U.S. patent application number 17/749044 was filed with the patent office on 2022-09-29 for neutralizing antibodies that bind to the zika virus domain iii envelope region.
The applicant listed for this patent is The Rockefeller University. Invention is credited to Michel NUSSENZWEIG, Davide ROBBIANI.
Application Number | 20220306729 17/749044 |
Document ID | / |
Family ID | 1000006379567 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220306729 |
Kind Code |
A1 |
ROBBIANI; Davide ; et
al. |
September 29, 2022 |
NEUTRALIZING ANTIBODIES THAT BIND TO THE ZIKA VIRUS DOMAIN III
ENVELOPE REGION
Abstract
Antibodies to Zika virus (ZIKV) and dengue 1 virus (DENV1) are
provided. The amino acid sequences of the antibodies may be
modified. Methods for prophylaxis and/or therapy by administering
the antibodies and combinations thereof are provided. Immunological
detection methods using the antibodies are provided. Also provided
are vaccine compositions which comprise peptides derived from ZIKV
and DENV1.
Inventors: |
ROBBIANI; Davide; (Brooklyn,
NY) ; NUSSENZWEIG; Michel; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Rockefeller University |
New York |
NY |
US |
|
|
Family ID: |
1000006379567 |
Appl. No.: |
17/749044 |
Filed: |
May 19, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16603341 |
Oct 7, 2019 |
11370830 |
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PCT/US2018/026676 |
Apr 9, 2018 |
|
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17749044 |
|
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62483001 |
Apr 7, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12N 2770/24134
20130101; C12N 2770/24022 20130101; C07K 2317/34 20130101; A61K
39/42 20130101; C07K 2317/33 20130101; C07K 2317/76 20130101; C07K
16/1081 20130101; C12N 15/86 20130101; A61K 39/12 20130101; C07K
2317/21 20130101; A61K 2039/505 20130101; C07K 2317/55
20130101 |
International
Class: |
C07K 16/10 20060101
C07K016/10; A61K 39/12 20060101 A61K039/12; A61K 39/42 20060101
A61K039/42; C12N 15/86 20060101 C12N015/86 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with government support under grant
no. UM1AI100663 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. An isolated or recombinant antibody comprising (Z021): a heavy
chain comprising: a CDR1 comprising GGSIDTYY (SEQ ID NO:6), a CDR2
comprising FYYSVDN (SEQ ID NO:7), and a CDR3 comprising
ARNQPGGRAFDY (SEQ ID NO:8) (a Z021 heavy chain); and a light chain
comprising: a CDR1 comprising QSVSNY (SEQ ID NO:9), a CDR2
comprising DTS, and a CDR3 comprising QERNNWPLTWT (SEQ ID NO:10) (a
Z021 light chain).
2. The antibody of claim 1 comprising at least one modification of
its constant region, wherein the modification increases in vivo
half-life of the antibody, or alters the ability of the antibody to
bind to Fc receptors, or alters the ability of the antibody to
cross placenta or to cross a blood-brain barrier or to cross a
blood-testes barrier, or inhibits aggregation of the antibodies, or
a combination of said modifications, or wherein the antibody is
attached to a label or a substrate.
3. The antibody of claim 2, comprising the modification that
increases in vivo half-life of the antibody.
4. The antibody of claim 2, comprising the modification that alters
the ability of the antibody to bind to Fc receptors.
5. The antibody of claim 2, comprising the modification that
increases in vivo half-life of the antibody and the modification
that alters the ability of the antibody to bind to Fc
receptors.
6. The antibody of claim 2, wherein the antibody is attached to the
label or the substrate.
7. The antibody of claim 6, wherein the antibody is present in an
enzyme-linked immunosorbent assay (ELISA) assay or an ELISA assay
control.
8. The antibody of claim 7 wherein the ELISA assay is a direct
ELISA assay, an indirect ELISA assay, a sandwich ELISA assay, or a
competition ELISA assay.
9. The antibody of claim 1, wherein the heavy chain comprises the
sequence of SEQ ID NO:13 and the light chain comprises the sequence
of SEQ ID NO:14.
10. A method for prophylaxis or therapy of a viral infection
comprising administering to an individual in need thereof an
effective amount of the antibody of claim 1.
11. The method of claim 10, wherein the antibody comprises at least
one modification of its constant region.
12. The method of claim 10, wherein the heavy chain comprises the
sequence of SEQ ID NO:13 and the light chain comprises the sequence
of SEQ ID NO:14.
13. The method of claim 10, wherein the individual is infected with
or is at risk of being infected with a virus selected from the
group consisting of Zika virus (ZIKV), dengue 1, 2, 3 or 4 viruses
(DENV1-4), yellow fever virus (YFV), West Nile virus (WNV), or a
combination thereof.
14. The method of claim 10, wherein at least two antibodies are
administered, and wherein at least one of the antibodies comprises
the Z021 antibody.
15. A polynucleotide encoding the heavy chain and the light chain
of the antibody of claim 1.
16. The polynucleotide of claim 15, wherein the polynucleotide is
in an expression vector.
17. The polynucleotide of claim 16, wherein the heavy chain
comprises the sequence of SEQ ID NO:13 and the light chain
comprises the sequence of SEQ ID NO:14.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 16/603,341, filed Oct. 7, 2019, which is a National Phase
of International patent application no. PCT/US2018/026676, filed
Apr. 9, 2018, which claims priority to U.S. provisional patent
application No. 62/483,001, filed Apr. 7, 2017, the disclosures of
each of which are incorporated herein by reference.
SEQUENCE LISTING
[0003] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Apr. 6, 2018, is named 076091_00046_SL.txt and is 507,614 bytes
in size.
BACKGROUND
[0004] Zika virus (ZIKV) infection typically produces mild symptoms
consisting of fever, rash and arthralgia that resolve rapidly, and
the infection is also occasionally associated with Guillain-Barre
Syndrome (Lessler et al., 2016; Miner and Diamond, 2017). However,
when infection occurs during pregnancy, vertical transmission can
lead to a spectrum of devastating neurodevelopmental aberrations,
collectively referred to as Congenital Zika Syndrome. Although the
data are still incomplete, infants born to mothers infected with
ZIKV during pregnancy carry an up to 42% risk of developing overt
clinical or neuroimaging abnormalities (Brasil et al., 2016; Costa
et al., 2016; Franca et al., 2016).
[0005] ZIKV belongs to the Flavivirus genus, which includes yellow
fever (YFV), West Nile (WNV), and the 4 serotypes of dengue virus
(DENV1-4). These positive-stranded RNA viruses are responsible for
considerable morbidity and mortality in the equatorial and
subequatorial regions populated by their mosquito vectors (Kramer
et al., 2007; Murray et al., 2013; Weaver and Reisen, 2010). Unlike
most other flaviviruses, ZIKV can also be transmitted sexually, and
on occasion persists for months (Barzon et al., 2016; Foy et al.,
2011; Murray et al., 2017; Suy et al., 2016).
[0006] All flaviviruses display a single envelope protein, E, that
is highly conserved between different members of this virus family.
The E protein ectodomain consists of three structural domains.
Domain I (EDI) contains the N-terminus, domain II (EDIT) is an
extended finger-like structure that includes the dimerization
domain and also a pH-sensitive fusion loop that mediates viral
fusion in the lysosomes. Finally, domain III (EDIII) is an
immunoglobulin-like domain that mediates attachment to target cells
(Barba-Spaeth et al., 2016; Dai et al., 2016; Kostyuchenko et al.,
2016; Modis et al., 2003; Mukhopadhyay et al., 2005; Rey et al.,
1995; Sirohi et al., 2016; Zhang et al., 2004). Several human
neutralizing antibodies targeting different E protein epitopes have
been described. Antibodies against the EDIII of flaviviruses are
among the most potent neutralizers in this group (Beasley and
Barrett, 2002; Crill and Roehrig, 2001; Screaton et al., 2015).
[0007] Due to the conserved structural features of the E protein,
antibodies that develop in response to infection by one flavivirus
may also recognize others (Heinz and Stiasny, 2017).
Cross-reactivity can lead to cross-protection as first documented
by Sabin who showed experimentally in humans that exposure to DENV1
could provide short-term protection from subsequent challenge with
DENV2. In contrast, immunity to the autologous strain was long
lasting (Sabin, 1950). More recently, human monoclonal antibodies
to DENV have been shown to cross-neutralize ZIKV, and vice versa
(Barba-Spaeth et al., 2016; Stettler et al., 2016; Swanstrom et
al., 2016). However, there is concern that cross-reacting
antibodies that fail to neutralize the virus may enhance rather
than curb subsequent flavivirus infections (Harrison, 2016; Wahala
and Silva, 2011). In vitro and in vivo experiments in mice suggest
that this phenomenon, commonly referred to as Antibody Dependent
Enhancement (ADE), extends to ZIKV (Bardina et al., 2017;
Dejnirattisai et al., 2016; Harrison, 2016; Priyamvada et al.,
2016). While several human antibodies to ZIKV have been cloned from
convalescent individuals by methods utilizing B cell transformation
with Epstein-Barr virus (Sapparapu et al., 2016; Stettler et al.,
2016), individual donors were not selected for high neutralization
titers; whether their antibodies are representative of optimal
immune responses, and how these antibodies might relate to previous
flavivirus exposure remains unknown.
[0008] Since no approved prophylaxis or treatment exists, there is
an ongoing need for compositions and methods that provide robust
protection against ZIKV and other flaviviruses (such as DENV1).
Because of the risk of ADE, it is preferable that such compositions
and methods avoid the generation of antibodies that bind to the
virus but are non-neutralizing and potentially enhancing. Passive
administration of monoclonal antibodies represents an alternative
approach to vaccines, and has the advantage that antibodies can be
modified to prevent interaction with cellular receptors that
mediate ADE. The present disclosure is pertinent to this need.
BRIEF SUMMARY
[0009] Antibodies to Zika virus (ZIKV) can be protective. To
examine the antibody response in individuals that develop high
titers of anti-ZIKV antibodies we screened cohorts in Brazil and
Mexico for ZIKV envelope domain III (ZEDIII) binding and
neutralization. Sequencing of nearly 300 antibodies showed that
donors with high ZIKV neutralizing antibody titers had expanded
clones of memory B cells that carried the same immunoglobulin
VH3-23/VK1-5 genes. These recurring antibodies cross-reacted with
DENV1, but not other flaviviruses. In particular, a VH3-23/VK1-5
antibody described in detail below as Z004 neutralized both DENV1
and ZIKV, and protected mice against ZIKV challenge. Structural
analyses revealed the mechanism of recognition of the ZEDIII
lateral ridge by VH3-23/VK1-5 antibodies. Serologic testing showed
that antibodies to this region correlate with serum neutralizing
activity to ZIKV, and that reactivity to dengue 1 virus (DENV1)
EDIII before ZIKV exposure was associated with increased ZIKV
neutralizing titers after exposure. Thus, high neutralizing
responses to ZIKV are associated with pre-existing reactivity to
DENV1. Accordingly, mice immunization experiments showed that
immunization with the EDIII of DENV1 followed by boosting with
ZEDIII resulted in higher neutralizing titers against ZIKV than
immunization with either component alone. The disclosure takes
advantage of these discoveries to provide novel compositions and
methods for approaching ZIKV and DENV1 prophylaxis and/or therapy.
Furthermore, the present disclosure demonstrates that a combination
of two different antibodies that recognize distinct but overlapping
epitopes on the EDIII lateral ridge of ZIKV and DENV1 has unique
properties. In particular, the antibody described below as Z021
potently neutralized ZIKV and DENV1 in vitro and prevented disease
in mice. In macaques, prophylactic co-administration of Z004 with
Z021 was protective and suppressed emergence of ZIKV resistant
variants. Thus, the present disclosure demonstrates that a
combination of two human monoclonal antibodies that recognize
distinct but overlapping epitopes on ZIKV EDIII is sufficient to
suppress infection and thwart viral escape in macaques, a natural
host for ZIKV. It is considered based on these data that similar
effects can be elicited in humans.
[0010] In embodiments the disclosure thus provides an isolated or
recombinant antibody, or polynucleotides encoding the antibody,
comprising a complementarity determining region (CDR) 3 (CDR3)
amino acid sequence selected from heavy chain and light chain CDR3
sequences in Table 1 and Table 2. Table 1 also provides variable
sequences for numerous antibody heavy and light chain from which
CDR1, CDR2 and CDR3 sequences can be determined.
[0011] In certain embodiments the disclosure provides a Z004
antibody comprising a heavy chain comprising: a CDR1 comprising
GFTFRDYA (SEQ ID NO:1), a CDR2 comprising YSGIDDST (SEQ ID NO:2),
and a CDR3 comprising AKDRGPRGVGELFDS (SEQ ID NO:3) (a Z004 heavy
chain); and a light chain comprising: a CDR1 comprising QSISKW (SEQ
ID NO:4), a CDR2 comprising TTS, and a CDR3 comprising QHFYSVPWT
(SEQ ID NO:5) (a Z004 light chain). In an embodiment the disclosure
provides a Z021 antibody comprising a heavy chain comprising: a
CDR1 comprising GGSIDTYY (SEQ ID NO:6), a CDR2 comprising FYYSVDN
(SEQ ID NO:7), and a CDR3 comprising ARNQPGGRAFDY (SEQ ID NO:8) (a
Z021 heavy chain); and a light chain comprising: a CDR1 comprising
QSVSNY (SEQ ID NO:9), a CDR2 comprising DTS, and a CDR3 comprising
QERNNWPLTWT (SEQ ID NO:10) (a Z021 light chain), or iii) a
bispecific antibody comprising the Z004 heavy chain CDR1, CDR2,
CDR3, and the Z004 light chain CDR1, CDR2, CDR3, and the Z021 heavy
chain CDR1, CDR2, CDR3, and the Z021 light chain CDR1, CDR2,
CDR3.
[0012] In embodiments, the Z004 antibody (also referred to herein
as MEX18_89) comprises a heavy chain having the sequence:
TABLE-US-00001 (SEQ ID NO: 11)
EVQLLESGGGLVQPGGSLRLTCATSGFTFRDYAMSWVRQAPGKGLEWVSS
YSGIDDSTYYADSVKGRFTISRDNSKSTLSLHMNSLRAEDSALYFC GQGTLVTVSS
[0013] and a light chain having the sequence:
TABLE-US-00002 (SEQ ID NO: 12)
DIQMTQSPSTLSASVGDRVTITCRASQSISKWLAWYQQKPGKAPKWYTTS
TLKSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGT KVEIK
[0014] In this Z004 sequence and Z021 sequence below, the CDR1 is
italicized, the CDR2 is bolded and the CDR3 is italicized and
bolded.
[0015] In embodiments, the Z021 antibody (also referred to herein
as MEX84_p4-23) has a heavy chain having the sequence:
TABLE-US-00003 (SEQ ID NO: 13)
QVQLQESGPGLVKPSETLSLTCTVSGGSIDTYYWSWIRQTPGKGLEWIGC
FYYSVDNHFNPSLESRVTISVDTSKNQFSLKMTSMTASDTAVYYC WGPGTLVTVSS
[0016] and a light chain having the sequence:
TABLE-US-00004 (SEQ ID NO: 14)
EIVLTQSPATLSLSPGQRATLSCRASQSVSNYFAWYQQKPGQAPRLLIYD
TSKRATGTPARFSGSGSGTDFTLTISSLEPEDFAVYYC F GLGTKVEIK.
