seen in FIGS. 21G-21H.
[0257] Lung pathology inflammation and edema scores from three
animals were added per group and plotted (FIG. 21I). These were the
same lungs used to score ISH. The convalescent sera positive
control median score was 2 and the negative control was 4. The only
groups with a median score lower than the negative control group
were 1 and 5 mg/kg 6-63, 10 and 5 mg/kg 6-3, and 5 mg/kg 1-20. The
highest median pathology scores were the 1 and 10 mg/kg 1-20
groups. The lowest median pathology score was the 5 mg/kg 6-63
group.
Example 9. VSV-Pseudotype Neutralization Analysis of Antibodies for
SARS-CoV-2 B.135 (South African Strain)
[0258] Antibodies described herein were tested in a VSV-pseudotype
neutralization assay for SARS-CoV-2 B.135 (South African
strain).
[0259] Briefly, aerial semi-log dilutions of all test antibodies
(TA) and control were prepared and mixed with the VSV-pseudotype
virus in a 1:1 ratio for 1 h at RT followed by incubation over Vero
cells (ATCC.RTM. CCL-81.TM.) seeded at 60,000 cells per well at
37.degree. C. The cells were lysed the following day and luciferase
activity was measured to assess the potency of each TA to block
viral entry into the Vero cells. All samples will be run in
triplicate. Data analysis is conducted using XLFit and Graphpad
Prism. The testing concentrations and plate plan are seen in Table
18A.
TABLE-US-00026 TABLE 18A Testing Concentrations and Plate Plan
Stock Target In plate Samples (mg/mL) conc/dilution concentration 1
6-63 6.39 100 ug/mL 50.00 ug/mL 2 6-3 10.05 100 ug/mL 50.00 ug/mL 3
1-12 2.24 100 ug/mL 50.00 ug/mL 4 mouse 1 1:25 1:50 pAb
[0260] Data is seen in FIGS. 22A-22B. FIG. 22A illustrates positive
control pAb has an NT50 of 1: 14, 993 dilution as expected. FIG.
22B illustrates antibodies 6-63 and 6-3 neutralize VSV-SARS B.135
strain with IC50s of .about.3.07 ug/mL and 0.143 ug/mL,
respectively. Antibody 1-12 failed to neutralize VSV-SARS B.135
strain.
Example 10. VSV-Pseudotype Neutralization Analysis of Antibodies
for SARS-CoV-2 D614G Variant
[0261] Antibodies described herein were tested in a VSV-pseudotype
neutralization assay for SARS-CoV-2 SARS CoV-2 S D614G variant.
[0262] Briefly, serial semi-log dilutions of all test antibodies
(TA) and control were prepared and mixed with the VSV-pseudotype
virus in a 1:1 ratio for 1 h at RT followed by incubation over Vero
cells (ATCC.RTM. CCL-81.TM.) seeded at 60,000 cells per well at
37.degree. C. The cells were lysed the following day and luciferase
activity was measured to assess the potency of each TA to block
viral entry into the Vero cells. All samples will be run in
triplicate. Data analysis is conducted using XLFit and Graphpad
Prism.
[0263] Data is seen in FIGS. 23A-23C. FIG. 23A shows the positive
control.
Example 11. Antibody Cocktails for Treating SARS-CoV-2 in Syrian
Hamsters
[0264] This Example demonstrates pre- and post-exposure efficacy of
antibody cocktails in Syrian hamsters.
[0265] Methods
[0266] In this study the hamsters were transiently immunosuppressed
using cyclophosphamide. As a strategy to de-risk selecting viruses
with neutralization escape mutations a cocktail of a nanobody (nAb)
and a monoclonal antibody (MAb) known to bind different spike
protein epitopes were combined and used. The combined dose was 20
mg/Kg in this proof-of-concept experiment. The cocktail consisted
of 10 mg/Kg of VHH nanobody 6-63 and 10 mg/Kg of monoclonal
antibody 1-20. An equal number of male and female animals were used
in each group.
[0267] Seventy-eight hamsters were used for this experiment
according to Table 18B. On Day 0, animals were exposed via
intranasal (IN) instillation to 1,000 pfu of SARS-CoV-2 virus in 50
.mu.L volume. The volume was distributed between both nares. To
transiently immunosuppress, all animals were treated with
cyclophosphamide starting on Day -3 (140 mg/kg dose) followed by
additional doses (100 mg/kg) on Days 1, 5, and 9.
[0268] On the indicated day post exposure, MAb/nAb cocktail or
c7D11 was administered via the intraperitoneal (IP) route. On Day 0
blood samples were collected from Group I for hematology to confirm
immunosuppression. Group I was also the control for any adverse
effects of cyclophosphamide treatment on the hamsters. Clinical
scores and individual animal weights were recorded daily.
Pharyngeal swabs and other key events were determined. Animals in
Groups A-I were euthanized on day 14 and lungs were collected for
virology and pathology. Group J animals were used for a serial
pathology component of this study. Two animals from Group J (2 male
and 2 female) were euthanized starting on Day 1 and then each day
up to and including Day 6.
TABLE-US-00027 TABLE 18B Experimental design Number of Virus
Hamsters (Pain Exposure.sup.a Group Category) (Day 0) Treatment
Treatment Day A 6 (3 male, 3 SARS Cocktail.sup.b 20 -1 female) (D)
CoV-2 mg/Kg B 6 (3 male, 3 Cocktail.sup.b 20 +1 female) (D) mg/Kg C
6 (3 male, 3 Cocktail.sup.b 20 +2 female) (D) mg/Kg D 6 (3 male, 3
Cocktail.sup.b 20 +3 female) (D) mg/Kg E 6 (3 male, 3
Cocktail.sup.b 20 +4 female) (D) mg/Kg F 6 (3 male, 3
Cocktail.sup.b 20 +5 female) (D) mg/Kg G 6 (3 male, 3
Cocktail.sup.b 20 +6 female) (E) mg/Kg H 6 (3 male, 3 Neg IgG +1
female) (E) control I 6 (3 male, 3 No virus none Cyclophosphamide
female)(C) control J 24 (12 male, 12 SARS none No treatment-
female) (E) CoV-2 pathology control.sup.d 78 Syrian hamsters
.sup.achallenge with 1,000 pfu of virus in 50 microliter volume
.sup.bcocktail = 6-63 combined with 1-20 1:1 w/v delivered 2.5 mL
per animal by i.p. route .sup.c negative control 20 mg/kg .sup.dTwo
animals (2 male and 2 female) from Group J were euthanized for
pathology/virology on Days 1, 2, 3, 4, 5, 6
[0269] Results
[0270] Cyclophosphamide treatment in uninfected animals does not
result in weight loss. Control animals (CYP Controls, Group I),
that were treated with CYP but not challenged gained weight
overtime.
[0271] Negative control antibody c7D11 at 20 mg/kg, Group H, does
not protect against disease associated weight loss. Hamsters in
Group H lost weight starting on Day 6 (FIG. 24A). Weight loss
continued until Day 10 when it leveled off Animals were still below
10% of their starting weight on the last day of the experiment (Day
14).
[0272] The cocktail administered one day prior to exposure
protected against weight loss. Hamsters in Group A maintained their
weight and stayed within 1% of starting weight (FIG. 24A). This
confirmed that treatment with neutralizing antibodies before
exposure was sufficient to protect against significant weight
loss.
[0273] Post-exposure treatment of CYP hamster model of COVID19
produces variable weight loss effects/patterns. A onetime treatment
of a cocktail containing 1-20 and 6-63 at final dose of 20 mg/Kg
was administered on Days 1 (B), 2 (C), 3 (D), 4 (E), 5 (F), and 6
(G). The percent weight change relative to Day 0 are shown in FIG.
24A. Arrows and dotted vertical lines indicate the day of treatment
specific for the treatment regimen being compared. The same data is
shown collectively in FIG. 24B. Note that there were two animals in
Group B (Day 1) that dropped weight atypically during the
experiment and one animal succumbed on Day 12. That animal had a
necrotic/hemorrhaging testicle due to an apparent torsion event and
was excluded from analysis. No assignable cause was identified for
the second animal so that animal was not excluded from analysis.
Statistical analysis was performed to compare both the CYP Control
(Group I) and the negative control antibody (c7d11, Group H) to all
other groups. The significance between groups at individual
timepoints and differences in area under the curve (AOC) were
determined. Treatment with the cocktail one day after exposure
(Group B) results were confounded by the outlier animal There was
not a significant differences in AOC between Group B and Group H
suggesting no protection; however, there was also no significant
difference in the AOC between Group A and Group I indicating Group
B weight loss was not significantly different from the CYP control
group that was not exposed. Treatment with the cocktail two days
after exposure (Group C) clearly protected. There was significant
differences in AOC between Group C and Group H; and no significant
difference in the AOC between Group C and Group I. Treatment after
three days (Day 3 Group D) did not result in a significant
difference in AOC between Group D and H. However, treatment on day
4 or 5 after exposure (Groups E and F, respectively) did
significant reduce the AOC relative to Group H. Treatment on day 6
(Group G) was similar to treatment on day 3 where no significant
difference in AOR between Group G and H. Although there was no
significance in the AOC for the Day 6 treatment group, the last
three timepoints weight loss was significantly less than the
negative control group. Interestingly, groups administered antibody
on Days 3, 4, 5, or 6 started to gain weight starting on Day 9
whereas the negative control antibody treated animals did not. This
suggests that there was a benefit of all cocktail treatment even at
as late as 6 days post-exposure.
[0274] Infectious virus in lungs (Day 14/15). In wild type
hamsters, virus is typically cleared by Day 7. However, in the
cyclophosphamide model virus is not suppressed unless there is
intervention (e.g. protective antibodies administered) or the
cyclophosphamide is discontinued to allow immune response and
clearance. Here, our controls demonstrate that unexposed hamsters
were negative for virus (Cyp Cont), whereas all hamsters exposed to
virus and treated with an off-target monoclonal antibody (Neg Cont)
had more than 10,000 pfu of virus per gram of lung tissue. Most of
the hamsters treated with the Cocktail one day prior or one day
post virus exposure had detectable levels of virus in lung samples
collected on Day 14 (Groups A and B). However, almost all of the
hamsters treated with antibody .gtoreq.2 day after exposure had
undetectable levels of antibody in their lungs. There was only a
single animal exception in the Day 2, 3, 4 and 6 treated groups.
All of the hamsters treated on Day 5 had lungs that were free of
infectious virus. See FIG. 24C.
[0275] Sequential Sampling. Hamsters immunosuppressed and exposed
to virus on Day 0 were sampled overtime to monitor the infection.
Infectious virus was detected in the lungs of 3 of 4 hamsters on
Day 1. Levels of infectious virus then increased more than 4 logs
by Day 2. Levels of virus then leveled off and stayed between 7-9
log 10 through the last sampling timepoint (Day 6) analyzed
to-date. Thus, animals administered the cocktail after Day 1 likely
had very high levels of infectious virus present in their lungs
before treatment with the antibody. See FIG. 24D.
CONCLUSION
[0276] The data demonstrates that when administered at or before
Day 2 relative to virus exposure, the combination of antibody and
nanobody at 20 mg/kg was sufficient to provide convincing benefit
as determined by the disease parameters analyzed. When treated
after Day 2, animals still developed weight loss but recovered in
approximately 4 days. Two weeks after virus exposure, more
infectious virus was detected in the lungs of hamsters receiving
antibody early (Day -1 or 1) than day 2 or later. Day 2 (or later)
treatment of exposed animals occurred at a time when viral burden
in the lungs was already remarkably high. CYP, by itself, does not
induce weight loss or clinical signs of disease.
Example 12. Immunity Conferred by SARS-CoV-2 and ACE2
Antibodies
[0277] Antibodies described in Examples 4-6 are used to confer
immunity in a subject. A subject is passively immunized with a
SARS-CoV-2 or ACE2 antibody. The subject is then exposed to
SARS-CoV-2 after immunization with the SARS-CoV-2 or ACE2 antibody.
Exposure can be within a few days or within a few months. The
subject can also receive the SARS-CoV-2 or ACE2 antibody
immediately following exposure with SARS-CoV-2. Although the
subject is exposed to SARS-CoV-2, the subject has developed an
immunity against SARS-CoV-2 and infection is prevented.
Example 13. Sequences
[0278] Tables 19-25 show exemplary sequences for CDRH1-H3 and
CDRL1-L3 as well as variant heavy chains and variant light chains
for the SARS-CoV-2 and ACE2 variants.
TABLE-US-00028 TABLE 19 SARS-CoV-2 S1 Variable Heavy Chain CDRs SEQ
SEQ SEQ Vari- ID ID ID ant NO CDRH1 NO CDRH2 NO CDRH3 1-1 1
FTFSSHAMY 37 SAISGSA 73 CAHDTKDFW GSTYYA SGYCIFDPW 1-2 2 FTFSSQAMS
38 SAISGSG 74 CAKDRRFGE GGTYYA FDPW 1-3 3 FTFSSQAMS 39 SAISGSG 75
CAKDRRFGE GGTYYA FDPW 1-4 4 FTFSSQAMS 40 SAISGSG 76 CAKDRRFGE
GGTYYA FDPW 1-5 5 FTFSSQAMS 41 SAISGSG 77 CAKDRRFGE GGTYYA FDPW 1-6
6 FTFSSQAMS 42 SAISGSG 78 CAKDRRFGE GGTYYA FDPW 1-7 7 FTFSSYDMS 43
SVISGSG 79 CAKGPLV GSTYYA GWYFDLW 1-8 8 FTFSSYDMS 44 SVISGSG 80
CAKGPLV GSTYYA GWYFDLW 1-9 9 FTFSSYDMS 45 SVISGSG 81 CAKGPLV GSTYYA
GWYFDLW 1-10 10 FTFSSYDMS 46 SVISGSG 82 CAKGPLVGW GSTYYA YFDLW 1-11
11 ITFSSYAMS 47 SGISGSG 83 CAKHGSGT GSTYYA IFGVVIAK YYFDYC 1-12 12
ITFSSYAMS 48 SGISGSG 84 CAKHGSGTI GSTYYA FGVVIAKYY FDYW 1-13 13
VTFSSYAMS 49 SAITGSG 85 CAKHGSGT GSTYYA IFGVVIAK YYFDYW 1-14 14
ITFSSYAMS 50 SGISGSG 86 CANHGSGT GSTYYA IFGVVIAK YYFDYW 1-15 15
FTFSSHAMY 51 SAISGSA 87 CARDTKD GSTYYA FWSGYSI FDPW 1-16 16
FTFSSYAMY 52 SAISGSA 88 CARDT GSTYYA NDFW 1-17 17 FTFSSYAMY 53
SAISGSA 89 CARDTND GSTYYA FWSGYSI FDPW 1-18 18 FTFSSYAMY 54 SAISGSA
90 CARDTND GSTYYA FWSGYSI FDPW 1-19 19 FTFTSYAMY 55 SAISGSA 91
CARDTNDF GSTYYA WSGYSIF DPW 1-20 20 FTFSSYAMY 56 SAISGSA 92 CARDTND
GSTYYA FWSGYSI FHPW 1-21 21 FTFSSYTMS 57 SIISGSG 93 CAREGYR GSTYYA
DYLWYFD LW 1-22 22 FTFSSYAMN 58 SIISGSG 94 CAREGYR GSTYYA DYLWYF
DLW 1-23 23 FTFSSYAIS 59 SIISGSG 95 CAREGYR GSTYYA DYLWYFD LW 1-24
24 FTFSSYAMN 60 SIISGSG 96 CAREGYR GSTYYA DYLWYF DLW 1-25 25
FTFSDYAMN 61 SIISGSG 97 CAREGYR GSTYYA DYLWYFDLW 1-26 26 FTFSSYAIS
62 SAISGSG 98 CARGAP YSTYYA DSSGYYFQ GEVYFDYW 1-27 27 FTFSSYAMT 63
SAISGSG 99 CASSSSWQ GGTYYA FDYW 1-28 28 FTFSSYGMS 64 SAISGSG 100
CASSSSWQ GGTYYA FDYW 1-29 29 FTFSSYAMT 65 SAISGSG 101 CASSSSWQ
GGTYYA FDYW 1-30 30 FTFSSYAMT 66 SAISGSG 102 CTRPPYGDY GSTFYA GDYW
1-31 31 FTFSSYAMN 67 SAISGSG 103 CTRPPYGDY GSTFYA GDYW 1-32 32
FTFSSYAMY 68 SAISGSG 104 CTRPPYGD GSTFYA YGDYW 1-33 33 FTFSSYAMI 69
SAISGSG 105 CTRPPYGD GSTFYA YGDYW 1-34 34 FTFSSYAMY 70 SAISSSG 106
CTRPPYG GSTYYA DYGDYW 1-35 35 FTFSNYAMS 71 SDISGSG 107 CVKGTI
GSTYYA PIFGVI RSAFDYW 1-36 36 LTFSSYAMS 72 SDISGSG 108 CVKGTIP
GSTYYA IFGVIRS AFDYW
TABLE-US-00029 TABLE 20 SARS-CoV-2 S1 Variable Light Chain CDRs SEQ
SEQ SEQ ID ID ID Variant NO CDRL1 NO CDRL2 NO CDRL3 1-1 109 TGTSSDI
145 EGTKRPS 181 CCSYAGS GSYNLVS RTYVF 1-2 110 TGTSSGV 146 EGIKRPS
182 CCSYAGS GSYNLVS SSFVVF 1-3 111 TGISSDV 147 EGTKRPS 183 CCSYAGS
GSYNLVS SSFVVF 1-4 112 TGTSSDV 148 EGSQRPS 184 CCSYAGS GTYNLVS SSF
VVF 1-5 113 TGTSSGV 149 EASKRPS 185 CCSYAGS GSYNLVS YTF AVF 1-6 114
TGTSSGV 150 EGIKRPS 186 CCSYAGS GSYNLVS SSFVVF 1-7 115 TGTSSDF 151
EGNKRPS 187 CCSYAGS GSYNLVS STFVVF 1-8 116 TGTSNDV 152 EGSKRPS 188
CCSYAGS GSYNLVS RYVVF 1-9 117 TGTSSDV 153 EGSNRPS 189 CCSYAGS
GDYNLVS SSFVVF 1-10 118 TGTSSNV 154 EGTKRPS 190 CCSYAGS GSYNLVS
SSFVVF 1-11 119 TGTSSDV 155 EGTKRPS 191 CCSYAGS GHYNLVS SSFVVF 1-12
120 TGTSSDV 156 EGTKRPS 192 CCSYAGS GHYNLVS SSFVVF 1-13 121 TGTSSDV
157 EGGKRPS 193 CCSYASS GRYNLVS STLVF 1-14 122 TGTSSDV 158 EGTKRPS
194 CCSYAGS GHYNLVS SSFVVF 1-15 123 TGTSSDI 159 EGTNRPS 195 CCSYAGS
GSYNLVS RTYVF 1-16 124 TGTSSDI 160 EGTKRPS 196 CCSYAGS GSYNLVS
RTYVF 1-17 125 TGTSSDI 161 EGTKRPS 197 CCSYAGS GSYNLVS RTYVF 1-18
126 TGTSSDI 162 EGTKRPS 198 CCSYAGS GSYNLVS RTYVF 1-19 127 TGTSSDI
163 EGTKRPS 199 CCSYAGS GSYNLVS RTYVF 1-20 128 TGTSSDI 164 EGTKRPS
200 CCSYAGS GSYNLVS RTYVF 1-21 129 TGTSSDV 165 EGNKRPS 201 CCSYAGS
GSNNLVS VVF 1-22 130 TGTSTDV 166 EGSQRPS 202 CCSYAGS GSYNLVS STVF
1-23 131 TGTSNDV 167 EGNKRPS 203 CCSYAGS GSYNLVS YTVF 1-24 132
TGTSSDV 168 EGNKRPS 204 CCSYAGG GYYNLVS SVVF 1-25 133 SGTSSDV 169
EASKRPS 205 CCSYAGS GSYNLVS STVF 1-26 134 TGTSSDV 170 EGTKRPS 206
CCSFVRS GGYNLVS SAHVVF 1-27 135 TGTSSYV 171 EGSRRPS 207 CCSYAGS
GHYNLVS YTHYVF 1-28 136 TGTSSGV 172 EGSQRPS 208 CCSYAGS GSYNLVS
STHYVF 1-29 137 TGTSSYV 173 EGSRRPS 209 CCSYAGS GHYNLVS YTHYVF 1-30
138 TGTSRDV 174 EGTKRPS 210 CCSYAGS GSYNLVS RTPVVF 1-31 139 TGTSSDV
175 EGSQRPS 211 CCSYAGS GKYNLVS RTPVVF 1-32 140 TGTSSDV 176 EGNKRPS
212 CCSYAGS GGYNLVS STFPV VF 1-33 141 TGTSSDV 177 EASKRPS 213
CCSYAGS GSYNLLS RTPVVF 1-34 142 TGTSSDV 178 EASKRPS 214 CCSYAGS
GGYNLVS YIPVVF 1-35 143 TGTSSDV 179 EGTKRPS 215 CCSYAGS GSYSLVS
YSYVVF 1-36 144 TGTSSDV 180 EGDKRPS 216 CCSYAGS GSYSLVS YSYVVF
TABLE-US-00030 TABLE 21 SARS-CoV-2 S1 Variable Heavy Chain CDRs SEQ
SEQ SEQ ID ID ID Name NO CDRH1 NO CDRH2 NO CDRH3 1-21 217 FTFSSYTMS
283 SIISGSG 349 CAREGYR GSTYYA DYLWYFD LW 1-22 218 FTFSSYAMN 284
SIISGSG 350 CAREGYR GSTYYA DYLWYFD LW 1-30 219 FTFSSYAMT 285
SAISGSG 351 CTRPPYG GSTFYA DYGDYW 1-35 220 FTFSNYAMS 286 SDISGSG
352 CVKGTIP GSTYYA IFGVIRS AFDYW 1-17 221 FTFSSYAMY 287 SAISGSA 353
CARDTND GSTYYA FWSGYSI FDPW 1-27 222 FTFSSYAMT 288 SAISGSG 354
CASSSSW GGTYYA QFDYW 1-12 223 ITFSSYAMS 289 SGISGSG 355 CAKHGSG
GSTYYA TIFGVVI AKYYFDY W 1-2 224 FTFSSQAMS 290 SAISGSG 356 CAKDRRF
GGTYYA GEFDPW 1-3 225 FTFSSQAMS 291 SAISGSG 357 CAKDRRF GGTYYA
GEFDPW 1-23 226 FTFSSYAIS 292 SIISGSG 358 CAREGYR GSTYYA DYLWYFD LW
1-7 227 FTFSSYDMS 293 SVISGSG 359 CAKGPLV GSTYYA GWYFDLW 1-31 228
FTFSSYAMN 294 SAISGSG 360 CTRPPYG GSTFYA DYGDYW 1-4 229 FTFSSQAMS
295 SAISGSG 361 CAKDRRF GGTYYA GEFDPW 1-8 230 FTFSSYDMS 296 SVISGSG
362 CAKGPLV GSTYYA GWYFDLW 1-9 231 FTFSSYDMS 297 SVISGSG 363
CAKGPLV GSTYYA GWYFDLW 1-32 232 FTFSSYAMY 298 SAISGSG 364 CTRPPYG
GSTFYA DYGDYW 1-33 233 FTFSSYAMI 299 SAISGSG 365 CTRPPYG GSTFYA
DYGDYW 1-24 234 FTFSSYAMN 300 SIISGSG 366 CAREGYR GSTYYA DYLWYFD LW
1-40 235 FTFSSYAMY 301 SAISGSA 367 CARDTND GSTYYA FWSGYSI FDPW 1-5
236 FTFSSQAMS 302 SAISGSG 368 CAKDRRF GGTYYA GEFDPW 1-28 237
FTFSSYGMS 303 SAISGSG 369 CASSSSW GGTYYA QFDYW 1-10 238 FTFSSYDMS
304 SVISGSG 370 CAKGPLV GSTYYA GWYFDLW 1-26 239 FTFSSYAIS 305
SAISGSG 371 CARGAPD YSTYYA SSGYYFQ GEVYFDY W 1-42 240 VTFSSYAMS 306
SAITGSG 372 CAKHGSG GSTYYA TIFGVVI AKYYFDY W 1-13 241 FTFSSHAMS 307
SAISGSA 373 CARDTKD GSTYYA FWSGYCI FDPW 1-14 242 FTFTSYAMS 308
SAISGSG 374 CANDTND GSTYYA FWFGYWI FDPW 1-6 243 FTFSSQAMS 309
TAISGSG 375 CAKDTIF GGTYYA GEFYPW 1-20 244 ITFSSYAMS 310 SGISGSG
376 CANHGSG GSTYYA TIFGVVI AKYYFDY W 1-47 245 FTFSSQAMS 311 SAISGSG
377 CAKDRRF GGTYYA GEFDPW 1-29 246 FTFSSYAMY 312 SAISGSA 378
CARDTND GSTYYA FWSGYSI FDPW 1-1 247 FTFSSHAMY 313 SAISGSA 379
CARDTKD GSTYYA FWSGYSI FDPW 1-19 248 ITFSSYAMS 314 SGISGSG 380
CAKHGSG GSTYYA TIFGVVI AKYYFDY C 1-16 249 LTFSSYAMS 315 SDISGSG 381
CVKGTIP GSTYYA IFGVIRS AFDYW 1-34 250 FTFSSYAMT 316 SAISGSG 382
CASSSSW GGTYYA QFDYW 1-48 251 FTFSSHAMY 317 SAISGSA 383 CAHDTKD
GSTYYA FWSGYCI FDPW 1-49 252 FTFSSYAMY 318 SAISGSA 384 CARDTND
GSTYYA FW 1-18 253 FTFSSHAMS 319 SAISGSA 385 CAHDTKD GSTYYA FWSGYCI
FDPW 1-11 254 FTFSSYDMS 320 SAISGSG 386 CARGPLD GTTYYA FW 1-25 255
FTFTSYAMY 321 SAISGSA 387 CARDTND GSTYYA FWSGYSI FDPW 1-36 256
FTFSDYAMN 322 SIISGSG 388 CAREGYR GSTYYA DYLWYFD LW 1-15 257
ITFSSHAMS 323 SGISGSG 389 CAKHGSG GSTYYA TIFGVVI AKYYFDY W 1-51 258
FTFSSYAMS 324 SVISGSG 390 CAREGYR GSTYYA DYLWYFD LW 1-52 259
FTFSNYAMS 325 SAISGSA 391 CARVRQG GSTYYA LRRTWYY FDYW 1-53 260
FTFSSYTMS 326 SVISGSG 392 CAREGYR GSTYYA DYLWYFD LW 1-54 261
FTFSSYAMY 327 SAISGSA 393 CARDTND GSTYYA FWSGYSI FDPW 1-55 262
FTFSSYAMA 328 SAISGSG 394 CASSSSW SSTYYA QFDYW 1-56 263 FTFSSYAMY
329 SAISGSA 395 CARDTND GSTYYA FWSGYSI FDPW 1-57 264 FTFSSYAMT 330
SAISGSG 396 CTRPPYG GSTFYA DYGDYW 1-58 265 FTFSSYAMG 331 SAISTSG
397 CAKGLWF GSTYYA GGGGFDP W 1-59 266 FTFSSYAMN 332 SVISGSG 398
CAREGYR GSTYYA DYLWYFD LW 1-6 267 FTFSSYAMY 333 SAISSSG 399 CTRPPYG
GSTYYA DYGDYW 1-61 268 FTFSSYAVS 334 SDISGSG 400 CVKGTIP GSTYYA
IFGVIRS AFDYW 1-62 269 FRFSSYAMS 335 SAISGSG 401 CAKDFHG GTTYYA
IAAAGID YW 1-63 270 FMFSSYAMS 336 SAISGSG 402 CAKDGAS GSTYYT
GWPNWHF DLW 1-64 271 FAFSSYAMS 337 SAISGSG 403 CAHSRDS GDTYYA
SSWYVDY W 1-37 272 FTFTSYAMN 338 TAISGSG 404 CTRPPYG GSTFYA DYGDYW
1-38 273 ITFSSYAMS 339 SGISGSG 405 CAKHGSG GSTYYA TIFGVVI AKYYFDY W
1-39 274 FTFSSYAMY 340 TAISGSG 406 CTRPPYG GSTFYA YYGDYW 1-41 275
FTFSSYDMS 341 SVISGSG 407 CAKGPLV GSTYYA GWYFDLW 1-43 276 FTFSSQAMS
342 TAISGSG 408 CAKDTIF GGTYYA GEFYPW 1-44 277 FTFSSQAMS 343
TAISGSG 409 CAKDRKF GGTYYA GEFDPW 1-45 278 FTFSSYAMS 344 SIISGSA
410 CARDGYK GSTYYA YCLW 1-46 279 FTFTSYAMS 345 SAISGSG 411 CANDTSD
GSTYYA FCFGYWI FDPW 1-50 280 FTFSSYDMS 346 SAISGSG 412 CARGPLD
GTTYYA FW 1-65 281 FTFSSHAMS 347 SAISGSA 413 CARDTKD GSTYYA FWSGYCI
FDPW 1-66 282 FTFTSYAMS 348 SAISGSG 414 CANDTND GSTYYA FWFGYWI
FDPW
TABLE-US-00031 TABLE 22 SARS-CoV-2 S1 Variable Light Chain CDRs SEQ
SEQ SEQ NO NO NO Name ID CDRL1 ID CDRL2 ID CDRL3 1-21 415
TGTSSDVGSNNLVS 474 EGNKRPS 533 CCSYAGSVVF 1-22 416 TGTSTDVGSYNLVS
475 EGSQRPS 534 CCSYAGSSTVF 1-30 417 TGTSRDVGSYNLVS 476 EGTKRPS 535
CCSYAGSRTPVVF 1-35 418 TGTSSDVGSYSLVS 477 EGTKRPS 536 CCSYAGSYSYVVF
1-17 419 TGTSSDIGSYNLVS 478 EGTKRPS 537 CCSYAGSRTYVF 1-27 420
TGTSSYVGHYNLVS 479 EGSRRPS 538 CCSYAGSYTHYVF 1-12 421
TGTSSDVGHYNLVS 480 EGTKRPS 539 CCSYAGSSSFVVF 1-2 422 TGTSSGVGSYNLVS
481 EGIKRPS 540 CCSYAGSSSFVVF 1-3 423 TGISSDVGSYNLVS 482 EGTKRPS
541 CCSYAGSSSFVVF 1-23 424 TGTSNDVGSYNLVS 483 EGNKRPS 542
CCSYAGSYTVF 1-7 425 TGTSSDFGSYNLVS 484 EGNKRPS 543 CCSYAGSSTFVVF
1-31 426 TGTSSDVGKYNLVS 485 EGSQRPS 544 CCSYAGSRTPVVF 1-4 427
TGTSSDVGTYNLVS 486 EGSQRPS 545 CCSYAGSSSFVVF 1-8 428 TGTSNDVGSYNLVS
487 EGSKRPS 546 CCSYAGSRYVVF 1-9 429 TGTSSDVGDYNLVS 488 EGSNRPS 547
CCSYAGSSSFVVF 1-32 430 TGTSSDVGGYNLVS 489 EGNKRPS 548 CCSYAGSST
FPVVF 1-33 431 TGTSSDVGSYNLLS 490 EASKRPS 549 CCSYAGSRTPVVF 1-24
432 TGTSSDVGYYNLVS 491 EGNKRPS 550 CCSYAGGSVVF 1-5 433
TGTSSGVGSYNLVS 492 EASKRPS 551 CCSYAGSYTFAVF 1-28 434
TGTSSGVGSYNLVS 493 EGSQRPS 552 CCSYAGSSTHYVF 1-10 435
TGTSSNVGSYNLVS 494 EGTKRPS 553 CCSYAGSSSFVVF 1-26 436
TGTSSDVGGYNLVS 495 EGTKRPS 554 CCSFVRSSAHVVF 1-42 437
TGTSSDVGRYNLVS 496 EGGKRPS 555 CCSYASSSTLVF 1-20 438 TGTSSDVGHYNLVS
497 EGTKRPS 556 CCSYAGSSSFVVF 1-47 439 TGTSSGVGSYNLVS 498 EGIKRPS
557 CCSYAGSSSFVVF 1-29 440 TGTSSDIGSYNLVS 499 EGTKRPS 558
CCSYAGSRTYVF 1-1 441 TGTSSDIGSYNLVS 500 EGTNRPS 559 CCSYAGSRTYVF
1-19 442 TGTSSDVGHYNLVS 501 EGTKRPS 560 CCSYAGSSSFVVF 1-16 443
TGTSSDVGSYSLVS 502 EGDKRPS 561 CCSYAGSYSYVVF 1-34 444
TGTSSYVGHYNLVS 503 EGSRRPS 562 CCSYAGSYTHYVF 1-48 445
TGTSSDIGSYNLVS 504 EGTKRPS 563 CCSYAGSRTYVF 1-49 446 TGTSSDIGSYNLVS
505 EGTKRPS 564 CCSYAGSRTYVF 1-25 447 TGTSSDIGSYNLVS 506 EGTKRPS
565 CCSYAGSRTYVF 1-36 448 SGTSSDVGSYNLVS 507 EASKRPS 566
CCSYAGSSTVF 1-51 449 TGTSSDVGSYDLVS 508 EGNKRPS 567 CCSYAGSSVVF
1-52 450 TGTSSDVGSSNLVS 509 EGSKRPS 568 CCSYAGSLYVF 1-53 451
TGTSTDVGSYNLVS 510 EGTKRPS 569 CCSYAGSYTSVVF 1-54 452
TGTSSDIGSYNLVS 511 EGTKRPS 570 CCYHSRTRTHVF 1-55 453 TGTSSDLGSYNIVS
512 EGSRRPS 571 CCSYAGSYTHYVF 1-56 454 TGTSSDIGSYNLVS 513 EGTKRPS
572 CCYHSRTRTHVS 1-57 455 TGTSSDVGKYNLVS 514 EGVKRPS 573
CCSYAGSRTPVVF 1-58 456 TGTRSDVGSYNLVS 515 EVSKRPS 574 CCSYAGDSFPYVF
1-59 457 TGTSSDVGSFNLVS 516 EVSKRPS 575 CCSYAGSSVVF 1-6 458
TGTSSDVGGYNLVS 517 EASKRPS 576 CCSYAGSYIPVVF 1-61 459
TGTSSDVGSYSLVS 518 EGGKRPS 577 CCSYAGSYSYVVF 1-62 460
TGTSSDVGSHNLVS 519 EGGKRPS 578 CCSYSGRYTYVF 1-63 461 TGTSSDVGSYYLVS
520 EGDKRPS 579 CCSHAGRYPYVF 1-64 462 TGTSSGVGSYNLVS 521 AGSKRPS
580 CCSYLGSGTF DVLF 1-37 463 TGTSSDIGSYNLVS 522 EGTKRPS 581
CCSYAGSRTYVF 1-38 464 TGTSSDIGSYNLVS 523 EGTKRPS 582 CCSYAGSRTYVF
1-39 465 TGTSSDIGSYNLVS 524 EGTKRPS 583 CCSYAGSRTYVF 1-41 466
TGTSSDIGSYNLVS 525 EGTKRPS 584 CCSYAGSRTYVF 1-43 467 TGTSSDIGSYNLVS
526 EGTKRPS 585 CCSYAGSRTYVF 1-44 468 TGTSSDIGSYNLVS 527 EGTKRPS
586 CCSYAGSRTYVF 1-45 469 TGTSSDIGSYNLVS 528 EGTKRPS 587
CCSYAGSRTYVF 1-46 470 TGTSSDIGSYNLVS 529 EGTKRPS 588 CCSYAGSRTYVF
1-50 471 TGTSSDIGSYNLVS 530 EGTKRPS 589 CCSYAGSRTYVF 1-65 472
TGTSSDIGSYNLVS 531 EGTKRPS 590 CCSYAGSRTYVF 1-66 473 TGTSSDIGSYNLVS
532 EGTKRPS 591 CCSYAGSRTYVF
TABLE-US-00032 TABLE 23 SARS-CoV-2 S1 Variant Sequences Variable
Heavy Chain Name SEQ ID Amino Acid Sequence 1-21 592
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYTMSWVRQAPGKGLEWVSI
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAREG
YRDYLWYFDLWGQGTLVTVSS 1-22 593 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-30 594