[0017] Any antibody described herein can comprise at least one
modification of its constant region. The modification is of any one
or more amino acids. The modification can have any of a number of
desirable effects. In certain approaches, the modification
increases in vivo half-life of the antibody, or alters the ability
of the antibody to bind to Fc receptors, or alters the ability of
the antibody to cross placenta or to cross a blood-brain barrier or
to cross a blood-testes barrier, or inhibits aggregation of the
antibodies, or a combination of said modifications, or wherein the
antibody is attached to a label or a substrate. In embodiments, the
modification improves the manufacturability of the antibody. In
embodiments, any antibody or combination thereof described herein
can be present in an immunological assay, such as an enzyme-linked
immunosorbent assay (ELISA) assay, or an ELISA assay control. The
ELISA assay can be any of a direct ELISA assay, an indirect ELISA
assay, a sandwich ELISA assay, or a competition ELISA assay.
[0018] In another aspect the disclosure provides a method for
prophylaxis or therapy of a viral infection comprising
administering to an individual in need thereof an effective amount
of at least one antibody or antigen binding fragment thereof. The
antibody may comprise at least one modification of the constant
region. In embodiments, the composition is administered to an
individual who is infected with or is at risk of being infected
with a virus selected from the group consisting of Zika virus
(ZIKV), dengue 1, 2, 3 or 4 viruses (DENV1-4), yellow fever virus
(YFV), West Nile virus (WNV), and combinations thereof. In one
approach, at least two antibodies are administered. In an
embodiment, administering at least two distinct antibodies
suppressed formation of viruses that are resistant to the
antibodies. In one embodiment, the Z004 antibody and the Z021
antibody are administered.
[0019] In another aspect the disclosure provides vaccine
formulations. In an embodiment a vaccine formulation comprises: i)
an isolated or recombinant polypeptide or a polynucleotide encoding
the polypeptide, wherein the polypeptide is derived from the ZIKV
EDIII protein, wherein the polypeptide comprises a segment of the
lateral ridge of ZIKV EDIII (ZEDIII); or ii) an isolated or
recombinant polypeptide or a polynucleotide encoding the
polypeptide, wherein the polypeptide is derived from the DENV1
EDIII protein, wherein the polypeptide comprises a segment of the
lateral ridge of the DENV1 EDIII protein, or a combination of i)
and ii).
[0020] In certain implementations, a vaccine formulation comprises
a ZEDIII polypeptide which comprises at least one contiguous
segment of ZEDIII comprising amino acids 305-311, 333-336, or
350-352, and/or wherein the segment comprises one or more of ZEDIII
amino acids L307, S306, T309, K394, A311, E393, T335, G334, A310,
and D336, and/or wherein the polypeptide comprises one or more of
DENV1 EDIII amino acids M301, V300, T303, E384, T329, K385, S305,
E327, G328, and D330. In certain approaches, a ZIKV EDIII epitope
and/or a DENV1 EDIII epitope is duplicated in the polypeptide,
and/or the polypeptide comprises both ZIKV EDIII and DENV1 EDIII
epitopes. In certain approaches, the polypeptide in the vaccine is
modified such that it comprises one or more glycans, and/or by
addition of amino acids that comprise epitope(s), and/or the
polypeptide is stapled, and/or is cyclicized, and/or is
multimerized.
[0021] In another approach the disclosure provides a method for
prophylaxis or therapy of a viral infection comprising
administering to an individual in need thereof an effective amount
of at least one vaccine formulation described herein. In certain
embodiments, a first vaccination is performed with a polypeptide or
a polynucleotide encoding the polypeptide, wherein the polypeptide
is derived from the DENV1 EDIII protein, and wherein the
polypeptide comprises a segment of the lateral ridge of the DENV1
EDIII. This can be followed by performing a second vaccination with
a polypeptide or polynucleotide encoding the polypeptide, wherein
the polypeptide is derived from the ZIKV EDIII protein, and wherein
the polypeptide comprises a segment of the lateral ridge of ZIKV
EDIII (ZEDIII). Such vaccination approaches can stimulate
production of neutralizing antibodies in the individual that
inhibit infectivity of a virus selected from the group of viruses
consisting of Zika virus, dengue 1, 2, 3 or 4 viruses (DENV1-4),
yellow fever virus (YFV), West Nile virus (WNV), and combinations
thereof.
[0022] In another aspect, a method for detecting antibodies to Zika
virus (ZIKV) and/or dengue 1 virus (DENV1) is provided, and
comprises: contacting a biological sample with an isolated or
recombinant polypeptide derived from ZIKV EDIII protein, wherein
the polypeptide comprises a contiguous segment of the ZIKV EDIII
protein that includes an epitope that comprises amino acids
E393-K394 of the EDIII protein, and/or with an isolated or
recombinant polypeptide derived from DENV1 EDIII protein that
comprises a contiguous segment of the DENV1 EDIII protein that
includes an epitope that comprises amino acids E384-K385 of the
DENV1 EDIII protein, and directly or indirectly detecting a complex
comprising the polypeptide and the antibodies if the antibodies are
present in the biological sample. In embodiments, the method is
performed using an ELISA assay, such as a competition ELISA assay.
A suitable assays may further comprise contacting the biological
sample with the isolated or recombinant polypeptide with added
antibodies, wherein the added antibodies are detectably labeled,
and wherein the added antibodies compete with antibodies in the
biological sample (if present prior to the adding) for binding to
the isolated or recombinant polypeptide, and wherein less binding
of the added antibodies relative to a control indicates serologic
activity against ZIKV and/or DENV1 in the biological sample.
[0023] In another embodiment, a suitable assay further comprises
performing a control reaction. The control reaction substitutes a
recombinant polypeptide derived from ZIKV EDIII protein with a
recombinant polypeptide derived from ZIKV EDIII protein that
comprises a mutation of E393 and/or K394, wherein the mutation is
optionally a substitution of E and/or K with an alanine, and
comparing an antibody binding value from the control reaction with
an antibody binding value to characterize serologic activity
against ZIKV in the biological sample.
[0024] In another aspect the disclosure provides one or more
recombinant expression vectors, and kits comprising the expression
vectors. The expression vectors encode the heavy chain and the
light chain of any of the antibodies of described herein. Cells
comprising the recombinant expression vectors are included, as are
methods of making antibodies by culturing cells that comprise
expression vectors that express the antibodies, and separating
antibodies from the cells. Cell culture media containing such cells
and/or antibodies is also included.
BRIEF DESCRIPTION OF THE FIGURES
[0025] FIGS. 1A-1B--Identification of individuals with high ZEDIII
binding and neutralization capacity.
[0026] FIG. 1A--Sera from the Brazilian and Mexican cohorts were
screened by ELISA for IgG antibodies binding to ZEDIII. Each dot
represents an individual donor. Optical densities are normalized to
control serum from a flavivirus naive individual vaccinated for
YFV. In black are sera selected for neutralization analysis. FIG.
1B--The neutralization capacity of selected sera from Mexico (dark
grey) and Brazil (light grey) was determined by a ZIKV luciferase
reporter viral particle (RVP) neutralization assay. The reciprocal
of the serum dilution that resulted in 50% inhibition compared to
RVP alone is reported as the 50% neutralization titer (NT.sub.50).
The dotted line indicates the lower limit of dilutions that were
examined. The five samples below the dotted line have NT.sub.50
values lower than 10.sup.3. Individuals from whom antibodies were
sequenced and cloned are indicated.
[0027] FIGS. 2A-2C--Discovery of ZEDIII-specific antibodies.
[0028] FIG. 2A--Frequency of ZEDIII-specific, IgG.sup.+ memory B
cells in peripheral blood of 6 donors. Flow cytometry plots display
the percentage of all IgG.sup.+ memory B cells that bind to a
fluorescently tagged ZEDIII bait. Flavivirus naive peripheral blood
samples are shown alongside as negative controls. FIG. 2B--Pie
charts show the distribution of antibody clones that share the same
IGHV and IGLV; the width of each colored or shaded slice is
proportional to the number of clones sharing a distinct combination
of IGHV and IGLV sequences. The total number of antibody clones
sequenced from each donor is indicated in the center of the pie
chart. VH3-23/VK1-5 clones are in red, while other VH3-23 clones
are indicated with different shades of blue. Non VH3-23 clones are
shown in shades of grey, and singlets are in white. None of the
grey clones are recurrent across individuals. FIG. 2C--V(D)J
assignments for the VH3-23/VK1-5 clones. IgBLAST was used to assign
the germline (GL) reference sequence for IGHV and IGLV. Red
highlights differences in D and J usage in the VH3-23 clones
between individuals.
[0029] See also FIG. 8, and Tables 1 and 2.
[0030] FIGS. 3A-3D--Binding of cloned antibodies to EDIII from ZIKV
and other flaviviruses.
[0031] FIG. 3A--Binding of human monoclonal antibodies to ZEDIII.
Human anti-HIV antibody 10-1074 was used as a negative control
(Mouquet et al., 2012). The average half effective concentration
(EC.sub.50) from at least two independent experiments is shown.
FIG. 3B--Somatic mutations are required for ZEDIII binding. Binding
of Z004 (arrow), its predicted germline (GL), and control
antibodies to ZEDIII as assessed by ELISA is shown. FIG. 3C--Human
monoclonal antibody cross-reactivity by ELISA. Reactivity to the
EDIII of the indicated flaviviruses is shown in grey. The list of
antibodies is reported on the left of panel A. FIG. 3D--Z004 binds
to the EDIII of DENV1. Binding of Z004 (arrow), its predicted
germline (GL), and control antibodies to DENV1 EDIII as assessed by
ELISA is shown.
[0032] See also FIGS. 9A-C.
[0033] FIGS. 4A-4I--VH3-23/VK1-5 antibodies neutralize ZIKV and
DENV1.
[0034] FIG. 4A--Neutralization potency of human monoclonal
antibodies by ZIKV luciferase RVP assay. The human anti-HIV
antibody 10-1074 serves as a negative control. Average values of
the half maximal inhibitory concentration (IC50) from at least two
independent experiments are shown. FIG. 4B and FIG. 4C--Z004
neutralizes ZIKV (B) and DENV1 (C) RVPs. Luciferase activity
relative to the no antibody control was determined in the presence
of increasing concentrations of Z004 (arrow) or of its predicted
germline antibody as indicated. Control antibody was tested at a
single concentration. Data are represented as mean.+-.SD. FIG. 4D,
FIG. 4E, and FIG. 4F--Z004 protects IFNAR1.sup.-/- mice from ZIKV
disease. Mice were infected by footpad (f.p.) injection with the
Puerto Rican PRVABC59 ZIKV strain and treated intraperitoneally
(i.p.) with Z004 (or 10-1074 control) either before (E) or 1 day
after (F) infection. Mice were monitored for symptoms and survival.
Survival: p<0.0001 (pre-exposure) and p=0.0027 (post-exposure).
Symptoms: p<0.0001 (both pre- and post-exposure, Mantel-Cox
test). Three independent experiments, of 4 to 7 mice per group,
were combined and displayed. FIG. 4G--Amino acid alignment of a
portion of the EDIII lateral ridge region for a panel of
flaviviruses (SEQ ID NOS 1061-1069, respectively, in order of
appearance). The corresponding accession numbers are indicated in
parenthesis. FIG. 4H--The K394 residue in the ZEDIII lateral ridge
is required for ZIKV neutralization by Z004. Luciferase activity
relative to no antibody control was determined for ZIKV wild type
or mutant E393A and K394A RVPs. FIG. 4I--Z004 neutralizes both
Asian/American and African strains. RVPs bearing Asian/American
ZIKV wild type (E393), mutant (Asian/American with E393D) and
African strain (D393) E proteins were neutralized by Z004. In H and
I data are represented as mean.+-.SD.
[0035] See also FIGS. 10A-10E.
[0036] FIGS. 5A-5F--Structures of Fab complexes with ZIKV and DENV1
EDIII domains.
[0037] FIG. 5A--Superimposition of Z006 Fab-ZEDIII and Z004
Fab-DENV1 EDIII crystal structures after alignment of the EDIII
domains. The V.sub.H domain positions differ by a 14.degree.
rotation about an axis passing through the center of the interface.
Inset: close-up of interactions between the
E393.sub.ZIKV-K394.sub.ZIKV/E384.sub.DENV1-K385.sub.DENV1 motif
(shown as sticks) within the EDIII lateral ridge and the two Fabs.
Fab CDRs are highlighted. FIG. 5B--Overlay of the Z006-ZEDIII
complex structure (EDIII in black) with previously solved
structures of antibodies in complex with ZIKV and DENV1 EDIII
domains. The E393.sub.ZIKV-K394.sub.ZIKV side chains in ZEDIII are
shown as spheres. Structures were aligned on the EDIII domains;
only ZEDIII is shown for clarity. FIG. 5C--ZEDIII epitope: EDIII
residues contacted by Z006 Fab are highlighted on a surface
representation of the EDIII structure. Residues making interactions
with both V.sub.H and V.sub.L are dark grey. The
E393.sub.ZIKV-K394.sub.ZIKV motif is outlined. Contacts between the
Z004 Fab and DENV1 EDIII were less extensive than Z006-ZEDIII
contacts, in part because of disorder of the CC' loop in DENV1
EDIII (residues 343-349). FIG. 5D to FIG. 5F--Comparison of key
antibody-antigen interactions for Z006 Fab-ZEDIII and Z004
Fab-DENV1 EDIII structures. Hydrogen bonds are shown as dotted
lines. FIG. 5D--Fab interactions with K394.sub.ZIKV/K385.sub.DENV1.
FIG. 5E--Fab interactions with E393.sub.ZIKV/E384.sub.DENV1. FIG.
5F--Y58.sub.HC (germline-encoded in VH3-23) interactions with
antigen.
[0038] See also Tables 5 and 6.
[0039] FIGS. 6A-6B--EDIII reactivity over time.
[0040] FIG. 6A--A set (n=63) of paired sera from the Brazilian
cohort participants were collected in April and November 2015 and
assayed for binding to flavivirus EDIII. Optical densities are
normalized as described in FIG. 1A. Paired sera from the same
individual are connected by a line. Each value represents the
average of two independent measurements. P values were determined
with the two-tailed paired t test (n.s., not significant). FIG.
6B--Correlation between DENV1 EDIII reactivity in April and ZEDIII
reactivity in November 2015. Circles and plus signs distinguish
data from two independent experiments. Pseudo-.rho.=0.48,
p<0.001 by univariate analysis.
[0041] FIGS. 7A-7E--EDIII antibodies contribute to the serologic
response and ZIKV neutralization capacity.
[0042] FIG. 7A--Competition ELISA shows the increase within
individuals of serum antibodies that block biotin-Z004 ZEDIII
binding after ZIKV exposure. Each dot represents a serum sample
(n=62 at each of the indicated time points). A line connects sera
from the same individual obtained at different time points. The p
value was determined with the two-tailed paired t test. FIGS. 7B
and 7C--The estimated quantity (.mu.g/ml) of Z004 blocking
antibodies in the serum obtained after ZIKV introduction (X axes)
was plotted with the overall serum binding activity to ZEDIII (Y
axis, B), and the change in that individual's serum ZEDIII binding
from before to after ZIKV (Y axis, C). Binding activity change was
determined by subtracting the pre- from the post-ZIKV ELISA
relative optical density value (average of two independent
measurements). Each dot represents an individual (n=62, two-tailed
Spearman r test). FIGS. 7D and 7E--Serum neutralization potency
expressed as NT.sub.50 versus the overall serum binding activity to
ZEDIII (D), or Z004 blocking antibody concentrations in sera (E)
obtained after ZIKV introduction are plotted. Each dot represents a
serum sample from a single donor (n=27, two-tailed Spearman r
test). Representative of two independent experiments is shown.