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMTWVRQAPGKGLEWVSA
ISGSGGSTFYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-35 595 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSNYAMSWVRQAPGKGLEWVSD ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCVKGT IPIFGVIRSAFDYWGQGTLVTVSS 1-17 596
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-27 597 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMTWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCASSS SWQFDYWGQGTLVTVSS 1-12 598
EVQLLESGGGLVQPGGSLRLSCAAS GITFSSYAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-2 599 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSQAMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDR RFGEFDPWGQGTLVTVSS 1-3 600
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-23 601 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAISWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-7 602
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-31 603 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-4 604
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-8 605 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYDMSWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKGP LVGWYFDLWGQGTLVTVSS 1-9 606
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-32 607 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVSA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-33 608
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMIWVRQAPGKGLEWVSA
ISGSGGSTFYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-24 609 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-40 610
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-5 611 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSQAMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDR RFGEFDPWGQGTLVTVSS 1-28 612
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYGMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCASSS
SWQFDYWGQGTLVTVSS 1-10 613 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYDMSWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKGP LVGWYFDLWGQGTLVTVSS 1-26 614
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAISWVRQAPGKGLEWVSA
ISGSGYSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARGA
PDSSGYYFQGEVYFDYWGQGTLVTV SS 1-42 615 EVQLLESGGGLVQPGGSLRLSCAAS
GVTFSSYAMSWVRQAPGKGLEWVSA ITGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKHG SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-13 616
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSHAMSWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
KDFWSGYCIFDPWGQGTLVTVSS 1-14 617 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFTSYAMSWVRQAPGKGLEWVSA ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCANDT NDFWFGYWIFDPWGQGTLVTVSS 1-6 618
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVTA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDT
IFGEFYPWGQGTLVTVSS 1-20 619 EVQLLESGGGLVQPGGSLRLSCAAS
GITFSSYAMSWVRQAPGKGLEWVSG ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCANHG SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-47 620
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-29 621 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDT NDFWSGYSIFDPWGQGTLVTVSS 1-1 622
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSHAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
KDFWSGYSIFDPWGQGTLVTVSS 1-19 623 EVQLLESGGGLVQPGGSLRLSCAAS
GITFSSYAMSWVRQAPGKGLEWVSG ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKHG SGTIFGVVIAKYYFDYCGQGTLVTV SS 1-16 624
EVQLLESGGGLVQPGGSLRLSCAAS GLTFSSYAMSWVRQAPGKGLEWVSD
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCVKGT
IPIFGVIRSAFDYWGQGTLVTVSS 1-34 625 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMTWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCASSS SWQFDYWGQGTLVTVSS 1-48 626
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSHAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAHDT
KDFWSGYCIFDPWGQGTLVTVSS 1-49 627 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDT NDFWGQGTLVTVSS 1-18 628
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSHAMSWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAHDT
KDFWSGYCIFDPWGQGTLVTVSS 1-11 629 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYDMSWVRQAPGKGLEWVSA ISGSGGTTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARGP LDFWGQGTLVTVSS 1-25 630
EVQLLESGGGLVQPGGSLRLSCAAS GFTFTSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-36 631 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSDYAMNWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS
1-15 632 EVQLLESGGGLVQPGGSLRLSCAAS GITFSSHAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-51 633 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMSWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-52 634
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSNYAMSWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARVR
QGLRRTWYYFDYWGQGTLVTVSS 1-53 635 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYTMSWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-54 636
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-55 637 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMAWVRQAPGKGLEWVSA ISGSGSSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCASSS SWQFDYWGQGTLVTVSS 1-56 638
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-57 639 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMTWVRQAPGKGLEWVSA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-58 640
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMGWVRQAPGKGLEWVSA
ISTSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGL
WFGGGGFDPWGQGTLVTVSS 1-59 641 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-6 642
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISSSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-61 643 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAVSWVRQAPGKGLEWVSD ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCVKGT IPIFGVIRSAFDYWGQGTLVTVSS 1-62 644
EVQLLESGGGLVQPGGSLRLSCAAS GFRFSSYAMSWVRQAPGKGLEWVSA
ISGSGGTTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDF
HGIAAAGIDYWGQGTLVTVSS 1-63 645 EVQLLESGGGLVQPGGSLRLSCAAS
GFMFSSYAMSWVRQAPGKGLEWVSA ISGSGGSTYYTDSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDG ASGWPNWHFDLWGQGTLVTVSS 1-64 646
EVQLLESGGGLVQPGGSLRLSCAAS GFAFSSYAMSWVRQAPGKGLEWVSA
ISGSGGDTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAHSR
DSSSWYVDYWGQGTLVTVSS 1-37 647 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFTSYAMNWVRQAPGKGLEWVTA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-38 648
EVQLLESGGGLVQPGGSLRLSCAAS GITFSSYAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-39 649 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVTA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGYYGDYWGQGTLVTVSS 1-41 650
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-43 651 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSQAMSWVRQAPGKGLEWVTA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDT IFGEFYPWGQGTLVTVSS 1-44 652
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVTA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
KFGEFDPWGQGTLVTVSS 1-45 653 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMSWVRQAPGKGLEWVSI ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDG YKYCLWGQGTLVTVSS 1-46 654
EVQLLESGGGLVQPGGSLRLSCAAS GFTFTSYAMSWVRQAPGKGLEWVSA
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCANDT
SDFCFGYWIFDPWGQGTLVTVSS 1-50 655 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYDMSWVRQAPGKGLEWVSA ISGSGGTTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARGP LDFWGQGTLVTVSS 1-65 656
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSHAMSWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
KDFWSGYCIFDPWGQGTLVTVSS 1-66 657 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFTSYAMSWVRQAPGKGLEWVSA ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCANDT NDFWFGYWIFDPWGQGTLVTVSS
TABLE-US-00033 TABLE 24 SARS-CoV-2 S1 Variant Sequences Variable
Light Chain Name ID NO SEQ Amino Acid Sequence 1-21 658
QSALTQPASVSGSPGQSITISCTGTSSDVGSNNLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSVVFGGGTKLTVL 1-22 659
QSALTQPASVSGSPGQSITISCTGTSTDVGSYNLVSWYQQHPGKAPKLMIYEGSQR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTVFGGGTKLTVL 1-30 660
QSALTQPASVSGSPGQSITISCTGTSRDVGSYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTPVVFGGGTKLTVL 1-35 661
QSALTQPASVSGSPGQSITISCTGTSSDVGSYSLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYSYVVFGGGTKLTVL 1-17 662
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-27 663
QSALTQPASVSGSPGQSITISCTGTSSYVGHYNLVSWYQQHPGKAPKLMIYEGSRR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-12 664
QSALTQPASVSGSPGQSITISCTGTSSDVGHYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-2 665
QSALTQPASVSGSPGQSITISCTGTSSGVGSYNLVSWYQQHPGKAPKLMIYEGIKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-3 666
QSALTQPASVSGSPGQSITISCTGISSDVGSYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-23 667
QSALTQPASVSGSPGQSITISCTGTSNDVGSYNLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTVFGGGTKLTVL 1-7 668
QSALTQPASVSGSPGQSITISCTGTSSDFGSYNLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTFVVFGGGTKLTVL 1-31 669
QSALTQPASVSGSPGQSITISCTGTSSDVGKYNLVSWYQQHPGKAPKLMIYEGSQR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTPVVFGGGTKLTVL 1-4 670
QSALTQPASVSGSPGQSITISCTGTSSDVGTYNLVSWYQQHPGKAPKLMIYEGSQR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-8 671
QSALTQPASVSGSPGQSITISCTGTSNDVGSYNLVSWYQQHPGKAPKLMIYEGSKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRYVVFGGGTKLTVL 1-9 672
QSALTQPASVSGSPGQSITISCTGTSSDVGDYNLVSWYQQHPGKAPKLMIYEGSNR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-32 673
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTFPVVFGGGTKLTVL 1-33 674
QSALTQPASVSGSPGQSITISCTGTSSDVGSYNLLSWYQQHPGKAPKLMIYEASKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTPVVFGGGTKLTVL 1-24 675
QSALTQPASVSGSPGQSITISCTGTSSDVGYYNLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGGSVVFGGGTKLTVL 1-5 676
QSALTQPASVSGSPGQSITISCTGTSSGVGSYNLVSWYQQHPGKAPKLMIYEASKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTFAVFGGGTKLTVL 1-28 677
QSALTQPASVSGSPGQSITISCTGTSSGVGSYNLVSWYQQHPGKAPKLMIYEGSQR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTHYVFGGGTKLTVL 1-10 678
QSALTQPASVSGSPGQSITISCTGTSSNVGSYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-26 679
QSALTQPASVSGSPGQSITISCTGTSSDVGGYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSFVRSSAHVVFGGGTKLTVL 1-42 680
QSALTQPASVSGSPGQSITISCTGTSSDVGRYNLVSWYQQHPGKAPKLMIYEGGKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYASSSTLVFGGGTKLTVL 1-20 681
QSALTQPASVSGSPGQSITISCTGTSSDVGHYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-47 682
QSALTQPASVSGSPGQSITISCTGTSSGVGSYNLVSWYQQHPGKAPKLMIYEGIKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-29 683
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-1 684
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTNRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-19 685
QSALTQPASVSGSPGQSITISCTGTSSDVGHYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSSFVVFGGGTKLTVL 1-16 686
QSALTQPASVSGSPGQSITISCTGTSSDVGSYSLVSWYQQHPGKAPKLMIYEGDKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYSYVVFGGGTKLTVL 1-34 687
QSALTQPASVSGSPGQSITISCTGTSSYVGHYNLVSWYQQHPGKAPKLMIYEGSRR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-48 688
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-49 689
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-25 690
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-36 691
QSALTQPASVSGSPGQSITISCSGTSSDVGSYNLVSWYQQHPGKAPKLMIYEASKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSTVFGGGTKLTVL 1-51 692
QSALTQPASVSGSPGQSITISCTGTSSDVGSYDLVSWYQQHPGKAPKLMIYEGNKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSSVVFGGGTKLTVL 1-52 693
QSALTQPASVSGSPGQSITISCTGTSSDVGSSNLVSWYQQHPGKAPKLMIYEGSKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSLYVFGGGTKLTVL 1-53 694
QSALTQPASVSGSPGQSITISCTGTSTDVGSYNLVSWYQQHPGKAPKLMIYEGTKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTSVVFGGGTKLTVL 1-54 695
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCYHSRTRTHVFGGGTKLTVL 1-55 696
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-56 697
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-57 698
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-58 699
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-59 700
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-6 701
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-61 702
QSALTQPASVSGSPGQSITISCTGTSSDLGSYNIVSWYQQHPGKAPKLMIYEGSRRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSYTHYVFGGGTKLTVL 1-62 703
QSALTQPASVSGSPGQSITISCTGTSSDVGSHNLVSWYQQHPGKAPKLMIYEGGKR
PSGVSNRFSgSKSGNTaslTISGLQAEDEADYYCCSYSGRYTYVFGGGtKLTVL 1-63 704
QSALTQPASVSGSPGQSITISCTGTSSDVGSYYLVSWYQQHPGKAPKLMIYEGDKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSHAGRYPYVFGGGTKLTVL 1-64 705
QSALTQPASVSGSPGQSITISCTGTSSGVGSYNLVSWYQQHPGKAPKLMIYAGSKR
PSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYLGSGTFDVLFGGGTKLTVL 1-37 706
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-38 707
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-39 708
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-41 709
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-43 710
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-44 711
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-45 712
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-46 713
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-50 714
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-65 715
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL 1-66 716
QSALTQPASVSGSPGQSITISCTGTSSDIGSYNLVSWYQQHPGKAPKLMIYEGTKRP
SGVSNRFSGSKSGNTASLTISGLQAEDEADYYCCSYAGSRTYVFGGGTKLTVL
TABLE-US-00034 TABLE 25 Reformatted SARS-CoV-2 S1 Variant Sequences
SEQ ID Amino Acid Name NO Sequence 1-H1 717
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYTMSWVRQAPGKGLEWVSI
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAREG
YRDYLWYFDLWGQGTLVTVSS 1-H2 718 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-H3 719
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMTWVRQAPGKGLEWVSA
ISGSGGSTFYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-H4 720 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSNYAMSWVRQAPGKGLEWVSD ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCVKGT IPIFGVIRSAFDYWGQGTLVTVSS 1-H5 721
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-H6 722 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMTWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCASSS SWQFDYWGQGTLVTVSS 1-H8 723
EVQLLESGGGLVQPGGSLRLSCAAS GITFSSYAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-H9 724 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSQAMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDR RFGEFDPWGQGTLVTVSS 1-H10 725
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-H11 726 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAISWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-H12 727
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-H13 728 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-H14 729
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-H16 730 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYDMSWVRQAPGKGLEWVSV ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKGP LVGWYFDLWGQGTLVTVSS 1-H17 731
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-H18 732 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVSA ISGSGGSTFYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCTRPP YGDYGDYWGQGTLVTVSS 1-H19 733
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMIWVRQAPGKGLEWVSA
ISGSGGSTFYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-H20 734 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMNWVRQAPGKGLEWVSI ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAREG YRDYLWYFDLWGQGTLVTVSS 1-H23 735
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSQAMSWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKDR
RFGEFDPWGQGTLVTVSS 1-H25 736 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYGMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCASSS SWQFDYWGQGTLVTVSS 1-H26 737
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYDMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKGP
LVGWYFDLWGQGTLVTVSS 1-H27 738 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAISWVRQAPGKGLEWVSA ISGSGYSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARGA PDSSGYYFQGEVYFDYWGQGTLVTV SS 1-H28 739
EVQLLESGGGLVQPGGSLRLSCAAS GVTFSSYAMSWVRQAPGKGLEWVSA
ITGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-H31 740 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSYAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDT NDFWSGYSIFHPWGQGTLVTVSS 1-H36 741
EVQLLESGGGLVQPGGSLRLSCAAS GITFSSYAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCANHG
SGTIFGVVIAKYYFDYWGQGTLVTV SS 1-H37 742 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSQAMSWVRQAPGKGLEWVSA ISGSGGGTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAKDR RFGEFDPWGQGTLVTVSS 1-H38 743
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT
NDFWSGYSIFDPWGQGTLVTVSS 1-H39 744 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSHAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDT KDFWSGYSIFDPWGQGTLVTVSS 1-H40 745
EVQLLESGGGLVQPGGSLRLSCAAS GITFSSYAMSWVRQAPGKGLEWVSG
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAKHG
SGTIFGVVIAKYYFDYCGQGTLVTV SS 1-H41 746 EVQLLESGGGLVQPGGSLRLSCAAS
GLTFSSYAMSWVRQAPGKGLEWVSD ISGSGGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCVKGT IPIFGVIRSAFDYWGQGTLVTVSS 1-H42 747
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMTWVRQAPGKGLEWVSA
ISGSGGGTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCASSS
SWQFDYWGQGTLVTVSS 1-H43 748 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSSHAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCAHDT KDFWSGYCIFDPWGQGTLVTVSS 1-H44 749
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISGSAGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCARDT NDFWGQGTLVTVSS
1-H47 750 EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMYWVRQAPGKGLEWVSA
ISSSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCTRPP
YGDYGDYWGQGTLVTVSS 1-H48 751 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFTSYAMYWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARDT NDFWSGYSIFDPWGQGTLVTVSS 1-H49 752
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSDYAMNWVRQAPGKGLEWVSI
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAREG
YRDYLWYFDLWGQGTLVTVSS 1-L1 753 QSALTQPASVSGSPGQSITISCTGT
SSDVGSNNLVSWYQQHPGKAPKLMI YEGNKRPSGVSNRFSGSKSGNTASL
TISGLQAEDEADYYCCSYAGSVVFG GGTKLTVL 1-L2 754
QSALTQPASVSGSPGQSITISCTGT STDVGSYNLVSWYQQHPGKAPKLMI
YEGSQRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSTVF GGGTKLTVL 1-L3
755 QSALTQPASVSGSPGQSITISCTGT SRDVGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTPV VFGGGTKLTVL
1-L4 756 QSALTQPASVSGSPGQSITISCTGT SSDVGSYSLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYSYV
VFGGGTKLTVL 1-L5 757 QSALTQPASVSGSPGQSITISCTGT
SSDIGSYNLVSWYQQHPGKAPKLMI YEGTKRPSGVSNRFSGSKSGNTASL
TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL 1-L6 758
QSALTQPASVSGSPGQSITISCTGT SSYVGHYNLVSWYQQHPGKAPKLMI
YEGSRRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYTHY VFGGGTKLTVL
1-L8 759 QSALTQPASVSGSPGQSITISCTGT SSDVGHYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L9 760 QSALTQPASVSGSPGQSITISCTGT SSGVGSYNLVSWYQQHPGKAPKLMI
YEGIKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L10 761 QSALTQPASVSGSPGQSITISCTGI SSDVGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L11 762 QSALTQPASVSGSPGQSITISCTGT SNDVGSYNLVSWYQQHPGKAPKLMI
YEGNKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYTVF GGGTKLTVL 1-L12
763 QSALTQPASVSGSPGQSITISCTGT SSDFGSYNLVSWYQQHPGKAPKLMI
YEGNKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSTFV VFGGGTKLTVL
1-L13 764 QSALTQPASVSGSPGQSITISCTGT SSDVGKYNLVSWYQQHPGKAPKLMI
YEGSQRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTPV VFGGGTKLTVL
1-L14 765 QSALTQPASVSGSPGQSITISCTGT SSDVGTYNLVSWYQQHPGKAPKLMI
YEGSQRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L16 766 QSALTQPASVSGSPGQSITISCTGT SNDVGSYNLVSWYQQHPGKAPKLMI
YEGSKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRYVV FGGGTKLTVL
1-L17 767 QSALTQPASVSGSPGQSITISCTGT SSDVGDYNLVSWYQQHPGKAPKLMI
YEGSNRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L18 768 QSALTQPASVSGSPGQSITISCTGT SSDVGGYNLVSWYQQHPGKAPKLMI
YEGNKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSTFP VVFGGGTKLTVL
1-L19 769 QSALTQPASVSGSPGQSITISCTGT SSDVGSYNLLSWYQQHPGKAPKLMI
YEASKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTPV VFGGGTKLTVL
1-L20 770 QSALTQPASVSGSPGQSITISCTGT SSDVGYYNLVSWYQQHPGKAPKLMI
YEGNKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGGSVVF GGGTKLTVL 1-L23
771 QSALTQPASVSGSPGQSITISCTGT SSGVGSYNLVSWYQQHPGKAPKLMI
YEASKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYTFA VFGGGTKLTVL
1-L25 772 QSALTQPASVSGSPGQSITISCTGT SSGVGSYNLVSWYQQHPGKAPKLMI
YEGSQRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSTHY VFGGGTKLTVL
1-L26 773 QSALTQPASVSGSPGQSITISCTGT SSNVGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L27 774 QSALTQPASVSGSPGQSITISCTGT SSDVGGYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSFVRSSAHV VFGGGTKLTVL
1-L28 775 QSALTQPASVSGSPGQSITISCTGT SSDVGRYNLVSWYQQHPGKAPKLMI
YEGGKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYASSSTLV FGGGTKLTVL
1-L31 776 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L36 777 QSALTQPASVSGSPGQSITISCTGT SSDVGHYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L37 778 QSALTQPASVSGSPGQSITISCTGT SSGVGSYNLVSWYQQHPGKAPKLMI
YEGIKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L38 779 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L39 780 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTNRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L40 781 QSALTQPASVSGSPGQSITISCTGT SSDVGHYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSSFV VFGGGTKLTVL
1-L41 782 QSALTQPASVSGSPGQSITISCTGT SSDVGSYSLVSWYQQHPGKAPKLMI
YEGDKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYSYV VFGGGTKLTVL
1-L42 783 QSALTQPASVSGSPGQSITISCTGT SSYVGHYNLVSWYQQHPGKAPKLMI
YEGSRRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYTHY VFGGGTKLTVL
1-L43 784 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L44 785 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L47 786 QSALTQPASVSGSPGQSITISCTGT SSDVGGYNLVSWYQQHPGKAPKLMI
YEASKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSYIPV VFGGGTKLTVL
1-L48 787 QSALTQPASVSGSPGQSITISCTGT SSDIGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSRTYV FGGGTKLTVL
1-L49 788 QSALTQPASVSGSPGQSITISCSGT SSDVGSYNLVSWYQQHPGKAPKLMI
YEASKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYAGSSTVF GGGTKLTVL 1-H51
789 EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYAMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAREG
YRDYLWYFDLWGQGTLVTVSS 1-H52 790 EVQLLESGGGLVQPGGSLRLSCAAS
GFTFSNYAMSWVRQAPGKGLEWVSA ISGSAGSTYYADSVKGRFTISRDNS
KNTLYLQMNSLRAEDTAVYYCARVR QGLRRTWYYFDYWGQGTLVTVSS 1-H53 791
EVQLLESGGGLVQPGGSLRLSCAAS GFTFSSYTMSWVRQAPGKGLEWVSV
ISGSGGSTYYADSVKGRFTISRDNS KNTLYLQMNSLRAEDTAVYYCAREG
YRDYLWYFDLWGQGTLVTVSS 1-L51 792 QSALTQPASVSGSPGQSITISCTGT
SSDVGSYDLVSWYQQHPGKAPKLMI YEGNKRPSGVSNRFSGSKSGNTASL
TISGLQAEDEADYYCCSYAG- SSVVFGGGTKLTVL 1-L52 793
QSALTQPASVSGSPGQSITISCTGT SSDVGSSNLVSWYQQHPGKAPKLMI
YEGSKRPSGVSNRFSGSKSGNTASL TISGLQAEDEADYYCCSYA- GSLYVFGGGTKLTVL
1-L53 794 QSALTQPASVSGSPGQSITISCTGT STDVGSYNLVSWYQQHPGKAPKLMI
YEGTKRPSGVSNRFSGSKSGNTASL TISGLQAZDEADYYCCSYAGSYTSV VFGGGTKLTVL
[0279] While preferred embodiments of the present disclosure have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
disclosure. It should be understood that various alternatives to
the embodiments of the disclosure described herein may be employed
in practicing the disclosure. It is intended that the following
claims define the scope of the disclosure and that methods and
structures within the scope of these claims and their equivalents
be covered thereby.