[0043] FIG. 8--Maximum likelihood tree of VH3-23/VK1-5 antibodies.
Related to FIGS. 2A-2C and Table 1.
[0044] Antibody amino acid sequences (heavy and light chain
combined) are clustered and labeled according to the donor ID
(MEX18, MEX105, MEX84, BRA112, BRA12) followed by the clone's
unique sequence ID.
[0045] FIGS. 9A-9C--Features of anti-ZIKV antibodies. Related to
FIGS. 3A-3D and Table 1.
[0046] FIG. 9A--Dose-dependent binding of recombinant human
monoclonal antibodies to ZEDIII as measured by ELISA.
Representative non-linear regression curves are shown. FIGS. 9B and
9C--VH3-23/VK1-5 antibodies have low levels of somatic mutation.
The number of V gene nucleotide (FIG. 9B) or amino acid (FIG. 9C)
mutations at Heavy (H) and Light (L) chain genes are shown for each
donor. Each dot represents one individual antibody V gene (n=69).
The average number of nucleotide mutations overall is 27.7 within
VH3-23 and 17.5 within VK1-5. The average number of amino acid
mutations overall is 14.3 at VH3-23 and 10.6 at VK1-5.
[0047] FIGS. 10A-10E--Neutralization and polyreactivity of
anti-ZIKV antibodies. Related to FIGS. 4A-4I.
[0048] FIG. 10A--Dose-dependent neutralization of ZIKV RVPs by
recombinant human monoclonal antibodies. Luciferase activity
relative to no antibody control is determined in the presence of
increasing antibody concentrations. Data are represented as
mean.+-.SD. FIG. 10B--ZIKV neutralization by Z004 antibody assessed
by PRNT assay. FIG. 10C--DENV1 neutralization by Z004 antibody
measured by a flow cytometry-based assay. The number of infected
cells was determined using the pan-flavivirus monoclonal antibody
4G2. Data are represented as mean.+-.SD. FIG. 10D--Z004 protects
IFNAR1.sup.-/- mice from ZIKV infection. Three independent
experiments were performed as described in FIG. 4D-F; results were
pooled and presented in FIG. 4. FIG. 10E--Low auto- and
polyreactivity profile of Z004. ELISA measures Z004 binding over a
range of concentrations against the following antigens:
single-stranded DNA (ssDNA), double-stranded DNA (dsDNA),
lipopolysaccharides (LPS), insulin, and keyhole limpet hemocyanin
(KLH).
[0049] FIGS. 11A-11D--Treatment with Z004 antibody alone leads to
the emergence of resistant ZIKV in rhesus macaques (Macaca
mulatta).
[0050] FIG. 11A--Macaques were administered Z004 (arrows) or
remained untreated (black) one day before intravenous inoculation
with 10.sup.5 PFU of ZIKV. Graph shows plasma viral RNA levels of
ZIKV over time as determined by RT-qPCR. FIG. 11B--Mutations
emerging in macaques treated with Z004 alone. An alignment in the
region of residues E393/K394 (in bold) is shown at the top (SEQ ID
NOS 1061, 1070, 1062, and 1070, respectively, in order of
appearance) and chromatograms of the PCR amplicons showing the
mutations (indicated by arrows) are shown at the bottom. In macaque
6414, E393D and K394R are on separate viruses, as determined by
sequencing of the cloned amplicon. FIG. 11C--Footprint of the
Z004-related antibody Z006 onto the EDIII of ZIKV. The E393/K394
residues are highlighted. FIG. 11D--Impaired binding of Z004 to the
EDIII escape mutants. ELISA demonstrates impaired binding of Z004
Fab to EDIII.sub.E393D and EDIII.sub.K394R. The positive control
antibody Z015 recognizes an epitope that is independent of Z004.
Data are represented as mean.+-.SD of triplicates and a
representative of two experiments is shown. See also FIGS.
5A-5F.
[0051] FIGS. 12A-12E--Antibody Z021 neutralizes ZIKV in vitro and
in mice.
[0052] FIG. 12A--Z021 is effective against ZIKV. ZIKV
neutralization was determined by measuring the ability of
increasing concentrations of Z021 to reduce the number of plaques
in a PRNT assay. Data are represented as mean.+-.SD of two
independent experiments. FIG. 12B--Z021 is effective against DENV1.
DENV1 neutralization was assessed by measuring the number of 4G2
positive infected cells by flow cytometry. Data are represented as
mean.+-.SD of triplicates and a representative of two experiments
is shown. In FIGS. 12A and 12B values are relative to control
antibody 10-1074 and antibody Z004 is shown alongside for
comparison.sup.5. FIGS. 12C-12E--Z021 protects mice from ZIKV
disease. FIG. 12C--Ifnar1.sup.-/- mice were treated with Z021 or
control 10-1074 antibody 1 day before (FIG. 12D) or 1 day after
(FIG. 12E) challenge with ZIKV in the footpad (f.p.). Mice were
monitored for symptoms and survival. The graph indicates death or
symptoms. Survival: p<0.0001 (pre-exposure) and p=0.0002
(post-exposure). Symptoms: p=0.0002 (pre-exposure) and p=0.0006
(post-exposure; Mantel-Cox test). Data represent two combined
experiments.
[0053] FIGS. 13A-13C--Antibodies Z021 and Z004 recognize distinct
epitopes.
[0054] FIG. 13A--Residues E393/K394 of ZIKV EDIII are dispensable
for Z021 binding. Graphs show ELISA binding to ZIKV EDIII by
increasing concentrations of antibody Z004 (left) or Z021 (right)
after blocking with wild type EDIII or EDIII.sub.E393A/K394A. FIG.
13B--Residues E393/K394 are dispensable for ZIKV neutralization by
Z021. Graphs show neutralization of ZIKV luciferase RVPs by Z021
and Z004 using wild type RVPs (left) or RVPs mutated at the Z004
binding site (E393A/K394A; right). Data are represented as
mean.+-.SD of triplicates and a representative of two experiments
is plotted. Values are relative to no antibody control. FIG.
13C--The epitopes of Z004 and Z021 are overlapping. ZIKV EDIII
antigen was immobilized with either Z021 IgG (left) or Z004 IgG
(right) before detection by ELISA with Fragments antigen binding
(Fab) of Z021 and Z004. The positive control Z015 Fab recognizes an
epitope that is independent of both Z021 and Z004.sup.5. Data are
represented as mean.+-.SD from one experiment done in
quadruplicate.
[0055] FIGS. 14A-14C--Comparison of Z021 and Z004 Fab binding to
the ZIKV and DENV1 EDIII domain.
[0056] FIG. 14A--Superimposition of Z021 Fab-ZIKV and Z021
Fab-DENV1. The E394 and K395 residues of ZIKV are highlighted. FIG.
14B--Superimposition of Z021 Fab-DENV1 EDIII with Z004 Fab-DENV1
(PDB ID: 5VIC). The V.sub.HV.sub.L of Z021 Fab is rotated
.about.48.degree. around an axis near CDRH2 compared to the Z004
V.sub.HV.sub.L bound to the same antigen. FIG. 14C--DENV1 EDIII
residues within 4 .ANG. of Z021 Fab, Z004 Fab, or both are
highlighted on surface representations of the DENV1 EDIII
structure. The E384/K385.sub.DENV1 motif is outlined. The two
panels are related by a 90.degree. rotation.
[0057] FIG. 15--The combination of Z004 and Z021 protects ZIKV
challenged macaques from viral escape.
[0058] Macaques were administered the combination of Z004 and Z021
or their Fc mutant version (Z004-GRLR and Z021-GRLR) one day before
intravenous inoculation with high-dose (10.sup.5 PFU) of ZIKV.
Graph shows plasma viral RNA levels of ZIKV over time as determined
by RT-qPCR. No mutations were detected in the EDIII region of the
emerging virus in the combination treated macaques.
[0059] FIG. 16--The combination of Z004-GRLR and Z021-GRLR
antibodies fully protects from subcutaneous challenge with 10.sup.3
PFU of ZIKV.
[0060] Macaques were co-administered Z004-GRLR and Z021-GRLR one
day before infection. Graph shows plasma viral RNA levels of ZIKV
over time, as determined by RT-qPCR.
[0061] FIG. 17--ZIKV mutations in Ifnar1.sup.-/- mice. Related to
FIGS. 11A-11D.
[0062] Summary of the analysis of ZIKV EDIII sequences from
infected mouse blood at the indicated time points. Empty cell is
sequence not determined, grey cell is symptomatic mouse, wt is wild
type EDIII sequence. The only identified mutation (K394R) was in a
mouse treated with Z004.
[0063] FIGS. 18--Z021 neutralizes ZIKV RVPs corresponding to both
the Asian/American and the African strain. Related to FIGS.
12A-12F.
[0064] Neutralization by Z004 is shown alongside for comparison.
Data are represented as mean.+-.SD of triplicates.
[0065] FIG. 19--Human IgG levels in macaque plasma over time.
Related to FIG. 15.
[0066] The levels of human IgG antibodies were determined by ELISA.
The top panel displays human IgGs in individual macaques, the
bottom panel shows the mean for each group. Macaques were
administered 15 mg/kg of each of the antibodies on day -1. The mean
peak antibody levels on the day of infection (day 0) were 334
.mu.g/ml in the Z004+Z021 group and 326 .mu.g/ml in the
Z004-GRLR+Z021-GRLR group. The antibody levels on day 15 were 32
.mu.g/ml in the Z004+Z021 group and 34 .mu.g/ml in the
Z004-GRLR+Z021-GRLR group, resulting in plasma half-lives of 4.4
days and 4.6 days, respectively.
[0067] FIGS. 20A-20D--Z004 with engineered modifications at the
antibody Fc portion that prevent Fc-gamma receptor binding (GRLR
mutation;.sup.25,26) and extend the half-life (LS
mutation;.sup.27,28) prevents ADE and remains effective against
ZIKV. Related to FIG. 15.
[0068] FIG. 20A--ADE of Fc-gamma receptor bearing K562 cells is
abrogated with Z004 antibodies bearing GRLR and GRLR/LS
substitutions. Data are represented as mean.+-.SD of triplicates.
Positive control (+) is wild type Z004 antibody (10 ng/ml). FIG.
20B--Surface plasmon resonance (SPR) binding profile of Z004
bearing the LS and GRLR mutations alone or in combination. FIGS.
20C-20D--Z004 antibodies bearing the LS and GRLR substitutions
alone or in combination remain effective against ZIKV RVPs in vitro
(FIG. 20C) or ZIKV in vivo (FIG. 20D).
[0069] FIGS. 21A-21C--Z021 with substitutions that prevent Fc-gamma
receptor binding (GRLR) and extend the half-life (LS) prevents ADE
and remains effective against ZIKV. Related to FIG. 15.
[0070] FIG. 21A--ADE is abrogated with Z021 antibodies bearing GRLR
and GRLR/LS substitutions. Data are represented as mean.+-.SD of
triplicates. Positive control (+) is wild type Z004 antibody (10
ng/ml). FIGS. 21B-21C--Z021 antibodies bearing the LS and GRLR
substitutions remain effective against ZIKV RVPs in vitro (FIG.
21B) or ZIKV in vivo (FIG. 21C).
[0071] FIGS. 22A-22B--Immunizing wild type mice with DENV1 EDIII
before ZIKV EDIII enhances the mice neutralizing antibody response
against ZIKV.
[0072] FIG. 22A--Sequential immunization with DENV1 followed by
ZIKV EDIII proteins improves antibody titers to the ZEDIII lateral
ridge. Competition ELISA with the biotinylated antibody Z004 was
used to estimate the concentration of antibodies to the lateral
ridge of ZIKV. * is p<0.05. FIG. 22B--Sequential immunization
with DENV1 followed by ZIKV EDIII proteins induces higher
neutralization in more mice. IgG was purified from mouse serum and
assayed for neutralization using ZIKV RVPs. IC50 is in
.mu.g/ml.
DESCRIPTION OF INVENTION
[0073] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
[0074] Every numerical range given throughout this specification
includes its upper and lower values, as well as every narrower
numerical range that falls within it, as if such narrower numerical
ranges were all expressly written herein.
[0075] This disclosure includes every nucleotide sequence described
herein, and in the tables and figures, and all sequences that are
complementary to them, RNA equivalents of DNA sequences, all amino
acid sequences described herein, and all polynucleotide sequences
encoding the amino acid sequences. Every antibody sequence and
functional fragments of them are included. Polynucleotide and amino
acid sequences having from 80-99% similarity, inclusive, and
including ranges of numbers there between, with the sequences
provided here are included in the invention. All of the amino acid
sequences described herein can include amino acid substitutions,
such as conservative substitutions, that do not adversely affect
the function of the protein or polypeptide that comprises the amino
acid sequences. It will be recognized that when reference herein is
made to an "antibody" it does not necessarily mean a single
antibody molecule. For example, "administering an antibody"
includes administering a plurality of the same antibodies.
Likewise, a composition comprising an "antibody" can comprise a
plurality of the same antibodies.
[0076] Those skilled in the art will recognize that representative
sequences from specific ZIKV and DENV1 viruses are presented for
use in vaccine formulations and diagnostic approaches, but other
sequences from different strains of these viruses are encompassed
by this disclosure. The disclosure includes polynucleotides
encoding antigens and antibodies from which introns present in the
genomic DNA have been removed, i.e., cDNA sequences and DNA
sequences complementary thereto.
[0077] For amino acid and polynucleotide sequences of this
disclosure contiguous segments of the sequences are included, and
can range from 2 amino acids, up to full-length viral protein
sequences. Polynucleotide sequences encoding such segments are also
included.
[0078] The disclosure includes DNA and RNA sequences encoding the
antibodies and virus peptides described herein for use in
prophylactic and therapeutic approaches as protein or DNA and/or
RNA vaccines, which may be formulated and/or delivered according to
known approaches, given the benefit of this disclosure.
[0079] From DNA sequences and amino acid sequences presented in the
tables of this disclosure antibody complementarity determining
region (CDR) sequences can be identified by using publicly
available databases, such as IGBLAST (www.ncbi.nlm.nih.gov/igblast)
using the germline database.
[0080] The disclosure includes antibodies described herein, which
are present in an in vitro complex with a ZIKV or a DENV1
protein.
[0081] In certain approaches compositions and methods of this
disclosure may be adapted for use in non-human animals that may be
determined to be an actual or potential reservoir or vector for the
Zika and/or dengue viruses. Thus, veterinary compositions and
methods of administering them are included.
[0082] From the examples and descriptions of this disclosure it
will be apparent to those skilled in the art that the instant
disclosure can be distinguished from studies that have examined
anti-ZIKV antibodies developing in a small number of available
individuals (Sapparapu et al., 2016; Stettler et al., 2016; Wang et
al., 2016). In contrast, we screened sera from more than 400 donors
from ZIKV epidemic areas of Mexico and Brazil to select high
responders. Serologic reactivity to ZIKV varied greatly among
individuals, with neutralization potencies spanning over more than
2 logs. To better understand this activity we isolated 290 memory B
cell antibodies from 6 individuals with high serum neutralizing
activity. The sequencing experiments revealed the existence of
expanded clones of memory B cells expressing E protein lateral
ridge-specific ZIKV and DENV1 neutralizing VH3-23/VK1-5 antibodies
in 4 of the 6 individuals.