Sequence CWU 1
1
79819PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 1Phe Thr Phe Ser Ser His Ala Met Tyr1
529PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 2Phe Thr Phe Ser Ser Gln Ala Met Ser1
539PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 3Phe Thr Phe Ser Ser Gln Ala Met Ser1
549PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 4Phe Thr Phe Ser Ser Gln Ala Met Ser1
559PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 5Phe Thr Phe Ser Ser Gln Ala Met Ser1
569PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 6Phe Thr Phe Ser Ser Gln Ala Met Ser1
579PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 7Phe Thr Phe Ser Ser Tyr Asp Met Ser1
589PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 8Phe Thr Phe Ser Ser Tyr Asp Met Ser1
599PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 9Phe Thr Phe Ser Ser Tyr Asp Met Ser1
5109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 10Phe Thr Phe Ser Ser Tyr Asp Met Ser1
5119PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 11Ile Thr Phe Ser Ser Tyr Ala Met Ser1
5129PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 12Ile Thr Phe Ser Ser Tyr Ala Met Ser1
5139PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 13Val Thr Phe Ser Ser Tyr Ala Met Ser1
5149PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 14Ile Thr Phe Ser Ser Tyr Ala Met Ser1
5159PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 15Phe Thr Phe Ser Ser His Ala Met Tyr1
5169PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 16Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5179PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 17Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5189PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 18Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5199PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 19Phe Thr Phe Thr Ser Tyr Ala Met Tyr1
5209PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 20Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5219PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 21Phe Thr Phe Ser Ser Tyr Thr Met Ser1
5229PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 22Phe Thr Phe Ser Ser Tyr Ala Met Asn1
5239PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 23Phe Thr Phe Ser Ser Tyr Ala Ile Ser1
5249PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 24Phe Thr Phe Ser Ser Tyr Ala Met Asn1
5259PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 25Phe Thr Phe Ser Asp Tyr Ala Met Asn1
5269PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 26Phe Thr Phe Ser Ser Tyr Ala Ile Ser1
5279PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 27Phe Thr Phe Ser Ser Tyr Ala Met Thr1
5289PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 28Phe Thr Phe Ser Ser Tyr Gly Met Ser1
5299PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 29Phe Thr Phe Ser Ser Tyr Ala Met Thr1
5309PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 30Phe Thr Phe Ser Ser Tyr Ala Met Thr1
5319PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 31Phe Thr Phe Ser Ser Tyr Ala Met Asn1
5329PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 32Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5339PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 33Phe Thr Phe Ser Ser Tyr Ala Met Ile1
5349PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 34Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
5359PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 35Phe Thr Phe Ser Asn Tyr Ala Met Ser1
5369PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 36Leu Thr Phe Ser Ser Tyr Ala Met Ser1
53713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 37Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr
Ala1 5 103813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 38Ser Ala Ile Ser Gly Ser Gly Gly Gly
Thr Tyr Tyr Ala1 5 103913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 39Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala1 5 104013PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 40Ser Ala Ile Ser Gly Ser
Gly Gly Gly Thr Tyr Tyr Ala1 5 104113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 41Ser
Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala1 5
104213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 42Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr
Ala1 5 104313PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 43Ser Val Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 104413PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 44Ser Val Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala1 5 104513PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 45Ser Val Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 104613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 46Ser
Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
104713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 47Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr
Ala1 5 104813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 48Ser Gly Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 104913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 49Ser Ala Ile Thr Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala1 5 105013PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 50Ser Gly Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 105113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 51Ser
Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala1 5
105213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 52Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr
Ala1 5 105313PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 53Ser Ala Ile Ser Gly Ser Ala Gly Ser
Thr Tyr Tyr Ala1 5 105413PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 54Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala1 5 105513PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 55Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 105613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 56Ser
Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala1 5
105713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 57Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr
Ala1 5 105813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 58Ser Ile Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 105913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 59Ser Ile Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala1 5 106013PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 60Ser Ile Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 106113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 61Ser
Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
106213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 62Ser Ala Ile Ser Gly Ser Gly Tyr Ser Thr Tyr Tyr
Ala1 5 106313PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 63Ser Ala Ile Ser Gly Ser Gly Gly Gly
Thr Tyr Tyr Ala1 5 106413PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 64Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala1 5 106513PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 65Ser Ala Ile Ser Gly Ser
Gly Gly Gly Thr Tyr Tyr Ala1 5 106613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 66Ser
Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala1 5
106713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 67Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr
Ala1 5 106813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 68Ser Ala Ile Ser Gly Ser Gly Gly Ser
Thr Phe Tyr Ala1 5 106913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 69Ser Ala Ile Ser Gly Ser Gly
Gly Ser Thr Phe Tyr Ala1 5 107013PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 70Ser Ala Ile Ser Ser Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 107113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 71Ser
Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
107213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 72Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr
Ala1 5 107318PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 73Cys Ala His Asp Thr Lys Asp Phe Trp
Ser Gly Tyr Cys Ile Phe Asp1 5 10 15Pro Trp7413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 74Cys
Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro Trp1 5
107513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 75Cys Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro
Trp1 5 107613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 76Cys Ala Lys Asp Arg Arg Phe Gly Glu
Phe Asp Pro Trp1 5 107713PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 77Cys Ala Lys Asp Arg Arg Phe
Gly Glu Phe Asp Pro Trp1 5 107813PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 78Cys Ala Lys Asp Arg Arg
Phe Gly Glu Phe Asp Pro Trp1 5 107914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 79Cys
Ala Lys Gly Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp1 5
108014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 80Cys Ala Lys Gly Pro Leu Val Gly Trp Tyr Phe Asp
Leu Trp1 5 108114PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 81Cys Ala Lys Gly Pro Leu Val Gly Trp
Tyr Phe Asp Leu Trp1 5 108214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 82Cys Ala Lys Gly Pro Leu Val
Gly Trp Tyr Phe Asp Leu Trp1 5 108322PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 83Cys
Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10
15Tyr Tyr Phe Asp Tyr Cys 208422PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 84Cys Ala Lys His Gly Ser
Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr
Trp 208522PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 85Cys Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val
Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr Trp 208622PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 86Cys
Ala Asn His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10
15Tyr Tyr Phe Asp Tyr Trp 208718PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 87Cys Ala Arg Asp Thr Lys
Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10 15Pro
Trp889PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 88Cys Ala Arg Asp Thr Asn Asp Phe Trp1
58918PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 89Cys Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr
Ser Ile Phe Asp1 5 10 15Pro Trp9018PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 90Cys
Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10
15Pro Trp9118PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 91Cys Ala Arg Asp Thr Asn Asp Phe Trp
Ser Gly Tyr Ser Ile Phe Asp1 5 10 15Pro Trp9218PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 92Cys
Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe His1 5 10
15Pro Trp9316PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 93Cys Ala Arg Glu Gly Tyr Arg Asp Tyr
Leu Trp Tyr Phe Asp Leu Trp1 5 10 159416PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 94Cys
Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10
159516PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 95Cys Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr
Phe Asp Leu Trp1 5 10 159616PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 96Cys Ala Arg Glu Gly Tyr Arg
Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10 159716PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 97Cys
Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10
159822PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 98Cys Ala Arg Gly Ala Pro Asp Ser Ser Gly Tyr Tyr
Phe Gln Gly Glu1 5 10 15Val Tyr Phe Asp Tyr Trp 209912PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 99Cys
Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp1 5 1010012PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 100Cys
Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp1 5 1010112PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 101Cys
Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp1 5 1010213PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 102Cys
Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp1 5
1010313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 103Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1010413PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 104Cys Thr Arg Pro Pro Tyr Gly Asp Tyr
Gly Asp Tyr Trp1
5 1010513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 105Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1010613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 106Cys Thr Arg Pro Pro Tyr Gly Asp Tyr
Gly Asp Tyr Trp1 5 1010719PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 107Cys Val Lys Gly Thr Ile
Pro Ile Phe Gly Val Ile Arg Ser Ala Phe1 5 10 15Asp Tyr
Trp10819PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 108Cys Val Lys Gly Thr Ile Pro Ile Phe Gly Val
Ile Arg Ser Ala Phe1 5 10 15Asp Tyr Trp10914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 109Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1011014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 110Thr Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn
Leu Val Ser1 5 1011114PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 111Thr Gly Ile Ser Ser Asp
Val Gly Ser Tyr Asn Leu Val Ser1 5 1011214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 112Thr
Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn Leu Val Ser1 5
1011314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 113Thr Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn
Leu Val Ser1 5 1011414PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 114Thr Gly Thr Ser Ser Gly
Val Gly Ser Tyr Asn Leu Val Ser1 5 1011514PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 115Thr
Gly Thr Ser Ser Asp Phe Gly Ser Tyr Asn Leu Val Ser1 5
1011614PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 116Thr Gly Thr Ser Asn Asp Val Gly Ser Tyr Asn
Leu Val Ser1 5 1011714PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 117Thr Gly Thr Ser Ser Asp
Val Gly Asp Tyr Asn Leu Val Ser1 5 1011814PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 118Thr
Gly Thr Ser Ser Asn Val Gly Ser Tyr Asn Leu Val Ser1 5
1011914PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 119Thr Gly Thr Ser Ser Asp Val Gly His Tyr Asn
Leu Val Ser1 5 1012014PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 120Thr Gly Thr Ser Ser Asp
Val Gly His Tyr Asn Leu Val Ser1 5 1012114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 121Thr
Gly Thr Ser Ser Asp Val Gly Arg Tyr Asn Leu Val Ser1 5
1012214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 122Thr Gly Thr Ser Ser Asp Val Gly His Tyr Asn
Leu Val Ser1 5 1012314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 123Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1012414PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 124Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1012514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 125Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1012614PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 126Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1012714PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 127Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1012814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 128Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1012914PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 129Thr Gly Thr Ser Ser Asp
Val Gly Ser Asn Asn Leu Val Ser1 5 1013014PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 130Thr
Gly Thr Ser Thr Asp Val Gly Ser Tyr Asn Leu Val Ser1 5
1013114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 131Thr Gly Thr Ser Asn Asp Val Gly Ser Tyr Asn
Leu Val Ser1 5 1013214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 132Thr Gly Thr Ser Ser Asp
Val Gly Tyr Tyr Asn Leu Val Ser1 5 1013314PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 133Ser
Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Leu Val Ser1 5
1013414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 134Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn
Leu Val Ser1 5 1013514PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 135Thr Gly Thr Ser Ser Tyr
Val Gly His Tyr Asn Leu Val Ser1 5 1013614PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 136Thr
Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn Leu Val Ser1 5
1013714PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 137Thr Gly Thr Ser Ser Tyr Val Gly His Tyr Asn
Leu Val Ser1 5 1013814PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 138Thr Gly Thr Ser Arg Asp
Val Gly Ser Tyr Asn Leu Val Ser1 5 1013914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 139Thr
Gly Thr Ser Ser Asp Val Gly Lys Tyr Asn Leu Val Ser1 5
1014014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 140Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn
Leu Val Ser1 5 1014114PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 141Thr Gly Thr Ser Ser Asp
Val Gly Ser Tyr Asn Leu Leu Ser1 5 1014214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 142Thr
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Leu Val Ser1 5
1014314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 143Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Ser
Leu Val Ser1 5 1014414PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 144Thr Gly Thr Ser Ser Asp
Val Gly Ser Tyr Ser Leu Val Ser1 5 101457PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 145Glu
Gly Thr Lys Arg Pro Ser1 51467PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 146Glu Gly Ile Lys Arg Pro
Ser1 51477PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 147Glu Gly Thr Lys Arg Pro Ser1
51487PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 148Glu Gly Ser Gln Arg Pro Ser1
51497PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 149Glu Ala Ser Lys Arg Pro Ser1
51507PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 150Glu Gly Ile Lys Arg Pro Ser1
51517PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 151Glu Gly Asn Lys Arg Pro Ser1
51527PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 152Glu Gly Ser Lys Arg Pro Ser1
51537PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 153Glu Gly Ser Asn Arg Pro Ser1
51547PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 154Glu Gly Thr Lys Arg Pro Ser1
51557PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 155Glu Gly Thr Lys Arg Pro Ser1
51567PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 156Glu Gly Thr Lys Arg Pro Ser1
51577PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 157Glu Gly Gly Lys Arg Pro Ser1
51587PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 158Glu Gly Thr Lys Arg Pro Ser1
51597PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 159Glu Gly Thr Asn Arg Pro Ser1
51607PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 160Glu Gly Thr Lys Arg Pro Ser1
51617PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 161Glu Gly Thr Lys Arg Pro Ser1
51627PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 162Glu Gly Thr Lys Arg Pro Ser1
51637PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 163Glu Gly Thr Lys Arg Pro Ser1
51647PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 164Glu Gly Thr Lys Arg Pro Ser1
51657PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 165Glu Gly Asn Lys Arg Pro Ser1
51667PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 166Glu Gly Ser Gln Arg Pro Ser1
51677PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 167Glu Gly Asn Lys Arg Pro Ser1
51687PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 168Glu Gly Asn Lys Arg Pro Ser1
51697PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 169Glu Ala Ser Lys Arg Pro Ser1
51707PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 170Glu Gly Thr Lys Arg Pro Ser1
51717PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 171Glu Gly Ser Arg Arg Pro Ser1
51727PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 172Glu Gly Ser Gln Arg Pro Ser1
51737PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 173Glu Gly Ser Arg Arg Pro Ser1
51747PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 174Glu Gly Thr Lys Arg Pro Ser1
51757PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 175Glu Gly Ser Gln Arg Pro Ser1
51767PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 176Glu Gly Asn Lys Arg Pro Ser1
51777PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 177Glu Ala Ser Lys Arg Pro Ser1
51787PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 178Glu Ala Ser Lys Arg Pro Ser1
51797PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 179Glu Gly Thr Lys Arg Pro Ser1
51807PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 180Glu Gly Asp Lys Arg Pro Ser1
518112PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 181Cys Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val
Phe1 5 1018213PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 182Cys Cys Ser Tyr Ala Gly Ser Ser Ser
Phe Val Val Phe1 5 1018313PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 183Cys Cys Ser Tyr Ala Gly
Ser Ser Ser Phe Val Val Phe1 5 1018413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 184Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1018513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 185Cys Cys Ser Tyr Ala Gly Ser Tyr Thr Phe Ala
Val Phe1 5 1018613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 186Cys Cys Ser Tyr Ala Gly Ser Ser Ser
Phe Val Val Phe1 5 1018713PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 187Cys Cys Ser Tyr Ala Gly
Ser Ser Thr Phe Val Val Phe1 5 1018812PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 188Cys
Cys Ser Tyr Ala Gly Ser Arg Tyr Val Val Phe1 5 1018913PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 189Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1019013PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 190Cys Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val
Val Phe1 5 1019113PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 191Cys Cys Ser Tyr Ala Gly Ser Ser Ser
Phe Val Val Phe1 5 1019213PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 192Cys Cys Ser Tyr Ala Gly
Ser Ser Ser Phe Val Val Phe1 5 1019312PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 193Cys
Cys Ser Tyr Ala Ser Ser Ser Thr Leu Val Phe1 5 1019413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 194Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1019512PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 195Cys Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val
Phe1 5 1019612PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 196Cys Cys Ser Tyr Ala Gly Ser Arg Thr
Tyr Val Phe1 5 1019712PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 197Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1019812PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 198Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1019912PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 199Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1020012PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 200Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1020110PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 201Cys Cys Ser Tyr Ala Gly
Ser Val Val Phe1 5 1020211PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 202Cys Cys Ser Tyr Ala Gly
Ser Ser Thr Val Phe1 5 1020311PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 203Cys Cys Ser Tyr Ala Gly
Ser Tyr Thr Val Phe1 5 1020411PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 204Cys Cys Ser Tyr Ala Gly
Gly Ser Val Val Phe1 5 1020511PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 205Cys Cys Ser Tyr Ala Gly
Ser Ser Thr Val Phe1 5 1020613PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 206Cys Cys Ser Phe Val Arg
Ser Ser Ala His Val Val Phe1 5 1020713PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 207Cys
Cys Ser Tyr Ala Gly Ser Tyr Thr His Tyr Val Phe1 5
1020813PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 208Cys Cys Ser Tyr Ala Gly Ser Ser Thr His Tyr
Val Phe1 5 1020913PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 209Cys Cys Ser Tyr Ala Gly Ser Tyr Thr
His Tyr Val Phe1 5 1021013PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 210Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Pro Val Val Phe1 5 1021113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 211Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Pro Val Val Phe1 5
1021214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptide 212Cys Cys Ser Tyr Ala Gly Ser Ser Thr Phe Pro Val Val Phe1
5 1021313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 213Cys Cys Ser Tyr Ala Gly Ser Arg Thr Pro Val
Val Phe1 5 1021413PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 214Cys Cys Ser Tyr Ala Gly Ser Tyr Ile
Pro Val Val Phe1 5 1021513PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 215Cys Cys Ser Tyr Ala Gly
Ser Tyr Ser Tyr Val Val Phe1 5 1021613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 216Cys
Cys Ser Tyr Ala Gly Ser Tyr Ser Tyr Val Val Phe1 5
102179PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 217Phe Thr Phe Ser Ser Tyr Thr Met Ser1
52189PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 218Phe Thr Phe Ser Ser Tyr Ala Met Asn1
52199PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 219Phe Thr Phe Ser Ser Tyr Ala Met Thr1
52209PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 220Phe Thr Phe Ser Asn Tyr Ala Met Ser1
52219PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 221Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52229PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 222Phe Thr Phe Ser Ser Tyr Ala Met Thr1
52239PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 223Ile Thr Phe Ser Ser Tyr Ala Met Ser1
52249PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 224Phe Thr Phe Ser Ser Gln Ala Met Ser1
52259PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 225Phe Thr Phe Ser Ser Gln Ala Met Ser1
52269PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 226Phe Thr Phe Ser Ser Tyr Ala Ile Ser1
52279PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 227Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52289PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 228Phe Thr Phe Ser Ser Tyr Ala Met Asn1
52299PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 229Phe Thr Phe Ser Ser Gln Ala Met Ser1
52309PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 230Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52319PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 231Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52329PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 232Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52339PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 233Phe Thr Phe Ser Ser Tyr Ala Met Ile1
52349PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 234Phe Thr Phe Ser Ser Tyr Ala Met Asn1
52359PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 235Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52369PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 236Phe Thr Phe Ser Ser Gln Ala Met Ser1
52379PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 237Phe Thr Phe Ser Ser Tyr Gly Met Ser1
52389PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 238Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52399PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 239Phe Thr Phe Ser Ser Tyr Ala Ile Ser1
52409PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 240Val Thr Phe Ser Ser Tyr Ala Met Ser1
52419PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 241Phe Thr Phe Ser Ser His Ala Met Ser1
52429PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 242Phe Thr Phe Thr Ser Tyr Ala Met Ser1
52439PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 243Phe Thr Phe Ser Ser Gln Ala Met Ser1
52449PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 244Ile Thr Phe Ser Ser Tyr Ala Met Ser1
52459PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 245Phe Thr Phe Ser Ser Gln Ala Met Ser1
52469PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 246Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52479PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 247Phe Thr Phe Ser Ser His Ala Met Tyr1