[0083] Three separate groups have cloned human anti-ZIKV E protein
reactive antibodies before the present disclosure (Sapparapu et
al., 2016; Stettler et al., 2016; Wang et al., 2016). In all they
studied 8 individuals and documented 92 antibodies to the E
protein. The great majority of these antibodies (79) were obtained
by screening supernatants of Epstein-Barr virus transformed B
lymphocytes for binding to ZIKV, and only a minority (15) were
directed to the ZEDIII. Among all of these antibodies there was
only a single expanded clone containing 3 related VH1-46/VK1-39
antibodies specific for a yet to be determined E epitope. These 3
antibodies were relatively poor neutralizers (3-257 .mu.g/ml) (Wang
et al., 2016). There was also a single VH3-23/VK1-5 antibody that
targeted the ZEDIII and neutralized ZIKV (ZIKV-116), but this
antibody is believed to be different than those of this disclosure
because it failed to neutralize the African ZIKV strain (Sapparapu
et al., 2016). Thus, there was no prior indication of a potent
recurrent neutralizing response to ZIKV.
[0084] We found a total of 69 individual VH3-23/VK1-5 memory B
cells antibodies in 5 out of 6 individuals. In addition to
recurring V gene segments, VH3-23/VK1-5 antibodies bear the same
IGL J gene, and a limited set of IGH D and J genes. These
antibodies are closely related and they are potent neutralizers
with IC.sub.50 values ranging from 0.7-4.6 ng/ml. This variation in
activity is likely due to somatic mutations, since predicted
germline versions of the VH3-23/VK1-5 antibodies bind to ZEDIII and
neutralize the virus only weakly. Thus, and without intending to be
constrained by any particular theory, it is considered that somatic
mutations are required for optimal VH3-23/VK1-5 antibody
neutralizing activity.
[0085] Recurring antibodies that share the same IGV genes and the
same molecular interactions with antigen have not been reported for
ZIKV or other flaviviruses before the present disclosure, but they
have been described in other viral infections including HIV-1 and
influenza. Broadly neutralizing antibodies targeting the CD4
binding site of HIV-1 frequently utilize VH1-2 or VH1-46 genes
(Scheid et al., 2011; West et al., 2012), and broadly neutralizing
antibodies to Influenza utilize VH1-69 (Laursen and Wilson, 2013;
Pappas et al., 2014; Sui et al., 2009; Throsby et al., 2008;
Wrammert et al., 2011). However, in both HIV-1 and influenza, the
VH genes can be paired with a collection of different VL genes, a
finding that was explained by structural analysis showing that many
of the essential contacts made by influenza and HIV-1 antibodies
involve variable portions of the IGHV (Ekiert et al., 2009; Pappas
et al., 2014; Scheid et al., 2011; Wrammert et al., 2011; Zhou et
al., 2010).
[0086] Although the Z004 and the related Z006 antibodies have
CDRH3s and CDRL3s of different lengths they share a common mode of
EDIII binding. Several shared sequence features may be important
for this binding mode. The most suggestive of these is R96.sub.HC.
This CDRH3 residue appears to derive from N region addition, thus
the different VH3-23/VK1-5 clones do not share this residue due to
shared germline genes. Examination of a large collection (n=44,270)
of VH3-23-derived antibody sequences indicates that only 13% have R
at position 100 (Rubelt et al., 2012). However, 68 of 69 of the
sequenced VH3-23/VK1-5 clones contain R96. The clones also tend to
conserve the germline residues forming the Z004/Z006/EDIII common
interactions: Y58.sub.HC, W32.sub.LC, Y91.sub.LC, and
S93.sub.LC.
[0087] Without intending to be bound by any particular
interpretation, the requirement for conserved IGHV and IGLV genes
in VH3-23/VK1-5 antibodies appears to be explained in part by
interactions using germline residues. For the light chain, CDRL1
germline residue W32.sub.LC interacts with K394.sub.ZIKV. Few IGLV
genes contain W32; the most common of these is VK1-5 (followed by
VK1-12, but this gene is several-fold less common than VK1-5). For
the heavy chain, residue Y58.sub.HC (present in the VH3-23
germline) makes a contact with EDIII residue 307.sub.ZIKV.
Y58.sub.HC is present in .about.50% of VH germlines, potentially
explaining a portion of the restriction. Finally, VH3-23 is among
the most frequently used VH genes as is VK1-5 (Arnaout et al.,
2011; DeKosky et al., 2015). Therefore it is likely that naive B
cell precursors carrying DENV1 and ZIKV reactive VH3-23/VK1-5
antibodies would also be common in the pre-immune repertoire making
this epitope a particularly attractive vaccine candidate.
[0088] VH3-23/VK1-5 antibodies recognize and neutralize both DENV1
and ZIKV, suggesting that clones of VH3-23/VK1-5 producing B cells
originally elicited in response to DENV1 were further expanded in
response to ZIKV. This prime-boost, or original antigenic sin
hypothesis, is supported by two observations. First, pre-existing
antibodies to DENV1 EDIII are associated with a higher antibody
response to ZEDIII. Second, at the population level, the
introduction of ZIKV correlates with an increase in DENV1
EDIII-reactive antibodies at a time when DENV1 was not circulating.
Although DENV1 and ZIKV only share 50% amino acid identity in
EDIII, they are structurally very similar, particularly in the
lateral ridge region that is recognized by VH3-23/VK1-5 (FIG. 5).
Thus, DENV1 EDIII reactive memory B cells have a significant
probability of being cross-reactive to ZEDIII. A primary response
to DENV1 would increase the frequency of these ZIKV cross-reactive
memory B cells and thereby increase their likelihood of undergoing
clonal expansion in response to ZIKV. Consistent with this, memory
B cells with VH3-23/VK1-5 antibodies represent close to half of all
ZEDIII-specific B cell clones in 3 of the 6 individuals
examined.
[0089] Infection by DENV1 confers transient protection to infection
by DENV2 (Sabin, 1950, 1952). Whether prior DENV1 infection also
protects from ZIKV by cross-priming or in other cases enhances
infection is unclear (Castanha et al., 2016; Dejnirattisai et al.,
2016; Priyamvada et al., 2016; Swanstrom et al., 2016; Wahala and
Silva, 2011). However, the existence of human antibodies to DENV
that cross-neutralize or enhance ZIKV in vitro indicates that
protection by cross-priming is possible (Barba-Spaeth et al., 2016;
Dejnirattisai et al., 2016; Harrison, 2016; Pierson and Graham,
2016; Priyamvada et al., 2016; Stettler et al., 2016; Swanstrom et
al., 2016).
[0090] ZIKV infection is asymptomatic in most people. Only 20% of
ZIKV infected individuals develop symptoms, and in those cases the
severity of the disease varies broadly (Miner and Diamond, 2017).
Similarly, the spectrum and incidence of developmental sequelae in
infants born to women infected with ZIKV during pregnancy differs
within and across geographic areas with risk estimates that range
from 6-42% (Brasil et al., 2016; Honein et al., 2017). Examples of
this disclosure indicate a cellular and molecular explanation for
how a history of DENV1 exposure could alter host responses and
susceptibility to ZIKV.
[0091] In embodiments, the disclosure provides an isolated or
recombinant antibody that binds with specificity to a neutralizing
epitope in the lateral ridge of Zika virus (ZIKV) envelope domain
III (ZEDIII) protein, wherein the epitope comprises E393-K394 of
the ZEDIII protein, and wherein the antibody optionally comprises a
modification of the amino acid sequence, including but not limited
to a modification of its constant region. Such antibodies can also
bind with specificity to a neutralizing epitope of dengue 1 virus
(DENV1) EDIII protein. Specific and non-limiting examples of
antibodies are provided herein, along with amino acid sequences of
pertinent parts of the antibodies, including heavy (H) and light
(L) chain sequences.
[0092] All combinations of H and L chains are included. In
embodiments, a single antibody of this disclosure may comprise an
H+L chain from one antibody, and an H+L chain from another antibody
that is described below. In embodiments, the modifications are not
coded for in any B cells obtained from an individual, and/or the
antibodies are not produced by immune cells in an individual from
which a biological sample from the individual is used at least in
part to identify and/or generate and/or characterize the antibodies
of this disclosure. In embodiments, antibodies provided by this
disclosure can be made recombinantly, and can be expressed with a
constant region of choice, which may be different from a constant
region that was coded for in any sample from which the amino acid
sequences of the antibodies were deduced.
[0093] In certain approaches the disclosure provides one or more
isolated or recombinant antibodies comprising a complementarity
determining region 3 (CDR3) amino acid sequence selected from heavy
chain and light chain CDR3 sequences in Table 1 and Table 2, and
combinations of said heavy and light chain CDR3 amino acid
sequences. In non-limiting embodiments the disclosure includes
amino acid sequences encoded by VH3-23/VK1-5 human immunoglobulin
genes, but all of the H and L gene segments described herein and
the proteins they encode are included in the invention.
[0094] In certain embodiments, the antibodies contain one or more
modifications, such as non-naturally occurring mutations,
non-limiting examples of which are further described herein. In
non-limiting examples, antibodies described herein can be modified
according to various approaches that will be apparent to those
skilled in the art, given the benefit of this disclosure. In
certain approaches the Fc region of the antibodies can be changed,
and may be of any isotype, including but not limited to any IgG
type, or an IgA type, etc. Antibodies of this disclosure can be
modified to improve certain biological properties of the antibody,
e.g., to improve stability, to modify effector functions, to
improve or prevent interaction with cell-mediated immunity and
transfer across tissues (placenta, blood-brain barrier,
blood-testes barrier), and for improved recycling, half-life and
other effects, such as manufacturability and delivery.
[0095] In embodiments, an antibody of this disclosure can be
modified by using techniques known in the art, such as those
described in Buchanan, et al., Engineering a therapeutic IgG
molecule to address cysteinylation, aggregation and enhance thermal
stability and expression mAbs 5:2, 255-262; March/April 2013, and
in Zalevsky J. et al., (2010) Nature Biotechnology, Vol. 28, No. 2,
p 157-159, and Ko, S-Y, et al., (2014) Nature, Vol. 514, p 642-647,
and Horton, H. et al., Cancer Res 2008; 68: (19), Oct. 1, 2008,
from which the descriptions are incorporated herein by reference.
In certain embodiments an antibody modification increases in vivo
half-life of the antibody (e.g. LS mutations), or alters the
ability of the antibody to bind to Fc receptors (e.g. GRLR
mutations), or alters the ability to cross the placenta or to cross
the blood-brain barrier or to cross the blood-testes barrier. In
embodiments bi-specific antibodies are provided by modifying and
combining segments of antibodies as described herein, such as by
combining heavy and light chain pairs from distinct antibodies into
a single antibody. Suitable methods of making bispecific antibodies
are known in the art, such as in Kontermann, E. et al., Bispecific
antibodies, Drug Discovery Today, Volume 20, Issue 7, July 2015,
Pages 838-847, the description of which is incorporated herein by
reference.
[0096] In embodiments, any antibody described herein comprises a
modified heavy chain, a modified light chain, a modified constant
region, or a combination thereof, thus rendering them distinct from
antibodies produced by humans. In embodiments, the modification is
made in a hypervariable region, and/or in a framework region (FR).
In certain embodiments an antibody modification increases in vivo
half-life of the antibody and/or alters the ability of the antibody
to bind to Fc receptors. In embodiments, the mutations comprise LS
or GRLR mutations. In certain embodiments an antibody modification
increases in vivo half-life of the antibody by way of LS mutations,
or alters the ability of the antibody to bind to Fc receptors by
way of GRLR mutations. In embodiments, the mutation(s) can thus
comprise a change of G to R, L to R, M to L, or N to S, or any
combination thereof.
[0097] In embodiments, mutations to an antibody described herein,
including but not limited to the antibodies described below as Z004
and Z021, comprise modifications relative to the antibodies
originally produced in humans. Such modifications include but are
not necessarily limited to the heavy chain of Z004, which can
comprise G241R and/or L333R mutations to prevent binding to Fc
gamma receptors, and/or M433L/N439S mutations to increase the
antibody half-life.
[0098] In an embodiment, a Z004 IgG1 heavy chain comprises or
consists of a contiguous segment or the entire sequence:
TABLE-US-00005 (SEQ ID NO: 15)
EVQLLESGGGLVQPGGSLRLTCATSGFTFRDYAMSWVRQAPGKGLEWVSS
YSGIDDSTYYADSVKGRFTISRDNSKSTLSLHMNSLRAEDSALYFCAKDR
GPRGVGELFDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL
VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL GPSVFLEPP
KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ
YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA PAPIEKTISKAKGQPRE
PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP
PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV HEALHSHYTQKSLSLSP G.
In this SEQ ID NO: 15 the variable sequence is bolded, and the
remaining sequence comprises Fc sequence which is shown with the
G241R and/or L333R mutations to prevent binding to Fc gamma
receptors and M433L/N439S mutations to increase the antibody
half-life in bold and italics. A C-terminal lysine was removed to
reduce micro-heterogeneity (removed lysine not shown).
[0099] In an embodiment, a Z004 light chain comprises or consists
of a contiguous segment or the entire sequence:
TABLE-US-00006 (SEQ ID NO: 16)
DIQMTQSPSTLSASVGDRVTITCRASQSISKWLAWYQQKPGKAPKWYTTS
TLKSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHFYSVPWTFGQGT
KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN
ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS
SPVTKSFNRGEC.
In this sequence the variable region is shown in bold.
[0100] In an embodiment, a Z021 heavy chain includes an IgG1, with
modifications that can include G237R/L329R mutations to prevent
binding to Fc gamma receptors, M429L/N435S mutations to increase
the antibody half-life, and a C-terminal lysine removed to reduce
micro-heterogeneity.
[0101] In an embodiment, a Z021 heavy chain comprises or consists
of a contiguous segment or the entire sequence:
TABLE-US-00007 (SEQ ID NO: 17)
QVQLQESGPGLVKPSETLSLTCTVSGGSIDTYYWSWIRQTPGKGLEWIGC
FYYSVDNHFNPSLESRVTISVDTSKNQFSLKMTSMTASDTAVYYCARNQP
GGRAFDYWGPGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL GPSVFLEPPKPKD
TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKA PAPIEKTISKAKGQPREPQVY
TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD
SDGSFFLYSKLTVDKSRWQQGNVFSCSV HEALHSHYTQKSLSLSPG.
In this SEQ ID NO: 17, the variable sequence is bolded, and the
remaining sequence comprises Fc sequence which is shown with the
G237R/L329R mutations to prevent binding to Fc gamma receptors and
M429L/N435S mutations to increase the antibody half-life in bold
and italics. A C-terminal lysine was removed to reduce
micro-heterogeneity (removed lysine not shown). In an embodiment,
the Z021 heavy chain sequence comprises a C50 modification, which
may reduce unwanted disulfide bond formation. Thus, in one
embodiment, the disclosure comprises a Z021 heavy chain of SEQ ID
NO: 17, wherein the C50 is changed, such as to a V, but other amino
acid substitutions can also be made provided they do not adversely
affect affinity of the antibody for its epitope and/or the
antibody's ability to neutralize ZIKV and/or DENV1.