52489PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 248Ile Thr Phe Ser Ser Tyr Ala Met Ser1
52499PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 249Leu Thr Phe Ser Ser Tyr Ala Met Ser1
52509PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 250Phe Thr Phe Ser Ser Tyr Ala Met Thr1
52519PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 251Phe Thr Phe Ser Ser His Ala Met Tyr1
52529PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 252Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52539PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 253Phe Thr Phe Ser Ser His Ala Met Ser1
52549PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 254Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52559PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 255Phe Thr Phe Thr Ser Tyr Ala Met Tyr1
52569PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 256Phe Thr Phe Ser Asp Tyr Ala Met Asn1
52579PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 257Ile Thr Phe Ser Ser His Ala Met Ser1
52589PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 258Phe Thr Phe Ser Ser Tyr Ala Met Ser1
52599PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 259Phe Thr Phe Ser Asn Tyr Ala Met Ser1
52609PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 260Phe Thr Phe Ser Ser Tyr Thr Met Ser1
52619PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 261Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52629PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 262Phe Thr Phe Ser Ser Tyr Ala Met Ala1
52639PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 263Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52649PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 264Phe Thr Phe Ser Ser Tyr Ala Met Thr1
52659PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 265Phe Thr Phe Ser Ser Tyr Ala Met Gly1
52669PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 266Phe Thr Phe Ser Ser Tyr Ala Met Asn1
52679PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 267Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52689PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 268Phe Thr Phe Ser Ser Tyr Ala Val Ser1
52699PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 269Phe Arg Phe Ser Ser Tyr Ala Met Ser1
52709PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 270Phe Met Phe Ser Ser Tyr Ala Met Ser1
52719PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 271Phe Ala Phe Ser Ser Tyr Ala Met Ser1
52729PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 272Phe Thr Phe Thr Ser Tyr Ala Met Asn1
52739PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 273Ile Thr Phe Ser Ser Tyr Ala Met Ser1
52749PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 274Phe Thr Phe Ser Ser Tyr Ala Met Tyr1
52759PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 275Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52769PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 276Phe Thr Phe Ser Ser Gln Ala Met Ser1
52779PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 277Phe Thr Phe Ser Ser Gln Ala Met Ser1
52789PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 278Phe Thr Phe Ser Ser Tyr Ala Met Ser1
52799PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 279Phe Thr Phe Thr Ser Tyr Ala Met Ser1
52809PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 280Phe Thr Phe Ser Ser Tyr Asp Met Ser1
52819PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 281Phe Thr Phe Ser Ser His Ala Met Ser1
52829PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 282Phe Thr Phe Thr Ser Tyr Ala Met Ser1
528313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 283Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala1 5 1028413PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 284Ser Ile Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1028513PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 285Ser Ala Ile Ser Gly Ser
Gly Gly Ser Thr Phe Tyr Ala1 5 1028613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 286Ser
Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1028713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 287Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr
Tyr Ala1 5 1028813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 288Ser Ala Ile Ser Gly Ser Gly Gly Gly
Thr Tyr Tyr Ala1 5 1028913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 289Ser Gly Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 1029013PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 290Ser
Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala1 5
1029113PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 291Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
Tyr Ala1 5 1029213PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 292Ser Ile Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1029313PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 293Ser Val Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 1029413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 294Ser
Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala1 5
1029513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 295Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
Tyr Ala1 5 1029613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 296Ser Val Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1029713PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 297Ser Val Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 1029813PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 298Ser
Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala1 5
1029913PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 299Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe
Tyr Ala1 5 1030013PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 300Ser Ile Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1030113PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 301Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 1030213PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 302Ser
Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala1 5
1030313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 303Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
Tyr Ala1 5 1030413PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 304Ser Val Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1030513PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 305Ser Ala Ile Ser Gly Ser
Gly Tyr Ser Thr Tyr Tyr Ala1 5 1030613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 306Ser
Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1030713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 307Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr
Tyr Ala1 5 1030813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 308Ser Ala Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1030913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 309Thr Ala Ile Ser Gly Ser
Gly Gly Gly Thr Tyr Tyr Ala1 5 1031013PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 310Ser
Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1031113PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 311Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
Tyr Ala1 5 1031213PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 312Ser Ala Ile Ser Gly Ser Ala Gly Ser
Thr Tyr Tyr Ala1 5 1031313PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 313Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 1031413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 314Ser
Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1031513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 315Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala1 5 1031613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 316Ser Ala Ile Ser Gly Ser Gly Gly Gly
Thr Tyr Tyr Ala1 5 1031713PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 317Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 1031813PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 318Ser
Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala1 5
1031913PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 319Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr
Tyr Ala1 5 1032013PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 320Ser Ala Ile Ser Gly Ser Gly Gly Thr
Thr Tyr Tyr Ala1 5 1032113PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 321Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 1032213PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 322Ser
Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1032313PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 323Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala1 5 1032413PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 324Ser Val Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1032513PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 325Ser Ala Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5
1032613PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 326Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala1 5 1032713PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 327Ser Ala Ile Ser Gly Ser Ala Gly Ser
Thr Tyr Tyr Ala1 5 1032813PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 328Ser Ala Ile Ser Gly Ser
Gly Ser Ser Thr Tyr Tyr Ala1 5 1032913PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 329Ser
Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala1 5
1033013PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 330Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe
Tyr Ala1 5 1033113PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 331Ser Ala Ile Ser Thr Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1033213PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 332Ser Val Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 1033313PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 333Ser
Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1033413PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 334Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala1 5 1033513PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 335Ser Ala Ile Ser Gly Ser Gly Gly Thr
Thr Tyr Tyr Ala1 5 1033613PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 336Ser Ala Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Thr1 5 1033713PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 337Ser
Ala Ile Ser Gly Ser Gly Gly Asp Thr Tyr Tyr Ala1 5
1033813PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 338Thr Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe
Tyr Ala1 5 1033913PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 339Ser Gly Ile Ser Gly Ser Gly Gly Ser
Thr Tyr Tyr Ala1 5 1034013PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 340Thr Ala Ile Ser Gly Ser
Gly Gly Ser Thr Phe Tyr Ala1 5 1034113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 341Ser
Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1034213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 342Thr Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
Tyr Ala1 5 1034313PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 343Thr Ala Ile Ser Gly Ser Gly Gly Gly
Thr Tyr Tyr Ala1 5 1034413PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 344Ser Ile Ile Ser Gly Ser
Ala Gly Ser Thr Tyr Tyr Ala1 5 1034513PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 345Ser
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala1 5
1034613PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 346Ser Ala Ile Ser Gly Ser Gly Gly Thr Thr Tyr
Tyr Ala1 5 1034713PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 347Ser Ala Ile Ser Gly Ser Ala Gly Ser
Thr Tyr Tyr Ala1 5 1034813PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 348Ser Ala Ile Ser Gly Ser
Gly Gly Ser Thr Tyr Tyr Ala1 5 1034916PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 349Cys
Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10
1535016PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 350Cys Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp
Tyr Phe Asp Leu Trp1 5 10 1535113PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 351Cys Thr Arg Pro Pro Tyr
Gly Asp Tyr Gly Asp Tyr Trp1 5 1035219PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 352Cys
Val Lys Gly Thr Ile Pro Ile Phe Gly Val Ile Arg Ser Ala Phe1 5 10
15Asp Tyr Trp35318PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 353Cys Ala Arg Asp Thr Asn Asp Phe Trp
Ser Gly Tyr Ser Ile Phe Asp1 5 10 15Pro Trp35412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 354Cys
Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp1 5 1035522PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 355Cys
Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10
15Tyr Tyr Phe Asp Tyr Trp 2035613PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 356Cys Ala Lys Asp Arg Arg
Phe Gly Glu Phe Asp Pro Trp1 5 1035713PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 357Cys
Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro Trp1 5
1035816PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 358Cys Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp
Tyr Phe Asp Leu Trp1 5 10 1535914PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 359Cys Ala Lys Gly Pro Leu
Val Gly Trp Tyr Phe Asp Leu Trp1 5 1036013PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 360Cys
Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp1 5
1036113PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 361Cys Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp
Pro Trp1 5 1036214PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 362Cys Ala Lys Gly Pro Leu Val Gly Trp
Tyr Phe Asp Leu Trp1 5 1036314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 363Cys Ala Lys Gly Pro Leu
Val Gly Trp Tyr Phe Asp Leu Trp1 5 1036413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 364Cys
Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp1 5
1036513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 365Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1036616PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 366Cys Ala Arg Glu Gly Tyr Arg Asp Tyr
Leu Trp Tyr Phe Asp Leu Trp1 5 10 1536718PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 367Cys
Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10
15Pro Trp36813PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 368Cys Ala Lys Asp Arg Arg Phe Gly Glu
Phe Asp Pro Trp1 5 1036912PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 369Cys Ala Ser Ser Ser Ser
Trp Gln Phe Asp Tyr Trp1 5 1037014PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 370Cys Ala Lys Gly Pro Leu
Val Gly Trp Tyr Phe Asp Leu Trp1 5 1037122PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 371Cys
Ala Arg Gly Ala Pro Asp Ser Ser Gly Tyr Tyr Phe Gln Gly Glu1 5 10
15Val Tyr Phe Asp Tyr Trp 2037222PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 372Cys Ala Lys His Gly Ser
Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr
Trp 2037318PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 373Cys Ala Arg Asp Thr Lys Asp Phe Trp Ser Gly
Tyr Cys Ile Phe Asp1 5 10 15Pro Trp37418PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 374Cys
Ala Asn Asp Thr Asn Asp Phe Trp Phe Gly Tyr Trp Ile Phe Asp1 5 10
15Pro Trp37513PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 375Cys Ala Lys Asp Thr Ile Phe Gly Glu
Phe Tyr Pro Trp1 5 1037622PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 376Cys Ala Asn His Gly Ser
Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr
Trp 2037713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 377Cys Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp
Pro Trp1 5 1037818PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 378Cys Ala Arg Asp Thr Asn Asp Phe Trp
Ser Gly Tyr Ser Ile Phe Asp1 5 10 15Pro Trp37918PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 379Cys
Ala Arg Asp Thr Lys Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10
15Pro Trp38022PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 380Cys Ala Lys His Gly Ser Gly Thr Ile
Phe Gly Val Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr Cys
2038119PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 381Cys Val Lys Gly Thr Ile Pro Ile Phe Gly Val
Ile Arg Ser Ala Phe1 5 10 15Asp Tyr Trp38212PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 382Cys
Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp1 5 1038318PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 383Cys
Ala His Asp Thr Lys Asp Phe Trp Ser Gly Tyr Cys Ile Phe Asp1 5 10
15Pro Trp3849PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 384Cys Ala Arg Asp Thr Asn Asp Phe Trp1
538518PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 385Cys Ala His Asp Thr Lys Asp Phe Trp Ser Gly
Tyr Cys Ile Phe Asp1 5 10 15Pro Trp3869PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 386Cys
Ala Arg Gly Pro Leu Asp Phe Trp1 538718PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 387Cys
Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10
15Pro Trp38816PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 388Cys Ala Arg Glu Gly Tyr Arg Asp Tyr
Leu Trp Tyr Phe Asp Leu Trp1 5 10 1538922PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 389Cys
Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys1 5 10
15Tyr Tyr Phe Asp Tyr Trp 2039016PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 390Cys Ala Arg Glu Gly Tyr
Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10 1539118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 391Cys
Ala Arg Val Arg Gln Gly Leu Arg Arg Thr Trp Tyr Tyr Phe Asp1 5 10
15Tyr Trp39216PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 392Cys Ala Arg Glu Gly Tyr Arg Asp Tyr
Leu Trp Tyr Phe Asp Leu Trp1 5 10 1539318PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 393Cys
Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10
15Pro Trp39412PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 394Cys Ala Ser Ser Ser Ser Trp Gln Phe
Asp Tyr Trp1 5 1039518PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 395Cys Ala Arg Asp Thr Asn
Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp1 5 10 15Pro
Trp39613PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 396Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1039715PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 397Cys Ala Lys Gly Leu Trp Phe Gly Gly
Gly Gly Phe Asp Pro Trp1 5 10 1539816PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 398Cys
Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp1 5 10
1539913PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 399Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1040019PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 400Cys Val Lys Gly Thr Ile Pro Ile Phe
Gly Val Ile Arg Ser Ala Phe1 5 10 15Asp Tyr Trp40116PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 401Cys
Ala Lys Asp Phe His Gly Ile Ala Ala Ala Gly Ile Asp Tyr Trp1 5 10
1540217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 402Cys Ala Lys Asp Gly Ala Ser Gly Trp Pro Asn
Trp His Phe Asp Leu1 5 10 15Trp40315PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 403Cys
Ala His Ser Arg Asp Ser Ser Ser Trp Tyr Val Asp Tyr Trp1 5 10
1540413PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 404Cys Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp
Tyr Trp1 5 1040522PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 405Cys Ala Lys His Gly Ser Gly Thr Ile
Phe Gly Val Val Ile Ala Lys1 5 10 15Tyr Tyr Phe Asp Tyr Trp
2040613PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 406Cys Thr Arg Pro Pro Tyr Gly Tyr Tyr Gly Asp
Tyr Trp1 5 1040714PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 407Cys Ala Lys Gly Pro Leu Val Gly Trp
Tyr Phe Asp Leu Trp1 5 1040813PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 408Cys Ala Lys Asp Thr Ile
Phe Gly Glu Phe Tyr Pro Trp1 5 1040913PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 409Cys
Ala Lys Asp Arg Lys Phe Gly Glu Phe Asp Pro Trp1 5
1041011PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 410Cys Ala Arg Asp Gly Tyr Lys Tyr Cys Leu Trp1 5
1041118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 411Cys Ala Asn Asp Thr Ser Asp Phe Cys Phe Gly
Tyr Trp Ile Phe Asp1 5 10 15Pro Trp4129PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 412Cys
Ala Arg Gly Pro Leu Asp Phe Trp1 541318PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 413Cys
Ala Arg Asp Thr Lys Asp Phe Trp Ser Gly Tyr Cys Ile Phe Asp1 5 10
15Pro Trp41418PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 414Cys Ala Asn Asp Thr Asn Asp Phe Trp
Phe Gly Tyr Trp Ile Phe Asp1 5 10 15Pro Trp41514PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 415Thr
Gly Thr Ser Ser Asp Val Gly Ser Asn Asn Leu Val Ser1 5
1041614PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 416Thr Gly Thr Ser Thr Asp Val Gly Ser Tyr Asn
Leu Val Ser1 5 1041714PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 417Thr Gly Thr Ser Arg Asp
Val Gly Ser Tyr Asn Leu Val Ser1 5 1041814PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 418Thr
Gly Thr Ser Ser Asp Val Gly Ser Tyr Ser Leu Val Ser1
5 1041914PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 419Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1042014PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 420Thr Gly Thr Ser Ser Tyr
Val Gly His Tyr Asn Leu Val Ser1 5 1042114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 421Thr
Gly Thr Ser Ser Asp Val Gly His Tyr Asn Leu Val Ser1 5
1042214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 422Thr Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn
Leu Val Ser1 5 1042314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 423Thr Gly Ile Ser Ser Asp
Val Gly Ser Tyr Asn Leu Val Ser1 5 1042414PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 424Thr
Gly Thr Ser Asn Asp Val Gly Ser Tyr Asn Leu Val Ser1 5
1042514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 425Thr Gly Thr Ser Ser Asp Phe Gly Ser Tyr Asn
Leu Val Ser1 5 1042614PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 426Thr Gly Thr Ser Ser Asp
Val Gly Lys Tyr Asn Leu Val Ser1 5 1042714PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 427Thr
Gly Thr Ser Ser Asp Val Gly Thr Tyr Asn Leu Val Ser1 5
1042814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 428Thr Gly Thr Ser Asn Asp Val Gly Ser Tyr Asn
Leu Val Ser1 5 1042914PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 429Thr Gly Thr Ser Ser Asp
Val Gly Asp Tyr Asn Leu Val Ser1 5 1043014PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 430Thr
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Leu Val Ser1 5
1043114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 431Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn
Leu Leu Ser1 5 1043214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 432Thr Gly Thr Ser Ser Asp
Val Gly Tyr Tyr Asn Leu Val Ser1 5 1043314PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 433Thr
Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn Leu Val Ser1 5
1043414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 434Thr Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn
Leu Val Ser1 5 1043514PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 435Thr Gly Thr Ser Ser Asn
Val Gly Ser Tyr Asn Leu Val Ser1 5 1043614PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 436Thr
Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Leu Val Ser1 5
1043714PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 437Thr Gly Thr Ser Ser Asp Val Gly Arg Tyr Asn
Leu Val Ser1 5 1043814PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 438Thr Gly Thr Ser Ser Asp
Val Gly His Tyr Asn Leu Val Ser1 5 1043914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 439Thr
Gly Thr Ser Ser Gly Val Gly Ser Tyr Asn Leu Val Ser1 5
1044014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 440Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1044114PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 441Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1044214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 442Thr
Gly Thr Ser Ser Asp Val Gly His Tyr Asn Leu Val Ser1 5
1044314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 443Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Ser
Leu Val Ser1 5 1044414PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 444Thr Gly Thr Ser Ser Tyr
Val Gly His Tyr Asn Leu Val Ser1 5 1044514PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 445Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1044614PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 446Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1044714PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 447Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1044814PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 448Ser
Gly Thr Ser Ser Asp Val Gly Ser Tyr Asn Leu Val Ser1 5
1044914PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 449Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Asp
Leu Val Ser1 5 1045014PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 450Thr Gly Thr Ser Ser Asp
Val Gly Ser Ser Asn Leu Val Ser1 5 1045114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 451Thr
Gly Thr Ser Thr Asp Val Gly Ser Tyr Asn Leu Val Ser1 5
1045214PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 452Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1045314PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 453Thr Gly Thr Ser Ser Asp
Leu Gly Ser Tyr Asn Ile Val Ser1 5 1045414PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 454Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1045514PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 455Thr Gly Thr Ser Ser Asp Val Gly Lys Tyr Asn
Leu Val Ser1 5 1045614PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 456Thr Gly Thr Arg Ser Asp
Val Gly Ser Tyr Asn Leu Val Ser1 5 1045714PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 457Thr
Gly Thr Ser Ser Asp Val Gly Ser Phe Asn Leu Val Ser1 5
1045814PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 458Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn
Leu Val Ser1 5 1045914PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 459Thr Gly Thr Ser Ser Asp
Val Gly Ser Tyr Ser Leu Val Ser1 5 1046014PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 460Thr
Gly Thr Ser Ser Asp Val Gly Ser His Asn Leu Val Ser1 5
1046114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 461Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr Tyr
Leu Val Ser1 5 1046214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 462Thr Gly Thr Ser Ser Gly
Val Gly Ser Tyr Asn Leu Val Ser1 5 1046314PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 463Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1046414PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 464Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1046514PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 465Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1046614PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 466Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1046714PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 467Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1046814PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 468Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1046914PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 469Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1047014PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 470Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 1047114PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 471Thr Gly Thr Ser Ser Asp
Ile Gly Ser Tyr Asn Leu Val Ser1 5 1047214PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 472Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn Leu Val Ser1 5
1047314PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 473Thr Gly Thr Ser Ser Asp Ile Gly Ser Tyr Asn
Leu Val Ser1 5 104747PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 474Glu Gly Asn Lys Arg Pro
Ser1 54757PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 475Glu Gly Ser Gln Arg Pro Ser1