[0102] In an embodiment, a Z021 light chain comprises or consists
of a contiguous segment or the entire sequence:
TABLE-US-00008 (SEQ ID NO: 18)
EIVLTQSPATLSLSPGQRATLSCRASQSVSNYFAWYQQKPGQAPRLLIYDT
SKRATGTPARFSGSGSGTDFTLTISSLEPEDFAVYYCQERNNWPLTWTFGL
GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD
NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS
SPVTKSFNRGEC.
In this sequence the variable region is shown in bold.
[0103] Similar mutations can be made in any antibody of this
disclosure.
[0104] In embodiments, antibodies of this disclosure have variable
regions that are described herein, and may comprise or consist of
any of these sequences, and may include sequences that have from
80-99% similarity, inclusive, and including ranges of numbers there
between, with the sequences expressly disclosed herein, provided
antibodies that have differing sequences retain the same or similar
binding affinity as an antibody with an unmodified sequence. In
embodiments, the sequences are at least 95%, 96%, 97%, 98% or 99%
similar to an expressly disclosed sequence herein.
[0105] Those skilled in the art will recognize that antibodies of
this disclosure are from time to time described using nomenclature
that includes a "Z" and a number, and that these are correlated
with nomenclature in the tables of this disclosure, such as "MEX"
or "BRA" followed by an alphanumeric designation. Those skilled in
the art will be able to readily attribute the particular Z number
with the MEX and BRA numbers in view of the description and tables
presented herein. For example, Z004 is also referred to herein as
MEX18 89 and Z021 is referred to as MEX84_p4-23.
[0106] In non-limiting embodiments the disclosure provides
antibodies with a CDR3 heavy chain sequence and a CDR3 light chain
sequence selected from amino acid sequences in Table 1 or Table 2
having one of the following designations:
[0107] Z001 (MEX18_21), Z006 (MEX105_42), Z010 (MEX105_88), Z012
(MEX105_57), Z014 (MEX18_91), Z015 (MEX84_p2-44), Z018
(MEX84_p2-45), Z024 (MEX84_p4-12), Z028 (MEX84_p4-53), Z031
(BRA112_46), Z035 (BRA112_71), Z037 (BRA112_57), Z038 (BRA12_2),
Z039 (BRA12_21), Z041 (BRA138_57), Z042 (BRA138_17), Z043
(BRA138_15), Z002 (MEX18_27), Z003 (MEX18_58), Z005 (MEX18_13),
Z007 (MEX105_50), Z008 (MEX105_60), Z009 (MEX105_64), Z011
(MEX105_15), Z013 (MEX18_84), Z016 (MEX84_p2-55), Z017
(MEX84_p2-58), Z019 (MEX84_p4-16), Z020 (MEX84_p4-30), Z032
(BRA112_24), Z034 (BRA112_09), Z036 (BRA112_91), Z040 (BRA12_81),
Z044 (BRA138_46), Z045 (BRA12_08), Z048 (BRA112_23), Z050
(BRA138_28), Z051 (BRA138_59), Z052 (BRA138_62), Z053 (BRA138_65),
Z054 (BRA138_94), Z055 (MEX84_p4-61), Z056 (MEX84_p2-94), Z057
(MEX84_p4-54), Z058 (MEX84_p2-53), Z059 (MEX84_p4-34), Z060
(BRA12_58), Z061 (BRA112_36), and Z062 (BRA112_70).
[0108] In embodiments an antibody of this disclosure comprises a
CDR1 and/or a CDR2 amino acid sequence comprised by IgH and/or IgL
amino acid sequences of Table 1.
[0109] Antibodies comprising the following list of variable
sequences have been expressed and characterized for at least
binding affinity, and as otherwise described herein. Bispecific
antibodies comprising distinct heavy and light chain pairs from
distinct antibodies listed below are included in the disclosure. In
the following sequences, the CDR1 is italicized, the CDR2 is bolded
and the CDR3 is italicized and bolded. All of these CDR1, CDR2 and
CDR3 sequences are included in this disclosure as separate
sequences, apart from the remainder of the disclosed
variable/framework sequences that are also disclosed in this
list:
TABLE-US-00009 Z004 (MEX18_89) Heavy Chain (HC) (SEQ ID NO: 11)
EVQLLESGGGLVQPGGSLRLTCATSGFTFRDYAMSWVRQAPGKGLEWVSSYSGIDD
STYYADSVKGRFTISRDNSKSTLSLHMNSLRAEDSALYFC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 12)
DIQMTQSPSTLSASVGDRVTITCRASQSISKWLAWYQQKPGKAPKLLIYTTSTLKSGV
PSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z021 (MEX84_p4-23) Heavy
Chain (HC) (SEQ ID NO: 13)
QVQLQESGPGLVKPSETLSLTCTVSGGSIDTYYWSWIRQTPGKGLEWIGCFYYSVDNH
FNPSLESRVTISVDTSKNQFSLKMTSMTASDTAVYYC WGPGTLV TVSS Light Chain (LC)
(SEQ ID NO: 14)
EIVLTQSPATLSLSPGQRATLSCRASQSVSNYFAWYQQKPGQAPRLLIYDTSKRATGT
PARFSGSGSGTDFTLTISSLEPEDFAVYYC FGLGTKVEIK Z001 (MEX18_21) Heavy
Chain (HC) (SEQ ID NO: 19)
EVQLLESGGGLVQPGGSRRLSCATSGFSFDTYAMSWLRQAPGKGLEWVSSFSGLDD
STYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 20)
DIQMTQSPSTLSASVGDRVTITCRASQSISRWLAWYQQKPGKAPKLLIYKTSTLKSEV
PSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z006 (MEX105_42) Heavy
Chain (HC) (SEQ ID NO: 21)
EVQLLESGGGLVQPGGSLRLSCAASGFTFKNYAMAWVRQAPGKGLEWVSLLYNSEE
STYYADSVKGRFTISRDNSKNTLFLQMNRLRVEDTAVYFC WGR GTLVTVSS Light Chain
(LC) (SEQ ID NO: 22)
DIQMTQSPSTLSASVGDRVTMTCRASQTISGWLAWYQQKPGKAPKLLIYQASRLESG
IPSRFSGSGSGTEFTLTISSLQPDDVATYYC FGLGTKVEIK Z010 (MEX105_88) Heavy
Chain (HC) (SEQ ID NO: 23)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMAWVRQAPGKGLEWVSLIYSGDD
STYYADFVKGRFTISRHNSKNTLSLQMNSLRAEDTAIYYC WGQ GTLVTVSS Light Chain
(LC) (SEQ ID NO: 24)
DIQMTQSPSTLSASVGDRVTITCRASQTISNWLAWYQQKPGKAPKLLIYQASSLESGV
PSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z012 (MEX105_57) Heavy
Chain (HC) (SEQ ID NO: 25)
QVQLVQSGAEVKKSGASVKVSCKASGYSFTTNYIHWVRQAPGQGPEWMGIINPRGG
STTYAQKFQGRVLMTSDTSTSTVYMELSSLRSEDRAVYYC WGQGTTVTVSS Light Chain
(LC) (SEQ ID NO: 26)
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLISAASSLQSGV
PSRFSGSGSGTDFTLTISNLQPEDFATYFC FGQGTKLEIK Z014 (MEX18_91) Heavy
Chain (HC) (SEQ ID NO: 27)
EVQLLESGGDLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVSSISGFDPS
TYYADSVRGRFTIARDNSKNTLYLQMKSLRVEDTAIYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 28)
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPREVPKLLIYAASTLHSGV
PSRFSGSGSGTDFTLTISGLQPEDVATYYC GQGTKVEIK Z015 (MEX84_p2-44) Heavy
Chain (HC) (SEQ ID NO: 29)
QVQLVQSGAEVKKPGASVKLSCKSSGYSFTSYYMHWVRQAPGQGLEWMGIINPSGV
FTSYAQRFQGRVTMTSDTATSTVYMELSSLRSGDTAVYYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 30)
EIVLTQSPGTLSLSPGERATLSCRASQSVSLSFLAWYQQKPGQAPRLLIYGASNRATGI
PDRFSGSGSGTDFTLTISRLEPGDFAVYYC FGPGTKVDIK Z018 (MEX84_p2-45) Heavy
Chain (HC) (SEQ ID NO: 31)
QVQLVQSGPGVKKPGASVKVSCKASGYIFSDYYILWVRQAPGQGLEYMGWMNPISG
FTHYAQNFQGRVTMTRDTSISTAYMELTRLASDDTAVYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 32)
EIVLTQSPATLSLSPGERATLSCRASQSISTFSLAWYQQKFGQAPRLLIYGASSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYYC FGGGTKVEIK Z024 (MEX84_p4-12) Heavy
Chain (HC) (SEQ ID NO: 33)
EVQLVQSGAEVRKPGESLRISCKTSGYTFTSHWVAWVRQMPGKGLEWMGIIYPGDS
DTRYSPSFQGQISISADKSINTAYLQWSSLKASDTGIYYC WGQGTTVTVSS Light Chain
(LC) (SEQ ID NO: 34)
DIQLTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPNLLIYAASSLQSGVP
SRFSGSGSGTDFTLTISSLQPEDYAIYYC FGQGTKVEIK Z028 (MEX84_p4-53) Heavy
Chain (HC) (SEQ ID NO: 35)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSAYAMSWVRQAPGKGLEWVSSINGHSDS
TYFADSVKGRFTISRDNSKNTLYLQMNSLRAEDTALYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 36)
DIQMTQSPSTLSASIGDRVTITCRASQSITPWLAWYQQKPGKAPKFLIYQTSILESGVP
SRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z031 (BRA112_46) Heavy
Chain (HC) (SEQ ID NO: 37)
EVQLLESGGGLVQPGGSLRLSCVASGFTFGSYGMAWVRQAPGKGLEWISSISSIDPST
YYADSVKGRFTVSRDNSENTLYLHMSSLKVEDTAVYFC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 38)
DIQMTQSPSTLSASVGDSVTITCRASQSISSWLAWYQQKPGKAPKFLIHKASSLESGIP
SRFSGSGSGTEFTLTINNLQPDDFATYYC FGQGTKVEIK Z035 (BRA112_71) Heavy
Chain (HC) (SEQ ID NO: 39)
EVQLLESGGGLIQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSGISGSGGA
SDNGASRYYADSVKGRFSISRDNSKNTVYLQMNSLRAEDTAVYYC WGQGTLVTVSS Light
Chain (LC) (SEQ ID NO: 40)
DIQMTQSPSTLAASVGDRVTITCRASQNINSWLAWYQQKPGKAPKFLIYKASTLESG
APSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z037 (BRA112_57) Heavy
Chain (HC) (SEQ ID NO: 41)
QVQLQESGPGLVKPSETLSLTCSVSGYFISSGHYWGWIRQSPGKGLEWIASIYQSGSK
FQTGNTYYNPSLESRVTISMDTSKNQFSLKLSSVTAADTAVYFC WGQGILVTVSS Light
Chain (LC) (SEQ ID NO: 42)
EIVLTQSPGTLSLSPGERATLSCRASQSLSSSFLAWYQQKPGQSPRLLIYGTSSRDTGIP
DRFSGSGSGTDFTLTISRLEPEDSAVYYC FGQGTKLEIK Z038 (BRA12_2) Heavy Chain
(HC) (SEQ ID NO: 43)
EVQLLESGGGLVQPGGSLRLSCEASGFTFSNYAMNWVRQAPGKGLEWVSTLGATDN
SGDSTYYVESAKGRFTISRDNSKNTLYLQMNSLRVEDTAVYFC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 44)
DIQMTQSPSTLSASVGDRVTITCRASHRISGWLAWYQQKPGKAPKLLIYQASGLESGV
PSRFSGSGYGTEFTLTISSLQADDFATYYC FGQGTKVEIK Z039 (BRA12_21) Heavy
Chain (HC) (SEQ ID NO: 45)
EVQLLESGGGLVQPGGSLRLSCAASGYIFDNYAMSWVRQAPGKGLEWVSYINGGGY
GTDYADSVKGRFTISRDNSKRILYLQMNSLRVGDTAVYYC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 46)
EIVLTQSPGTLSLSPGERATLSCRASQTIFFNYLAWYQKKPGQAPRLLVHGASTRATG
IPDRFSGSGSGTDFTLTINSLDPEDFAVYYC FGGGTKVEIK Z041 (BRA138_57) Heavy
Chain (HC) (SEQ ID NO: 47)
QVQLVQSGAEVKKPGSSVRLSCKASGGSYSTYAISWVRQAPGQGLEWMGRIIPSLGK
THLAQKFQGRVTFTADESTTTVYMILSSLKSEDTALYYC WG QGTLVTVSS Light Chain
(LC)
(SEQ ID NO: 48)
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSTGYNYLDWYLQKPGQSPQLLIYLGSNR
ASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC FGPGTKVDIK Z042 (BRA138_17)
Heavy Chain (HC) (SEQ ID NO: 49)
QVQLQESGPGLVKPSETLSLSCTVSSGSISNYYWNWIRQPPGKGLEWIGYIYYSGSISY
NPSLKSRVTISVDTSKNQLSLKLNSVTAADTAVYYC WGQGTLVTVSS Light Chain (LC)
(SEQ ID NO: 50)
EIVMTQSPATLSVSPGERVTLSCRASQSVSYNLAWHQQKPGQAPRLLIYGASTRATGI
PARFSGSGSGTEFTLTISNMQSEDFAVYYC FGPGTKVDIK Z043 (BRA138_15) Heavy
Chain (HC) (SEQ ID NO: 51)
QVQLVQSGAEVKKPGASVKVSCKTSGYTFTSYYMNWVRQAPGQGLEWMGIIKPSDG
STNYAQKFQGRVTMTRDTSTSTVYMELRSLRSEDTAVYYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 52)
QSALTQPASVSGSPGQSITISCAGTSSDVGNYNLVSWYQQHPGKAPKLLIYEVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEADYYC FGTGTEVTVL Z002 (MEX18_27) Heavy
Chain (HC) (SEQ ID NO: 53)
EVQLLESGGGLVQPGGSLRLSCATSGFTFSTYAMSWVRQAPGKGLEWVSSFSGVDDS
TYYAESVKGRFTISRDNSKNTVYLQMTRLRAEDTAVYYC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 54)
DIQMTQSPSTLSASVGDRVTMTCRASQSINRWLAWYQQKPGKAPKWYTTSTLKSG
VPSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z003 (MEX18_58) Heavy
Chain (HC) (SEQ ID NO: 55)
EVQLLESGGGLVQPGGSLRLSCATSGFTFTTFAMSWVRQAPGKGLEWVSSISGADDS
TYYAASVKGRFTISRDNSRSTLFLQMNSLRAEDTAVYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 56)
DIQMTQSPSTLSASVGDRVTITCRASQSISKWLAWYQQKPGKAPRLLIYTTSTLKSGV
PSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z005 (MEX18_13) Heavy
Chain (HC) (SEQ ID NO: 57)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSFSGIDDS
TWYADSVKGRFTISRDNSKSTLYLQMNSLRAEDTAVYYC W GRGTLVTVSS Light Chain
(LC) (SEQ ID NO: 58)
DIQMTQSPSSLSASVGDRVTITCRASQDISKYLAWYQQRPGKVPNLLIYTASTLQSGV
PSRFSGSGSGTHFTLTISSLQPEDVATYYC FGQGTKVEIK Z007 (MEX105_50) Heavy
Chain (HC) (SEQ ID NO: 59)
EVQLLESGGGLVRPGGSLRLSCTASGFTFRRYAMAWVRQAPGKGLEWVSLIYDGDD
STYYAKSVKGRFAISRDNSKNTLSLQMNSLRAEDTAVYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 60)
DIQMTQSPSTLSASVGDRVTITCRASHSISGWLAWYQQKPGKAPKLLIYQASILESGV
PSRFSGSGSGTEFTLTIGSLQPEDFATYFC FGQGTKVEIK Z008 (MEX105_60) Heavy
Chain (HC) (SEQ ID NO: 61)
EVQLLESGGGLVRPGGSLRLSCTASGFTFRRFAMAWVRQAPGKGLEWVSLIWNGDD
STYYAESVRGRFTISRDNSHNTLSLQMRSLRAEDTAIYYC WGQ GTLVTVSS Light Chain
(LC) (SEQ ID NO: 62)
DIQMTQSPSTLSASVGDRVTITCRASQTIGNWLAWYQQKPGKAPKLLIYQASVLESG
VPSRFSGSGSGTEFTLTISSLQPEDFATYFC FGQGTKVEIK Z009 (MEX105_64) Heavy
Chain (HC) (SEQ ID NO: 63)
EVQLLESGGGLVRPGGSLRLSCTASGFTFRRYAMAWVRQAPGKGLEWVSLIYNGDD
STYYAESVKGRFTVSRDNSQNTLSLQMNSLRAEDTAIYYC WGQ GTLVTVSS Light Chain
(LC) (SEQ ID NO: 64)
DIQMTQSPSTLSASVGDRVTITCRASRTIGSWLAWYQQKPGKAPKLLIYQASILEGGV
PSRFSGSVSGTEFTLTIRSLQPEDFATYFC FGQGTKVEIK Z011 (MEX105_15) Heavy
Chain (HC) (SEQ ID NO: 65)
EVQLLESGGGLVQPGGSLRLSCAASGFTFRTYAMSWVRQPPGKGLEWVSSISAREDS
TYFAASVRGRFTISRDNSKNTLYLQMNNLRAEDTALYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 66)
DIQMTQSPSTLSASVGDRVTITCRASQNINSWLAWYQQKPGKAPKLLIYMASSLQSG
VPSRFSGSGSGTEFTLTVSSLQPDDFATYYC FGQGTKVEIK Z013 (MEX18_84) Heavy
Chain (HC) (SEQ ID NO: 67)
EVQLLESGGGLVQPGGSLRLSCAASGFTFTSYAMNWVRQAPGKGLEWVSGIGGRGA
IAGDGSIYYADSVKGRFTISRDNSKNIVYLQMNGLRVEDTAVYYC WGQGTLVTVSS Light
Chain (LC) (SEQ ID NO: 68)
DIQMTQSPPTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGV
PSRFSGSGSGTEFSLTISSLQPEDFATYYC FGQGTKVEIK Z016 (MEX84_p2-55) Heavy
Chain (HC) (SEQ ID NO: 69)
QVQLVQSGAEVKKPGASVKLSCKASGYTFTSYYVHWVRQAPGQGLEWMGIINPGNN
FVSFAQNFYDRATMTRDTSTNTVYMELTNLQSEDTAVYYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 70)
EIVLTQSPGTLSLSPGERGTLSCRASQYITTGHFAWYQQKPGRAPRLLIYGASVRATG
VPDRFSGSGAETDFTLTISRLDPEDVGVYYC FGPGTKVDIK Z017 (MEX84_p2-58) Heavy
Chain (HC) (SEQ ID NO: 71)
QVQLVQSGAGMRKPGASVKVSCKASGYSFNDYYIHWVRQAPGQGLEWMGWINPKS
GFTNYAQRFQGRVTMTGDTSNSVAYMELTRLTSDDTAVYYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 72)
EIVLTQSPDTLSLSPGETATLSCRASQSIGSISLGWYQQKFGQAPRLLIYGASTRATGTP
DRFSGSGSETDFTLTISRLEPEDSAVYYC FGGGTKVEIK Z019 (MEX84_p4-16) Heavy
Chain (HC) (SEQ ID NO: 73)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYFIHWVRQAPGQGLEWMGIINPNSG
STNYAQKIQGRVTMTTDTSASTVYMELSGLRSEDTAVYYC WGQGTMVTVSS Light Chain
(LC) (SEQ ID NO: 74)
DIQLTQSPSSLSASVGDRVTITCRASQSISNYLNWYQQKPGKAPNLLIFATSSLQSGVP
SRFSGSGSGTDFTLTISSLQPEDFATYYC FGGGTKVEIK Z020 (MEX84_p4-30) Heavy
Chain (HC) (SEQ ID NO: 75)
QVQLQQWGARPLKPSETLSLTCGVNGGSFSGYHWSWIRQPPGKGLEWIGEIDHNGRI
NYNPSLKSRVTISIDTFKSQFSLRLTSIIAADTAVYYC WGQGTTVTVSS Light Chain (LC)
(SEQ ID NO: 76)
EIVLTQSPGTLSLSPGDRATLSCGASQSVSSNYLAWYQQKLGQAPRLLIYAASTRATGI
PDRFSGGGSGTDFTLTINKLEAEDFAMYYC FGQGTKVEIK Z032 (BRA112_24) Heavy
Chain (HC) (SEQ ID NO: 77)
EVQLLESGGRLVQPGGSLTLSCAASGFPFSTYAMSWLRQAPGKGLEWVSGITGDSGS
TYYAASVKGRFTISRDNSKNTLYLQMNSLTADDTAVYYC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 78)
DIQMTQSPSTLSASVGDRVNITCRASQSINQWLAWYQQKPGKAPKFLMYKASTLETG
VPSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z034 (BRA112_09) Heavy
Chain (HC) (SEQ ID NO: 79)
EVQLLESGGGLAQPGGSLRLSCETSGFTFRSYGMGWVRQAPGKGLEWVSSIYISGDS
TYYAASVKGRFTISRDNSKSTLYLQMDRLTAEDTAVYYC WG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 80)
DIQMTQSPSTLSASVGDRVTMTCRASQSVNKWLAWYQQKPGKAPKLLIYETSILESG
VSSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z036 (BRA112_91) Heavy
Chain (HC) (SEQ ID NO: 81)
EVQLLESGGDLVQPGGSLRLSCAASGFTFSTYGMAWVRQAPGKGLEWLSSISSVDDS
KYYAASVKGRFTISRDNSRNTLYLHMNSLRVDDTAVYYC W GQGTLVTVSS
Light Chain (LC) (SEQ ID NO: 82)
DIQMTQSPSTLSASVGDRVTITCRASQSISGWLAWYQQKPGKAPRLLMHKASNLYSG
VPSRFSGSGSGTEFTLTISSLQPDDFATYYC FGQGTKVEIK Z040 (BRA12_81) Heavy
Chain (HC) (SEQ ID NO: 83)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGLEWVSAISGSGRS
TYYADSVKGRFTISRDNSKNTLYLQMNSLRGEDTAVYYC WGQGTTVTVSS Light Chain
(LC) (SEQ ID NO: 84)
DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVP
SRFSGSGSGTEFTLTISSLQPEDFATYYC FGPGTKVDIK Z044 (BRA138_46) Heavy
Chain (HC) (SEQ ID NO: 85)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSTYIHWVRQAPGQGLEWMGIINPSSSN
TNYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYC WGQGTMVTVSS Light Chain
(LC) (SEQ ID NO: 86)
QSALTQPASVSGSPGQSITISCTGTSSDVGSFNLVSWYQQHPGKAPKLIIYEVSKRPSG
VSNRFSGSKSGNTASLTISGLQAEDEVHYYC FGTGTKVTVL Z045 (BRA12_08) Heavy
Chain (HC) (SEQ ID NO: 87)
EVQLLESGGALVQPGGSLRLSCAASGFTFNYYAMTWVRQAPGRGLEWVSTITDNGG
TTYLADSVKGRFTISRDNSQNTQSLQMNNLRADDTAVYFC WGQ GTLVTVSS Light Chain
(LC) (SEQ ID NO: 88)
EIVLTQSPGTLSLSPGERATLSCRASQSVSGSYLAWYQQKPGQAPRLLIYGASRRATGI
PDRFSGSGSGTDFTLTISRLEPEDFAVYYC FGQGTKLEIK Z048 (BRA112_23) Heavy
Chain (HC) (SEQ ID NO: 89)
EVQLLESGGGLVKPGGSLRLSCAASGLTFSTYAMSWVRQAPGKGLEWVSAISPGSGD
NIYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC WGQG TLVTVSS Light Chain
(LC) (SEQ ID NO: 90)
EIVLTQSPATLSLSPGERATLSCRASQSVSNYLAWYQQKPGQAPRLLIYDASNMAPGIP
ARFSGSGSGTDFTLTISSLEPEDFAVYYC FGGGTKVDIK Z050 (BRA138_28) Heavy
Chain (HC) (SEQ ID NO: 91)
QVQLVQSGAEVKKPGSSVKVSCKAPGGTFSRYSIAWVRQAPGQGLEWMGGINPTFT
TPNYAQKFQGRVTITADESTNTAYLDLSSLRSEDTAVYYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 92)
EIVLTQSPATLSLSPGERVTLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIP
ARFTGSGSGTDFTLTISSLEPEDFAVYYC FGGGTKVEIK Z051 (BRA138_59) Heavy
Chain (HC) (SEQ ID NO: 93)
QVQLQESGPGLVKPSQTLSLTCTVSGVSISSGGYYYSWFRQLPGKGLEWIGHIYYTGN
THYNPSLRSRLTISVDTSKNQFSLKLSSVTAADTARYYC WG RGTLVTVSS Light Chain
(LC) (SEQ ID NO: 94)
EIVLTQSPGTLSLSPGERATLSCRASQSVTSSYLAWYQHKPGQAPRLLIYGASSRAPGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYWC FGQGTKLEIK Z052 (BRA138_62) Heavy
Chain (HC) (SEQ ID NO: 95)
QVQLQESGPGLVKPSQTLSLTCTVSGGSITGGVYYWNWIRHHPGKGLEWIGYMFYSG
DTDYNPSLRSRVTISGDTSKNKFSLNLNSVTAADTAVYYC W GQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 96)
EIVLTQSPATLSLSPGERATLSCRASQSVSSTYLVWYQQKPGQAPRLLIYGASSRATGI
PDRFSGSGSGTDFTLTISRLEPEDFAVYFC FGQGTKLEIK Z053 (BRA138_65) Heavy
Chain (HC) (SEQ ID NO: 97)
QLQLQESGPGLVKPSETLSLTCTVSGGSISSYNYYWGWIRQPPGKGLEFIGSIYYTGST
YYNPSLRSRVTISVDTSKNQFSLKLTSVTAADTAVYYC WG RGTLVTVSS Light Chain
(LC) (SEQ ID NO: 98)
EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRAPGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYC FGGGTKVEIK Z054 (BRA138_94) Heavy
Chain (HC) (SEQ ID NO: 99)
QLQLQESGPRLVKPSETLFLTCTVSGDSISSSSYFWGWIRQPPGKGLEWIGSISYSGST
YYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTVVYYC WG PGTLVTVSS Light Chain
(LC) (SEQ ID NO: 100)
EIVLTQSPATLSLSPGERATLSCRASQSVSIYLAWYQQKPGQAPRLLIYDASSRATGIPA
RFSGSGSGTDFTLTISSLEPEDFAVYYC FGQGTKVEIK Z055 (MEX84_p4-61) Heavy
Chain (HC) (SEQ ID NO: 101)
EVQLVQSGAEVKKPGASVKVSCKASGYTFSGYYIHWLRQAPGQGLEWMGWINSNSG
GADSGPRFHGRVTMTRDTSINTAYLELTNLRSDDTAVYYC WGRGTLVTVSS Light Chain
(LC) (SEQ ID NO: 102)
AIRMTQSPSSLSASVGDRVTITCRASQDIGSYLNWYQQKPGKAPNVLISAASTLQSGV
PSRISGIGSGTDFTLTISSLQPEDFATYYC FGQGTKLEIK Z056 (MEX84_p2-94) Heavy
Chain (HC) (SEQ ID NO: 103)
EVQLVQSGAEVKKPGASVKVSCKASGNTFMGYYFHWVRQAPGQGLEWMGWINPNS
GHANIAQTFQGRVTMTRDPSITTAYMELSRLRSDDTAVFYC WGQGTLVTVSS Light Chain
(LC) (SEQ ID NO: 104)
DIQMTQSPSTLSASVGDRVTITCRASQSISHWLAWYQQRPGEAPKLLIYQASTLESGV
PSRFSGSGSGTEFTLSISSLQPDDFATYYC FGQGTKLEIK Z057 (MEX84_p4-54) Heavy
Chain (HC) (SEQ ID NO: 105)
EVQLVQSGAEVKRPGASVKVSCKASGYTFADYYIHWVRQAPGLGLEWMGWINPKT
GFSHYEQTFQGRVTMARDTSIPAAYMELSSLKSDDTAIYYC W GQGSLVTVSS Light Chain
(LC) (SEQ ID NO: 106)
DIQMTQSPSTLSTFVGDRVTITCRASQTIGDWLAWYQQKPGKAPKLLISKATRLESGV
PSRFSGSGSETEFSLTINSLQPDDVAAYYC FGQGTKLEIK Z058 (MEX84_p2-53) Heavy
Chain (HC) (SEQ ID NO: 107)
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIIWVRQAPGQGLEWMGGIIPIFGT
TNYAQKFRGRVTIATDASKSAAYMDLSSLKSEDTAIYYC QWG QGTLVTVSS Light Chain
(LC) (SEQ ID NO: 108)
EIVMTQSPATLSVSPGERATLSCRASHSVTSNLAWYQQKPGQAPRLLIYGASTRATGI
PARFSGSGSGTEFTLTISSLQSEDSAVYYC FGQGTKLEIK Z059 (MEX84_p4-34) Heavy
Chain (HC) (SEQ ID NO: 109)
EVQLVQSGAEVKTPGSSVKVSCKTSGGTFSNFAITWVRQAPGQGLEWMGGIIPLFGI
TNYTQKFQGRVTITTDESKTTAYMDLSGLRSEDTAVYFCA WGQG TLVTVSS Light Chain
(LC) (SEQ ID NO: 110)
EIVMTQSPATLSVSPGERATLSCRASQTVNRNLAWYQQKPGQAPRLLIYAASARATG
VPARFSGSGSGTEFTLTISSLQSEDFVVYYC FGGGTKLEIK Z060 (BRA12_58) Heavy
Chain (HC) (SEQ ID NO: 111)
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGFIYYSGSTNY
NPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYC WGQ GTLVTVSS Light Chain (LC)
(SEQ ID NO: 112)
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSSLAWYQQKPGQAPRLLIYGASNRATGI
PDRFSGSGSGTDFTLTISRLEPEDFAVYYC FGGGTKVEIK Z061 (BRA112_36) Heavy
Chain (HC) (SEQ ID NO: 113)
EVQLVESGGGVVQPGRSLRLSCAASGFTFSISTIHWVRQAPGKGLEYVVVISHDGNT
KYYADSVKGRFIISRDNSKNTVFLQMNSLRPVDTAVYYC WGRGTLV TVSS Light Chain
(LC) (SEQ ID NO: 114)
EIVLTQSPATLSLSPGERATLSCRASQSVSSFLAWYQQKPGQPPRLLIYDASTRATGIP
ARFSGSGSGTDFTLTISSLEPEDFAVYYC FGQGTRLEIK Z062 (BRA112_70) Heavy
Chain (HC) (SEQ ID NO: 115)
EVQLVESGGGVVQPGRSLRLSCAASGFSFSSHAMYWVRQAPGKGLEWVAIVSYDGS
TKNYADSVKGRFTISRDNSKNTIYLHLNSLRAEDTAVYFC WGQ GTLVTVSS Light Chain
(LC) (SEQ ID NO: 116)
EIVLTQSPATLSLSPGERATLSCRARQNVRNFLAWYQQKPGQAPRLLIYDASNRATDI
PARFSGSGSGTDFTLTISSLEPEDFAVYYC FGQGTRLEIK
[0110] The following Table A table provides a summary of
neutralizing and binding properties that pertain to the immediately
forgoing 32 antibodies.
TABLE-US-00010 TABLE A ZIKV ZIKV EDIII neutralization binding
EC.sub.50 DENV1 DENV2 DENV3 DENV4 YFV WNV Antibody IC.sub.50
(ng/ml) (ng/ml) binding binding binding binding binding binding
Z002 1.5 25.2 + - - - - - Z003 1 25.5 + - - - - - Z005 1.3 216.3 +
- - - - - Z007 1.5 34.6 + - - - - - Z008 1.7 32.6 + - - - - - Z009
1.4 28.4 + - - - - - Z011 1 38.0 + - - - - - Z013 4.1 >10000 + -
- - - - Z016 68.9 72.4 - - - - + + Z017 n.d. >10000 - - - - - +
Z019 n.d. >10000 n.d. n.d. n.d. n.d. n.d. n.d. Z020 n.d.
>10000 n.d. n.d. n.d. n.d. n.d. n.d. Z032 0.9 19.5 n.d. n.d.
n.d. n.d. n.d. n.d. Z034 1.3 23.5 + - - - - - Z036 0.7 17.2 + - - -
- - Z040 n.d. >10000 - - - - - - Z044 n.d. >10000 - - - - - -
Z045 n.d. >10000 n.d. n.d. n.d. n.d. n.d. n.d. Z048 n.d.
>10000 n.d. n.d. n.d. n.d. n.d. n.d. Z050 36.7 30.3 - - - - - +
Z051 n.n. 1864.5 - - - - - - Z052 10.9 13.1 - - - - - + Z053 n.n.
1683 - - - - - - Z054 n.n. >10000 - - - - - - Z055 54.4 1878 - -
- - + + Z056 36.7 982 - - - - + + Z057 28.8 82.8 - - - - + + Z058
n.n. >10000 n.d. n.d. n.d. n.d. n.d. n.d. Z059 96.0 610.4 - - -
- + + Z060 n.d. >10000 n.d. n.d. n.d. n.d. n.d. n.d. Z061 n.d.
311.3 - - - - - - Z062 n.d. 208.2 - - - - - - n.d. = not determined
n.n. = non-neutralizing
[0111] In embodiments the disclosure provides neutralizing
antibodies. The term "neutralizing antibody" refers to an antibody
or a plurality of antibodies that inhibits, reduces or completely
prevents viral infection. Whether any particular antibody is a
neutralizing antibody can be determined by in vitro assays
described in the examples below, and as is otherwise known in the
art.
[0112] Antibodies of this disclosure can be provided as intact
immunoglobulins, or as fragments of immunoglobulins, including but
not necessarily limited to antigen-binding (Fab) fragments, Fab'
fragments, (Fab').sub.2 fragments, Fd (N-terminal part of the heavy
chain) fragments, Fv fragments (the two variable domains), dAb
fragments, single domain fragments or single monomeric variable
antibody domains, isolated CDR regions, single-chain variable
fragment (scFv), and other antibody fragments that retain
virus-binding capability and preferably virus neutralizing activity
as further described below.
[0113] Antibodies and peptides or mRNA or DNA vaccines of this
disclosure can be provided in pharmaceutical formulations. It is
considered that administering a DNA or RNA vaccine encoding any
protein (including peptides and polypeptides) antigen described
herein is also a method of delivering such peptide antigens to an
individual, provided the DNA and RNA are expressed in the
individual. Methods of delivering DNA and RNAs encoding proteins
are known in the art and can be adapted to deliver the protein
antigens, given the benefit of the present disclosure. Similarly,
the antibodies of this disclosure can be administered as DNA
molecules encoding for such antibodies using any suitable
expression vector(s), or as RNA molecules encoding the
antibodies.
[0114] Pharmaceutical formulations containing antibodies or viral
antigens can be prepared by mixing them with pharmaceutically
acceptable carriers. Pharmaceutically acceptable carriers include
solvents, dispersion media, isotonic agents and the like. The
carrier can be liquid, semi-solid, e.g. pastes, or solid carriers.
Examples of carriers include water, saline solutions or other
buffers (such as phosphate, citrate buffers), oil, alcohol,
proteins (such as serum albumin, gelatin), carbohydrates (such as
monosaccharides, disaccharides, and other carbohydrates including
glucose, sucrose, trehalose, mannose, mannitol, sorbitol or
dextrins), gel, lipids, liposomes, resins, porous matrices,
binders, fillers, coatings, stabilizers, preservatives, liposomes,
antioxidants, chelating agents such as EDTA; salt forming
counter-ions such as sodium; non-ionic surfactants such as TWEEN,
PLURONICS or polyethylene glycol (PEG), or combinations thereof. In
embodiments, a pharmaceutical/vaccine formulation exhibits an
improved activity relative to a control, such as antibodies that
are delivered without adding additional agents, or a particular
added agent improves the activity of the antibodies.
[0115] The formulation can contain more than one antibody type or
antigen, and thus mixtures of antibodies, and mixtures of antigens,
and combinations thereof as described herein can be included. These
components can be combined with a carrier in any suitable manner,
e.g., by admixture, solution, suspension, emulsification,
encapsulation, absorption and the like, and can be made in
formulations such as tablets, capsules, powder (including
lyophilized powder), syrup, suspensions that are suitable for
injections, ingestions, infusion, or the like. Sustained-release
preparations can also be prepared.
[0116] The antibodies and vaccine components of this disclosure are
employed for the treatment and/or prevention of ZIKV and/or DENV1
infection in a subject, as well as for inhibition and/or prevention
of their transmission from one individual to another, and in
particular in the case of transmission of Zika virus from a mother
to a fetus, or from one partner to another during sexual
intercourse wherein transmission between the individuals can take
place. Accordingly, while embodiments of the disclosure are
appropriate for use with any individual who is at risk of, is
suspected of having, or has been diagnosed with a Zika virus
infection, or a dengue 1 virus infection (or other related
viruses), in particular embodiments of the disclosure comprise
administering a composition of this invention to a female who is
known to be pregnant, intending to become pregnant, suspected of
being pregnant, or is engaging in sexual activity which raises a
likelihood of pregnancy. Administration soon after delivery is also
included, and direct administration to a fetus or to a newborn is
also included.
[0117] The term "treatment" of viral infection refers to effective
inhibition of the viral infection so as to delay the onset, slow
down the progression, reduce viral load, and/or ameliorate the
symptoms caused by the infection.
[0118] The term "prevention" of viral infection means the onset of
the infection is delayed, and/or the incidence or likelihood of
contracting the infection is reduced or eliminated.
[0119] The term "prevention" of viral transmission means the
incidence or likelihood of a viral infection being transmitted from
one individual to another (e.g., from a ZIKV-positive woman to her
child during pregnancy, labor or delivery, or breastfeeding; or
between sexual partners) is reduced or eliminated.
[0120] In embodiments, to treat and/or prevent viral infection, a
therapeutic amount of an antibody or antigen vaccine disclosed
herein is administered to a subject in need. The term
"therapeutically effective amount" means the dose required to
effect an inhibition of infection so as to treat and/or prevent the
infection.
[0121] In embodiments, the disclosure comprises co-administration
of a combination of antibodies. In an embodiment, administration of
a combination of distinct antibodies suppresses formation of
viruses that are resistant to the effects of either one of the
antibodies alone. In embodiments, a combination of at least two
antibodies includes at least two antibodies that each recognize
distinct epitopes on Zika Envelope Domain III (EDIII), non-limiting
examples of which are described below. In one non-limiting example,
a combination of antibodies described herein as Z004 and Z021 is
protective and suppresses emergence of resistant variants and/or
fully suppresses virus emergence altogether. Thus, in embodiments,
such a co-administration of a combination of at least two distinct
antibodies described herein suppresses formation of variant Zika
viruses that are resistant to treatment and/or prevents infection.
In embodiments, the Z004 and Z021 antibodies can be administered
concurrently or sequentially.
[0122] The dosage of an antibody or antigen vaccine depends on the
disease state and other clinical factors, such as weight and
condition of the subject, the subject's response to the therapy,
the type of formulations and the route of administration. The
precise dosage to be therapeutically effective and non-detrimental
can be determined by those skilled in the art. As a general rule, a
suitable dose of an antibody for the administration to adult humans
parenterally is in the range of about 0.1 to 20 mg/kg of patient
body weight per day, once a week, or even once a month, with the
typical initial range used being in the range of about 2 to 10
mg/kg. Since the antibodies will eventually be cleared from the
bloodstream, re-administration may be required. Alternatively,
implantation or injection of the antibodies provided in a
controlled release matrix can be employed.
[0123] The antibodies and/or antigen vaccines (as proteins or
polynucleotides encoding the proteins) can be administered to the
subject by standard routes, including oral, transdermal, and
parenteral (e.g., intravenous, intraperitoneal, intradermal,
subcutaneous or intramuscular). In addition, the antibodies and/or
the antigen vaccines can be introduced into the body, by injection
or by surgical implantation or attachment such that a significant
amount of an antibody or the vaccine is able to enter blood stream
in a controlled release fashion. In certain embodiments antibodies
described herein are incorporated into one or more prophylactic
compositions or devices to, for instance, neutralize a virus before
it enters cells of the recipient's body. For example, in certain
embodiments a composition and/or device comprises a polymeric
matrix that may be formed as a gel, and comprises at least one of
hydrophilic polymers, hydrophobic polymers, poly(acrylic acids)
(PAA), poly(lactic acids) (PLA), carageenans, polystyrene
sulfonate, polyamides, polyethylene oxides, cellulose,
poly(vinylpyrrolidone) (PVP), poly(vinyl alcohol) (PVA), chitosan,
poly(ethylacrylate), methylmethacrylate, chlorotrimethyl ammonium
methylmethacrylate, hydroxyapatite, pectin, porcine gastric mucin,
poly(sebacic acid) (PSA), hydroxypropyl methylcellulose (HPMC),
cellulose acetate phthalate (CAP), magnesium stearate (MS),
polyethylene glycol, gum-based polymers and variants thereof, poly
(D,L)-lactide (PDLL), polyvinyl acetate and povidone,
carboxypolymethylene, and derivatives thereof. In certain aspects
the disclosure comprises including antibodies in micro- or
nano-particles formed from any suitable biocompatible material,
including but not necessarily limited to poly(lactic-co-glycolic
acid) (PLGA). Liposomal and microsomal compositions are also
included. In certain aspects a gel of this disclosure comprises a
carbomer, methylparaben, propylparaben, propylene glycol, sodium
carboxymethylcellulose, sorbic acid, dimethicone, a sorbitol
solution, or a combination thereof. In embodiments a gel of this
disclosure comprises one or a combination of benzoic acid, BHA,
mineral oil, peglicol 5 oleate, pegoxol 7 stearate, and purified
water, and can include any combination of these compositions.
[0124] The disclosure includes devices and kits that relate to
inserting into vagina an intravaginal medicated device comprising
antibodies of the disclosure. In certain embodiments the disclosure
provides a vaginal tampon, vaginal ring, vaginal cup, vaginal
tablet, vaginal sponge, a vaginal bioadhesive tablet, a vaginal
lubricant, a condom, or a modified female hygiene or other vaginal
health care product, such as prescription and over-the-counter
antifungal products that treat and/or cure vaginal yeast
infections, or bacterial vaginosis, but that have been adapted to
include antibodies of this disclosure. Applicators that are
provided with female hygiene or vaginal health care products can be
adapted for intravaginal administration of the antibodies. In
certain aspects a method of the invention comprises intravaginal
insertion of a medicated device antibodies of this disclosure. The
delivery composition can be formulated to adhere to and act
directly on the vaginal epithelium and/or mucosa. In certain
aspects a composition and/or device of this may comprise one or
more additional agents known to be suitable for treatment of viral,
or other bacterial or parasitic infections. Such compositions
include but are not limited to antibiotics and previously known
anti-viral agents, and chemical compounds that act as biocides or
antiseptic agents, such as benzalkonium chloride. Additional agents
include but are not limited to soothing compositions that contain,
for example anti-irritant and/or anti-inflammatory agents, such as
hydrocortisone or related compounds, or emollients, or
anti-hemorrhagic or hemostatic or anti-allergic agents. In
embodiments a composition and/or device of this disclosure
comprises a contraceptive agent, such as a spermicide or a hormonal
or non-hormonal contraceptive drug that is combined with one or
more antibodies of this disclosure.
[0125] Antibodies of this disclosure can be produced by utilizing
techniques available to those skilled in the art. For example, one
or distinct DNA molecules encoding one or both of the H and L
chains of the antibodies can be constructed based on the coding
sequence using standard molecular cloning techniques. The resulting
DNAs can be placed into a variety of suitable expression vectors
known in the art, which are then transfected into host cells, which
are preferably human cells cultured in vitro, but may include E.
coli or yeast cells, simian COS cells, Chinese Hamster Ovary (CHO)
cells, and human embryonic kidney 293 cells, etc.
[0126] In certain approaches the invention includes neutralizing
antibodies as discussed above, and methods of stimulating the
production of such antibodies. Antibodies can be produced from a
single, or separate expression vectors, including but not limited
to separate vectors for heavy and light chains, and may include
separate vectors for kappa and lambda light chains as
apporpriate.
[0127] The antibodies may be neutralizing with respect to
infectivity by ZIKV, DENV1, and combinations thereof.
Neutralization may extend beyond ZIKV and DENV1 to include other
viruses of the same genus (such as but not limited to DENV2, DENV3,
DENV4, YFV, WNV), given that the EDIII of these viruses shares
structural similarities. In this regard, the present disclosure
demonstrates that at least some of the antibodies described herein
bind to DENV2-4, yellow fever virus (YFV) and West Nile virus (WNV)
(see e.g. FIG. 3C). In embodiments antibodies are neutralizing with
respect to Asian/American strains of ZIKV, and also to African
ZIKV, wherein the African ZIKV comprises an amino acid difference
in its EDIII protein relative to the ZIKV Asian/American EDIII
protein, and wherein the difference is optionally at position 393
in the African ZIKV EDIII protein, and wherein the difference at
position 393 is optionally D393 instead of E393.
[0128] In certain approaches the disclosure includes methods for
prophylaxis and/or therapy for a viral infection(s) comprising
administering to an individual a vaccine formulation comprising
antibodies and/or viral antigens described herein. The compositions
can be administered to any individual in need thereof, wherein the
individual is infected with or is at risk of being infected with
Zika virus and/or dengue 1 virus. In one approach, administration
of a vaccine comprising and/or encoding Zika polypeptides described
herein is preceded by administering to the individual a composition
comprising a DENV1 antigen, which without intending to be bound by
any particular theory is believed to be able at least in some
instances to enhance protection against Zika virus.