54767PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 476Glu Gly Thr Lys Arg Pro Ser1
54777PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 477Glu Gly Thr Lys Arg Pro Ser1
54787PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 478Glu Gly Thr Lys Arg Pro Ser1
54797PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 479Glu Gly Ser Arg Arg Pro Ser1
54807PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 480Glu Gly Thr Lys Arg Pro Ser1
54817PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 481Glu Gly Ile Lys Arg Pro Ser1
54827PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 482Glu Gly Thr Lys Arg Pro Ser1
54837PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 483Glu Gly Asn Lys Arg Pro Ser1
54847PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 484Glu Gly Asn Lys Arg Pro Ser1
54857PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 485Glu Gly Ser Gln Arg Pro Ser1
54867PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 486Glu Gly Ser Gln Arg Pro Ser1
54877PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 487Glu Gly Ser Lys Arg Pro Ser1
54887PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 488Glu Gly Ser Asn Arg Pro Ser1
54897PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 489Glu Gly Asn Lys Arg Pro Ser1
54907PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 490Glu Ala Ser Lys Arg Pro Ser1
54917PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 491Glu Gly Asn Lys Arg Pro Ser1
54927PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 492Glu Ala Ser Lys Arg Pro Ser1
54937PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 493Glu Gly Ser Gln Arg Pro Ser1
54947PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 494Glu Gly Thr Lys Arg Pro Ser1
54957PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 495Glu Gly Thr Lys Arg Pro Ser1
54967PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 496Glu Gly Gly Lys Arg Pro Ser1
54977PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 497Glu Gly Thr Lys Arg Pro Ser1
54987PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 498Glu Gly Ile Lys Arg Pro Ser1
54997PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 499Glu Gly Thr Lys Arg Pro Ser1
55007PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 500Glu Gly Thr Asn Arg Pro Ser1
55017PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 501Glu Gly Thr Lys Arg Pro Ser1
55027PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 502Glu Gly Asp Lys Arg Pro Ser1
55037PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 503Glu Gly Ser Arg Arg Pro Ser1
55047PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 504Glu Gly Thr Lys Arg Pro Ser1
55057PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 505Glu Gly Thr Lys Arg Pro Ser1
55067PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 506Glu Gly Thr Lys Arg Pro Ser1
55077PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 507Glu Ala Ser Lys Arg Pro Ser1
55087PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 508Glu Gly Asn Lys Arg Pro Ser1
55097PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 509Glu Gly Ser Lys Arg Pro Ser1
55107PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 510Glu Gly Thr Lys Arg Pro Ser1
55117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 511Glu Gly Thr Lys Arg Pro Ser1
55127PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 512Glu Gly Ser Arg Arg Pro Ser1
55137PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 513Glu Gly Thr Lys Arg Pro Ser1
55147PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 514Glu Gly Val Lys Arg Pro Ser1
55157PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 515Glu Val Ser Lys Arg Pro Ser1
55167PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 516Glu Val Ser Lys Arg Pro Ser1
55177PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 517Glu Ala Ser Lys Arg Pro Ser1
55187PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 518Glu Gly Gly Lys Arg Pro Ser1
55197PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 519Glu Gly Gly Lys Arg Pro Ser1
55207PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 520Glu Gly Asp Lys Arg Pro Ser1
55217PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 521Ala Gly Ser Lys Arg Pro Ser1
55227PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 522Glu Gly Thr Lys Arg Pro Ser1
55237PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 523Glu Gly Thr Lys Arg Pro Ser1
55247PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 524Glu Gly Thr Lys Arg Pro Ser1
55257PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 525Glu Gly Thr Lys Arg Pro Ser1
55267PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 526Glu Gly Thr Lys Arg Pro Ser1
55277PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 527Glu Gly Thr Lys Arg Pro Ser1
55287PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 528Glu Gly Thr Lys Arg Pro Ser1
55297PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 529Glu Gly Thr Lys Arg Pro Ser1
55307PRTArtificial SequenceDescription of Artificial Sequence
Synthetic
peptide 530Glu Gly Thr Lys Arg Pro Ser1 55317PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 531Glu
Gly Thr Lys Arg Pro Ser1 55327PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 532Glu Gly Thr Lys Arg Pro
Ser1 553310PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 533Cys Cys Ser Tyr Ala Gly Ser Val Val Phe1 5
1053411PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 534Cys Cys Ser Tyr Ala Gly Ser Ser Thr Val Phe1 5
1053513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 535Cys Cys Ser Tyr Ala Gly Ser Arg Thr Pro Val
Val Phe1 5 1053613PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 536Cys Cys Ser Tyr Ala Gly Ser Tyr Ser
Tyr Val Val Phe1 5 1053712PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 537Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1053813PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 538Cys Cys Ser Tyr Ala Gly
Ser Tyr Thr His Tyr Val Phe1 5 1053913PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 539Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1054013PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 540Cys Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val
Val Phe1 5 1054113PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 541Cys Cys Ser Tyr Ala Gly Ser Ser Ser
Phe Val Val Phe1 5 1054211PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 542Cys Cys Ser Tyr Ala Gly
Ser Tyr Thr Val Phe1 5 1054313PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 543Cys Cys Ser Tyr Ala Gly
Ser Ser Thr Phe Val Val Phe1 5 1054413PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 544Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Pro Val Val Phe1 5
1054513PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 545Cys Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val
Val Phe1 5 1054612PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 546Cys Cys Ser Tyr Ala Gly Ser Arg Tyr
Val Val Phe1 5 1054713PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 547Cys Cys Ser Tyr Ala Gly
Ser Ser Ser Phe Val Val Phe1 5 1054814PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 548Cys
Cys Ser Tyr Ala Gly Ser Ser Thr Phe Pro Val Val Phe1 5
1054913PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 549Cys Cys Ser Tyr Ala Gly Ser Arg Thr Pro Val
Val Phe1 5 1055011PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 550Cys Cys Ser Tyr Ala Gly Gly Ser Val
Val Phe1 5 1055113PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 551Cys Cys Ser Tyr Ala Gly Ser Tyr Thr
Phe Ala Val Phe1 5 1055213PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 552Cys Cys Ser Tyr Ala Gly
Ser Ser Thr His Tyr Val Phe1 5 1055313PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 553Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1055413PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 554Cys Cys Ser Phe Val Arg Ser Ser Ala His Val
Val Phe1 5 1055512PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 555Cys Cys Ser Tyr Ala Ser Ser Ser Thr
Leu Val Phe1 5 1055613PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 556Cys Cys Ser Tyr Ala Gly
Ser Ser Ser Phe Val Val Phe1 5 1055713PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 557Cys
Cys Ser Tyr Ala Gly Ser Ser Ser Phe Val Val Phe1 5
1055812PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 558Cys Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val
Phe1 5 1055912PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 559Cys Cys Ser Tyr Ala Gly Ser Arg Thr
Tyr Val Phe1 5 1056013PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 560Cys Cys Ser Tyr Ala Gly
Ser Ser Ser Phe Val Val Phe1 5 1056113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 561Cys
Cys Ser Tyr Ala Gly Ser Tyr Ser Tyr Val Val Phe1 5
1056213PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 562Cys Cys Ser Tyr Ala Gly Ser Tyr Thr His Tyr
Val Phe1 5 1056312PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 563Cys Cys Ser Tyr Ala Gly Ser Arg Thr
Tyr Val Phe1 5 1056412PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 564Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1056512PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 565Cys Cys Ser Tyr Ala Gly
Ser Arg Thr Tyr Val Phe1 5 1056611PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 566Cys Cys Ser Tyr Ala Gly
Ser Ser Thr Val Phe1 5 1056711PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 567Cys Cys Ser Tyr Ala Gly
Ser Ser Val Val Phe1 5 1056811PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 568Cys Cys Ser Tyr Ala Gly
Ser Leu Tyr Val Phe1 5 1056913PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 569Cys Cys Ser Tyr Ala Gly
Ser Tyr Thr Ser Val Val Phe1 5 1057012PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 570Cys
Cys Tyr His Ser Arg Thr Arg Thr His Val Phe1 5 1057113PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 571Cys
Cys Ser Tyr Ala Gly Ser Tyr Thr His Tyr Val Phe1 5
1057212PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 572Cys Cys Tyr His Ser Arg Thr Arg Thr His Val
Ser1 5 1057313PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 573Cys Cys Ser Tyr Ala Gly Ser Arg Thr
Pro Val Val Phe1 5 1057413PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 574Cys Cys Ser Tyr Ala Gly
Asp Ser Phe Pro Tyr Val Phe1 5 1057511PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 575Cys
Cys Ser Tyr Ala Gly Ser Ser Val Val Phe1 5 1057613PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 576Cys
Cys Ser Tyr Ala Gly Ser Tyr Ile Pro Val Val Phe1 5
1057713PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 577Cys Cys Ser Tyr Ala Gly Ser Tyr Ser Tyr Val
Val Phe1 5 1057812PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptide 578Cys Cys Ser Tyr Ser Gly Arg Tyr Thr
Tyr Val Phe1 5 1057912PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 579Cys Cys Ser His Ala Gly
Arg Tyr Pro Tyr Val Phe1 5 1058014PRTArtificial SequenceDescription
of Artificial Sequence Synthetic peptide 580Cys Cys Ser Tyr Leu Gly
Ser Gly Thr Phe Asp Val Leu Phe1 5 1058112PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 581Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058212PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 582Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058312PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 583Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058412PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 584Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058512PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 585Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058612PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 586Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058712PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 587Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058812PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 588Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1058912PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 589Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1059012PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 590Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5 1059112PRTArtificial
SequenceDescription of Artificial Sequence Synthetic peptide 591Cys
Cys Ser Tyr Ala Gly Ser Arg Thr Tyr Val Phe1 5
10592121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 592Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu
Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120593121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
593Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120594118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 594Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115595124PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
595Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Gly Thr Ile Pro Ile Phe Gly
Val Ile Arg Ser Ala Phe Asp 100 105 110Tyr Trp Gly Gln Gly Thr Leu
Val Thr Val Ser Ser 115 120596123PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 596Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120597117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 597Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Ser
Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115598127PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 598Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys
Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 125599118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 599Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Gln 20 25
30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser
Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro
Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115600118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 600Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp
Arg Arg Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115601121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 601Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp
Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115
120602119PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 602Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly
Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr
Leu Val Thr Val Ser Ser 115603118PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 603Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115604118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
604Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe
Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115605119PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 605Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly
Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr
Leu Val Thr Val Ser Ser 115606119PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 606Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln
Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115607118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
607Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly
Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115608118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 608Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ile Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro
Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115609121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 609Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp
Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115
120610123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 610Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp
Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp Pro 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120611118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
611Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe
Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115612117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 612Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Ser
Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115613119PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 613Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln
Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115614127PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
614Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Tyr Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ala Pro Asp Ser Ser Gly
Tyr Tyr Phe Gln Gly Glu Val 100 105 110Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120 125615127PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
615Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe
Gly Val Val Ile Ala Lys Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120 125616123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
616Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
His 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Lys Asp Phe Trp Ser
Gly Tyr Cys Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120617123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 617Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Asn Asp Thr Asn Asp Phe Trp Phe Gly Tyr Trp Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120618118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
618Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Thr Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Thr Ile Phe Gly Glu Phe
Tyr Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115619127PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 619Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Asn His
Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys Tyr 100 105 110Tyr
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
125620118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 620Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp
Arg Arg Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115621123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 621Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120622123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 622Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser His 20 25 30Ala Met Tyr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp
Thr Lys Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp Pro 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120623127PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
623Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe
Gly Val Val Ile Ala Lys Tyr 100 105 110Tyr Phe Asp Tyr Cys Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120 125624124PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
624Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Gly Thr Ile Pro Ile Phe Gly
Val Ile Arg Ser Ala Phe Asp 100 105 110Tyr Trp Gly Gln Gly Thr Leu
Val Thr Val Ser Ser 115 120625117PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 625Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr
Leu 100 105 110Val Thr Val Ser Ser 115626123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
626Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
His 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala His Asp Thr Lys Asp Phe Trp Ser
Gly Tyr Cys Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120627114PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 627Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Gly Gln Gly Thr Leu Val Thr
Val 100 105 110Ser Ser628123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 628Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala His Asp Thr Lys Asp Phe Trp Ser Gly Tyr Cys Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120629114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 629Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly
Pro Leu Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser
Ser630123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 630Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp
Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp Pro 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120631121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
631Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120632127PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 632Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser His 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys
Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 125633121PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 633Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp
Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115
120634123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 634Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Val
Arg Gln Gly Leu Arg Arg Thr Trp Tyr Tyr Phe Asp Tyr 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120635121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
635Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120636123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 636Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser
Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr
Ser Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120637117PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 637Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ala
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Ser Ser Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr
Leu 100 105 110Val Thr Val Ser Ser 115638123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
638Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser
Gly Tyr Ser Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120639118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 639Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115640120PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
640Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Thr Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Leu Trp Phe Gly Gly Gly
Gly Phe Asp Pro Trp Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser
Ser 115 120641121PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 641Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala
Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly
Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala
Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp Gly 100 105
110Gln Gly Thr Leu Val Thr Val Ser Ser 115 120642118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
642Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Ser Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly
Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115643124PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 643Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Val Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asp Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Gly
Thr Ile Pro Ile Phe Gly Val Ile Arg Ser Ala Phe Asp 100 105 110Tyr
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120644121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 644Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Arg Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Thr Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp
Phe His Gly Ile Ala Ala Ala Gly Ile Asp Tyr Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120645122PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
645Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Met Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Thr
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Gly Ala Ser Gly Trp Pro
Asn Trp His Phe Asp Leu Trp 100 105 110Gly Gln Gly Thr Leu Val Thr
Val Ser Ser 115 120646120PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 646Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala His Ser Arg Asp Ser Ser Ser Trp Tyr Val Asp Tyr Trp Gly
Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115
120647118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 647Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Ala Ile Ser Gly Ser Gly
Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro
Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115648127PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 648Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys
Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 125649118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 649Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Tyr Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115650119PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
650Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr
Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115651118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 651Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp
Thr Ile Phe Gly Glu Phe Tyr Pro Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115652118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 652Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Thr Ala
Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Asp Arg Lys Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115653116PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
653Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Gly Tyr Lys Tyr Cys Leu
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
115654123PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 654Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Asn Asp
Thr Ser Asp Phe Cys Phe Gly Tyr Trp Ile Phe Asp Pro 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120655114PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
655Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Thr Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Pro Leu Asp Phe Trp Gly
Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser656123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
656Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
His 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Lys Asp Phe Trp Ser
Gly Tyr Cys Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120657123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 657Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Asn Asp Thr Asn Asp Phe Trp Phe Gly Tyr Trp Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120658108PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 658Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Asn 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Val Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105659109PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
659Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Thr Asp Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105660111PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 660Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Ser Tyr 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Arg Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110661111PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 661Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr
Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30Ser Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly
Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr
Ser Tyr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110662110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 662Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110663111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 663Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Tyr Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110664111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 664Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110665111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 665Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ile Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110666111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 666Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Ile
Ser Ser Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110667109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 667Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Asn Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105668111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
668Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Phe Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110669111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
669Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Lys
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Pro Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110670111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
670Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Thr
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110671110PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
671Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Asn Asp Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Arg Tyr Val Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110672111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
672Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Asn Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110673112PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
673Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Phe Pro Val Val Phe Gly Gly
Gly Thr Lys Leu Thr Val Leu 100 105 110674111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
674Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser
Tyr 20 25 30Asn Leu Leu Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Pro Val Val Phe Gly Gly Gly
Thr Lys
Leu Thr Val Leu 100 105 110675109PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 675Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Tyr Tyr 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly
85 90 95Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100
105676111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 676Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr Phe
Ala Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110677111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 677Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110678111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 678Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asn Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110679111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 679Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Gly Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Phe Val Arg Ser 85 90 95Ser Ala His
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110680110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 680Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Arg Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Gly Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Ser Ser 85 90 95Ser Thr Leu
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110681111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 681Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110682111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 682Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ile Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110683110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 683Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110684110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 684Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Asn
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110685111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 685Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110686111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 686Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Ser Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asp Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Ser Tyr
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110687111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 687Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Tyr Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110688110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 688Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110689110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 689Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110690110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 690Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110691109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 691Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Ser Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105692109PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
692Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser
Tyr 20 25 30Asp Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Val Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105693109PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 693Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Ser 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Leu Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100
105694111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 694Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Thr Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90
95Tyr Thr Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100
105 110695110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 695Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly
Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Tyr His Ser Arg Thr 85 90 95Arg
Thr His Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110696111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 696Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110697111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 697Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110698111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 698Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110699111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 699Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110700111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 700Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110701111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 701Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110702111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 702Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Leu Gly Ser Tyr 20 25 30Asn Ile Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110703110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 703Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser His 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Gly Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ser Gly Arg 85 90 95Tyr Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110704110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 704Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Tyr Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asp Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser His Ala Gly Arg 85 90 95Tyr Pro Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110705112PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 705Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Ala Gly Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Leu Gly Ser 85 90 95Gly Thr Phe
Asp Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110706110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 706Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110707110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 707Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110708110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 708Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110709110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 709Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110710110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 710Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110711110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 711Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110712110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 712Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110713110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 713Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110714110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 714Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65
70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly
Ser 85 90 95Arg Thr Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110715110PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 715Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr
Gly Thr Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly
Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg
Thr Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110716110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 716Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110717121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 717Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu
Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120718121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
718Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120719118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 719Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115720124PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
720Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Asp Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Gly Thr Ile Pro Ile Phe Gly
Val Ile Arg Ser Ala Phe Asp 100 105 110Tyr Trp Gly Gln Gly Thr Leu
Val Thr Val Ser Ser 115 120721123PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 721Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120722117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 722Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Ser
Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115723127PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 723Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys
Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 125724118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 724Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115725118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
725Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe
Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115726121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 726Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu
Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120727119PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
727Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr
Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115728118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 728Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro
Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115729118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 729Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115730119PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
730Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr
Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser
115731119PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 731Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Gly
Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln Gly 100 105 110Thr
Leu Val Thr Val Ser Ser 115732118PRTArtificial SequenceDescription
of Artificial Sequence Synthetic polypeptide 732Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115733118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
733Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ile Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Phe Tyr Ala
Asp Ser Val 50
55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95Thr Arg Pro Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp
Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115734121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 734Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu
Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120735118PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
735Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Gln 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe
Asp Pro Trp Gly Gln Gly Thr 100 105 110Leu Val Thr Val Ser Ser
115736117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 736Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Ser
Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115737119PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 737Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Asp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Gly Pro Leu Val Gly Trp Tyr Phe Asp Leu Trp Gly Gln
Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115738127PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
738Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly Tyr Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Ala Pro Asp Ser Ser Gly
Tyr Tyr Phe Gln Gly Glu Val 100 105 110Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120 125739127PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
739Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Thr Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys His Gly Ser Gly Thr Ile Phe
Gly Val Val Ile Ala Lys Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 115 120 125740123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
740Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser
Gly Tyr Ser Ile Phe His Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120741127PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 741Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Asn His Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys
Tyr 100 105 110Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 125742118PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 742Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Gln 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Asp Arg Arg Phe Gly Glu Phe Asp Pro Trp Gly Gln Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115743123PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
743Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser
Gly Tyr Ser Ile Phe Asp Pro 100 105 110Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120744123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 744Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Lys Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120745127PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 745Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Ile Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys His
Gly Ser Gly Thr Ile Phe Gly Val Val Ile Ala Lys Tyr 100 105 110Tyr
Phe Asp Tyr Cys Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
125746124PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 746Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Leu Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Asp Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Val Lys Gly
Thr Ile Pro Ile Phe Gly Val Ile Arg Ser Ala Phe Asp 100 105 110Tyr
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120747117PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 747Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Gly
Gly Gly Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Ser
Ser Ser Trp Gln Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115748123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 748Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser His 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala His Asp Thr Lys Asp Phe Trp Ser Gly Tyr Cys Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120749114PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 749Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Gly Ser Ala
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp
Thr Asn Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser
Ser750118PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 750Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Tyr Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Ser Ser Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Pro
Pro Tyr Gly Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr 100 105 110Leu
Val Thr Val Ser Ser 115751123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 751Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Ser Tyr 20 25 30Ala Met Tyr
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Thr Asn Asp Phe Trp Ser Gly Tyr Ser Ile Phe Asp
Pro 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120752121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
752Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ile Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120753108PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 753Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Asn 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100
105754109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 754Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Thr Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105755111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
755Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Arg Asp Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Pro Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110756111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
756Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser
Tyr 20 25 30Ser Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Ser Tyr Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110757110PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
757Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110758111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
758Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Tyr Val Gly His
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His Tyr Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110759111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
759Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly His
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110760111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
760Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Gly Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ile Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110761111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
761Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Ile Ser Ser Asp Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110762109PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
762Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Asn Asp Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105763111PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 763Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Asp Phe Gly Ser Tyr 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Asn Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Ser Thr Phe Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110764111PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 764Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr
Gly Thr Ser Ser Asp Val Gly Lys Tyr 20 25 30Asn Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly
Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg
Thr Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110765111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 765Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Thr Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Gln
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110766110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 766Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Asn Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Tyr Val
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110767111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 767Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Asp Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Asn
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110768112PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 768Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Gly Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Phe
Pro Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110769111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 769Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Asn Leu Leu Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Pro
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110770109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 770Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Tyr Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Gly 85 90 95Ser Val Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105771111PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
771Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Gly Val Gly Ser
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr Phe Ala Val Phe Gly Gly Gly
Thr Lys Leu Thr
Val Leu 100 105 110772111PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 772Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Ser Thr His Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110773111PRTArtificial SequenceDescription of Artificial
Sequence Synthetic polypeptide 773Gln Ser Ala Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr
Gly Thr Ser Ser Asn Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly
Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser
Ser Phe Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110774111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 774Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Gly Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Phe Val Arg Ser 85 90 95Ser Ala His
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110775110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 775Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Arg Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Gly Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Ser Ser 85 90 95Ser Thr Leu
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110776110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 776Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110777111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 777Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110778111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 778Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Gly Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ile Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110779110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 779Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110780110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 780Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Asn
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110781111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 781Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Ser Phe
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110782111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 782Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Ser Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asp Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Ser Tyr
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110783111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 783Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Tyr Val Gly His Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Arg
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Thr His
Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110784110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 784Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110785110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 785Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110786111PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 786Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Gly Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Tyr Ile Pro
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110787110PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 787Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Ile Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Thr Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Arg Thr Tyr
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110788109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 788Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Ser Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Ala Ser Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Thr Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105789121PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
789Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala
Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu
Trp Tyr Phe Asp Leu Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120790123PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 790Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala
Ile Ser Gly Ser Ala Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Val Arg Gln Gly Leu Arg Arg Thr Trp Tyr Tyr Phe Asp
Tyr 100 105 110Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120791121PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 791Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30Thr Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Val Ile Ser Gly Ser Gly
Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55
60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys 85 90 95Ala Arg Glu Gly Tyr Arg Asp Tyr Leu Trp Tyr Phe Asp Leu
Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115
120792109PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 792Gln Ser Ala Leu Thr Gln Pro Ala Ser Val
Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Ser Tyr 20 25 30Asp Leu Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile Tyr Glu Gly Asn Lys
Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly
Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp
Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Val Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105793109PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
793Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser
Ser 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Met Ile Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu65 70 75 80Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Cys Ser Tyr Ala Gly Ser 85 90 95Leu Tyr Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105794111PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 794Gln Ser Ala Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1 5 10 15Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Thr Asp Val Gly Ser Tyr 20 25 30Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Met Ile
Tyr Glu Gly Thr Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60Ser
Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu65 70 75
80Gln Ala Glx Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser
85 90 95Tyr Thr Ser Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 11079562DNAArtificial SequenceDescription of Artificial
Sequence Synthetic
oligonucleotidemodified_base(51)..(52)Thymidine-succinyl hexamide
CED phosphoramidite 795agacaatcaa ccatttgggg tggacagcct tgacctctag
acttcggcat tttttttttt 60tt 62796112DNAArtificial
SequenceDescription of Artificial Sequence Synthetic
polynucleotidemodified_base(101)..(102)Thymidine-succinyl hexamide
CED phosphoramidite 796cgggatcctt atcgtcatcg tcgtacagat cccgacccat
ttgctgtcca ccagtcatgc 60tagccatacc atgatgatga tgatgatgag aaccccgcat
tttttttttt tt 11279719DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 797atgcggggtt ctcatcatc
1979820DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 798cgggatcctt atcgtcatcg 20
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