[0129] In certain embodiments the disclosure provides for
consecutive or concurrent administration of ZIKV and DENV1
antigens, as well as other EDIII-derived antigens from other
structurally similar viruses, including but not limited to DENV2-4,
YFV, and WNV. In connection with this, it is contemplated that
administering an antigen described herein, or a structurally
similar antigen, may provide for stimulating production and/or
proliferation of B lymphocytes that express a VH3-23/VK1-5 gene
combination, which without intending to be bound by any particular
theory, may provide for enhanced neutralizing antibodies against
ZIKV, DENV1 and other related viruses.
[0130] An aspect of the disclosure is illustrated in FIG. 22. Data
summarized in FIG. 22 show results of immunizing mice using the
EDIII of flaviviruses as the immunogen. The antibody response to
the EDIII lateral ridge region, which as discussed above is the
neutralizing epitope recognized by antibody Z004, is enhanced if
the immunization with the ZIKV EDIII is preceded by priming with
the EDIII of DENV1 (Panel A). Moreover, this regimen results in
antibodies with higher neutralization capacity (Panel B). This
result is consistent with the observation that the lateral ridge
represents a shared neutralizing epitope for both ZIKV and DENV1,
and that individuals exposed to DENV1 are more likely to become
high responders to ZIKV.
[0131] In certain implementations the invention includes antigens
and segments thereof for use in vaccine formulations and diagnostic
approaches. In non-limiting examples the ZEDIII polypeptide for use
as antigen in vaccination comprises or consists of all or a
contiguous or non-contiguous segment of the ZIKV EDIII
sequence:
TABLE-US-00011 i) (SEQ ID NO: 117)
VSYSLCTAAFTFTKIPAETLHGTVTVEVQYAGTDGPCKVPAQMAVDMQTLT
PVGRLITANPVITESTENSKMMLELDPPFGDSYIVIGVGEKKITMWHRS (ZIKV E protein
residues 303-403);
and/or comprises or consists of all or a contiguous or
non-contiguous segments of the DENV1 EDIII sequence:
TABLE-US-00012 ii) (SEQ ID NO: 118)
MSYVMCTGSFKLEKEVAETQHGTVLVQVKYEGTDAPCKIPFSSQDEKGVTQ
NGRLITANPIVTDKEKPVNIEAEPPFGESYIVVGAGEKALKLSWFKK (DENV1 E protein
residues 297-394),
[0132] or sequences having from 80-99% identity with the sequence
of i) and/or ii).
[0133] In embodiments a ZEDIII polypeptide of this disclosure
optionally comprises at least one contiguous segment of ZEDIII
comprising amino acids 305-311, 333-336, or 350-352 (and
combinations thereof), and/or the segment optionally comprises one
or more of ZEDIII amino acids L307, S306, T309, K394, A311, E393,
T335, G334, A310, and D336, and/or the polypeptide comprises a
segment of the DENV1 EDIII that includes an epitope that comprises
amino acids M301, V300, T303, E384, T329, K385, S305, E327, G328,
D330 DENV1 EDIII protein.
[0134] In certain approaches the disclosure includes vaccinating an
individual using a composition described herein, and determining
the presence, absence, and/or an amount of neutralizing antibodies
produced in response to the vaccination. Thus, methods of
determining and monitoring efficacy of a vaccination at least in
terms of neutralizing antibody production are included.
Determination of the neutralizing antibodies can be performed using
any suitable approach, one of which includes a competitive ELISA
assay as described herein. In an embodiment, subsequent to
determining an absence of neutralizing antibodies, and/or an amount
of neutralizing antibodies below a suitable reference value, the
invention includes administering a composition disclosed herein to
the individual. Subsequent administrations and measurements can be
made to track the treatment efficacy and make further adjustments
to treatment accordingly. In one embodiment the presence, absence
and/or amount of ZIKV and/or DENV1 neutralizing antibodies is
determined using a biological sample from a pregnant human female,
and the determination of the antibodies is used in estimating risk
of fetal complications, including but not necessarily a risk of the
fetus developing microcephaly. In one approach, determining an
absence of neutralizing antibodies, and/or an amount of
neutralizing antibodies below a suitable reference value for a
pregnant female is followed by administering a composition
described herein for the purpose of inhibiting development of the
fetal complications.
[0135] Antibodies and proteins of this disclosure can be detectably
labeled and/or attached to a substrate. Any substrate and
detectable label conventionally used in immunological assays and/or
devices is included. In embodiments the substrate comprises biotin,
or a similar agent that binds specifically with another binding
partner to facilitate immobilization and/or detection and/or
quantification of antibodies and/or viral proteins.
[0136] In embodiments the disclosure comprises immunological assays
to, for example, characterize serologic activity against ZIKV or
DENV1.
[0137] In embodiments any type of enzyme-linked immunosorbent
(ELISA) assay can be used, and can be performed using polypeptides
and/or antibodies of this disclosure for diagnostic purposes, and
can include direct, indirect, and competitive ELISA assays, and
adaptations thereof that will be apparent to those skilled in the
art given the benefit of this disclosure.
[0138] In embodiments the disclosure provides for a competition
ELISA using, for example, assay plates coated with any ZEDII
protein described herein. Upon exposure of a patient sample, such
as a blood or serum sample, patient antibodies to the lateral ridge
(LR) epitope present on the ZEDII protein (if such patient
antibodies are present) will bind to the ZEDII protein. Taking a
labeled Z004 antibody as a non-limiting example of a detecting
antibody, the presence in serum of antibodies to the LR-epitope
will block binding of labeled Z004, whereas absence of (or less)
patient antibodies to the LR-epitope will allow binding of labeled
Z004, enabling detection. The concentration of Z004 blocking
antibodies can then extrapolated from a standard curve.
[0139] In another embodiment an ELISA is conducted after serum
blocking is performed. To perform such an assay, patient serum
dilutions are incubated (`blocked`) with saturating amounts of
either wild type ZEDIII protein or with ZEDIII protein mutated as
described herein, such as by alanine at the E393 and K394 residues.
(Alternatively, DENV1 proteins can be adapted for similar use, and
can include, for example, using DENV1 EDIII protein mutated at the
E384 and/or K385 residues). Next, the remaining IgG binding to wild
type ZEDIII is measured by ELISA and the BT.sub.50 values (=50% of
maximal binding titer, binding titer 50) for the samples blocked
with ZEDIII wild type or with ZEDIII mutant proteins are
determined. The shift in binding activity between the two blocking
can be represented graphically as the .DELTA.BT.sub.50 and is a
measure of the amount of LR-epitope specific antibodies in the
patient sample.
[0140] Any diagnostic result described herein can be compared to
any suitable control. Further, any diagnostic result can be fixed
in a tangible medium of expression and communicated to a health
care provider, or any other recipient. In one aspect the disclosure
comprises diagnosing an individual as infected with ZIKV and/or
DENV1 and administering a composition of this invention to the
individual.
[0141] In certain embodiments the disclosure includes one or more
recombinant expression vectors encoding H and L chains of an
antibody of this disclosure, cells and cell cultures comprising the
expression vectors, methods comprising culturing such cells and
separating antibodies from the cell culture, the cell culture media
that comprises the antibodies, antibodies that are separated from
the cell culture, and kits comprising the expression vectors
encoding an antibody and/or a polypeptide of this disclosure.
Products containing the antibodies and/or the polypeptides are
provided, wherein the antibodies and/or the polypeptides are
provided as a pharmaceutical formulation contained in one or more
sealed containers, which may be sterile and arranged in any manner
by which such agents would be suitable for administration to a
human or non-human subject. The products/kits may further comprise
one or more articles for use in administering the compositions.
[0142] The following Examples are intended to illustrate but not
limit the invention.
Example 1
[0143] Serologic Responses to ZIKV in Brazil and Mexico
[0144] Individuals infected with pathogens display a spectrum of
antibody responses ranging from low levels of non-neutralizing
antibodies to high titers of neutralizing antibodies. To determine
whether a population infected with ZIKV also displays a range of
antibody responses we screened 405 individuals living in ZIKV
epidemic areas for serum IgG capable of binding to ZIKV E Domain
III (ZEDIII, FIG. 1A).
[0145] Nearly three hundred sera were obtained in November 2015,
shortly after ZIKV was introduced in Salvador, Brazil, from
participants who were enrolled in a prospective study in 2013 from
Pau da Lima, an urban slum community within the city (Cardoso et
al., 2015; Felzemburgh et al., 2014; Hagan et al., 2016). An
additional 108 sera were from Santa Maria Mixtequilla, a rural town
in Oaxaca, Mexico. ZIKV infections were documented by PCR in Santa
Maria Mixtequilla at the time of sample collection in April of
2016. Dengue virus (DENV) is endemic at both sites. Sera obtained
from the Pau da Lima cohort in 2010 following a DENV outbreak, but
before the introduction of ZIKV into Brazil, served as non-ZIKV
flavivirus-exposed control for background reactivity against ZIKV
(Silva et al., 2016). ZIKV introduction was associated with a broad
distribution of serologic reactivity against ZEDIII in both
Brazilian and Mexican samples by ELISA (FIG. 1A).
[0146] To determine whether serologic reactivity to ZEDIII is
associated with ZIKV neutralizing activity, we assessed the top 31
sera (black symbols in FIG. 1A) for neutralization of
luciferase-expressing reporter viral particles (RVP) bearing ZIKV
structural proteins (see Methods; FIG. 1B). Neutralizing titers,
expressed as the reciprocal of the dilution resulting in a 50%
reduction of the luciferase signal achieved in the absence of serum
(NT.sub.50), varied by over 2 logs indicating a broad range of
humoral immune responses to ZIKV (FIG. 1B).
[0147] Human Monoclonal Antibodies to ZIKV
[0148] To further characterize the antibody response in 6
individuals with high neutralizing titers, 3 from each cohort, we
used fluorescently-labeled ZEDIII to identify and purify single
memory B cells in the peripheral blood (FIG. 2A). ZEDIII-specific
memory B cells were found at frequencies ranging from 0.13-1.98% of
all circulating IgG.sup.+ memory B cells (FIG. 2A, see Methods).
Although the sample size is limited, the frequency of
ZEDIII-specific memory B cells did not appear to correlate with
either ZEDIII binding or neutralizing activity (FIG. 1). We
conclude that there is significant variability in the frequency of
ZEDIII-specific memory B cells in individuals that show serum ZIKV
neutralizing activity.
[0149] Antibody heavy (IGH) and light (IGL) chain genes were
amplified from single purified ZEDIII binding B cells by RT-PCR and
sequenced (Scheid et al., 2009; von Boehmer et al., 2016). Overall,
290 antibodies were identified from the 6 individuals. Nearly one
half of all of the antibodies (133) were found in expanded clones
that shared the same IGH and IGL variable (IGVH and IGVL) gene
segments, and the remaining half were unique (FIG. 2B and Tables 1
and 2).
[0150] Memory B cells expressing antibodies composed of VH3-23
paired with VK1-5 were found in 5 out of the 6 individuals assayed
(FIG. 2B, and FIG. 8). Moreover, VH3-23/VK1-5 was present as an
expanded clone in 4 individuals, and was the largest expanded clone
in 3 out of the 6 individuals. The sequence of the VH3-23/VK1-5
antibodies in the expanded clones was further limited in that the
VK1-5 gene segment was always recombined with JK1 (FIG. 2C). In
addition to VH3-23/VK1-5 clones we also found expanded clones of
memory B cells expressing antibodies composed of VH3-23 paired with
other IGL genes (VH3-23/VK1-27, VH3-23/VK3-11 and VH3-23/VK3-20;
FIG. 2B). Of the 6 individuals examined, only BRA 138, who
exhibited the lowest level of neutralizing activity, did not have
any detectable memory B cells expressing VH3-23/VK1-5 antibodies.
We conclude that individuals with high serologic neutralizing
titers to ZIKV in geographically distinct outbreak areas frequently
show clonally expanded ZEDIII-specific memory B cells that express
VH3-23/VK1-5 antibodies.
[0151] Cross-Reactivity with Other Flaviviruses
[0152] Nineteen representative antibodies obtained from expanded
memory B cell clones from the 6 individuals were expressed for
further testing. This antibody panel included 8 different
VH3-23/VK1-5 antibodies from 5 separate volunteers. Antibody
binding activity to ZEDIII was measured by ELISA, and found to vary
broadly even among the closely related VH3-23/VK1-5 antibodies,
with EC.sub.50 values ranging from 20 to >4000 ng/ml (FIGS. 3A,
3B, and 9A). Like other human antibodies derived from memory B
cells, anti-ZEDIII antibodies showed somatic mutations. For
example, the number of IGH V gene mutations in the VH3-23/VK1-5
clones ranged from 12-40 nucleotides (average=27.7, FIG. 9B), which
is far lower than that seen in antibodies during chronic HIV-1
infection (Escolano et al., 2017). Nevertheless, the mutations in
anti-ZEDIII antibodies are essential to the binding activity of the
antibodies since reversion of the mutations to the predicted
germline sequence impaired binding to the antigen (FIG. 3B).
[0153] To determine whether the antibodies cloned from our cohorts
cross-react to the EDIII proteins of other flaviviruses, we
screened for binding to the four DENV serotypes (DENV1-4), YFV
(Asibi and 17D strains), and WNV. We observed 5 different patterns
of cross-reactivity with other flaviviruses (FIG. 3C). All 8 of the
VH3-23/VK1-5 antibodies tested cross-reacted with DENV1, but not
with the other flaviviruses in our panel (FIGS. 3C and 3D). Other
antibodies showed singular cross-reactivity to WNV, or broader
reactivity to DENV1-4, or YF and WNV, and some antibodies were
uniquely specific for ZIKV (FIG. 3C). Similar to ZIKV, mutations in
the VH3-23/VK1-5 antibodies were required for optimal binding to
DENV1 EDIII since reversion to the predicted germline sequence
impaired binding to the DENV1 antigen (FIG. 3D). We conclude that
anti-ZEDIII VH3-23/VK1-5 antibodies cross-react with DENV1 but not
with other flaviviruses.
[0154] Neutralizing Activity In Vitro and In Vivo
[0155] To determine whether the anti-ZEDIII antibodies neutralize
ZIKV in vitro we measured their neutralizing activity in the ZIKV
luciferase RVP assay described above. Neutralizing activity varied
among the different antibodies ranging from sub-nanogram 50%
inhibitory concentrations (IC.sub.50) to non-neutralizing (FIGS.
4A, 4B and 10A). The most potent antibody, Z004, a member of one of
the VH3-23/VK1-5 clones, displayed an IC.sub.50 of 0.7 ng/ml (FIGS.
4A, 4B). Similar results were obtained by plaque reduction
neutralization test (PRNT) using a Puerto Rican strain of ZIKV
(IC.sub.50 of 2.2 ng/ml, FIG. 10B). All of the other VH3-23/VK1-5
antibodies tested were also potent neutralizers of ZIKV with
IC.sub.50 values ranging from 0.7-4.6 ng/ml (FIG. 4A).
[0156] Z004 is a member of the VH3-23/VK1-5 family that
cross-reacts with DENV1. To determine whether Z004 also neutralizes
DENV1, we measured its neutralizing activity against DENV1
luciferase RVPs and by flow cytometry using authentic DENV1. We
found that Z004 is a potent neutralizer of DENV1 in both assays
(IC.sub.50=1.6 ng/ml by luciferase assay, and IC.sub.50=16.4 ng/ml
by flow cytometry; FIGS. 4C and 10C). Thus, the VH3-23/VK1-5
antibody Z004 binds and neutralizes both ZIKV and DENV1.
[0157] To determine whether VH3-23/VK1-5 antibodies also neutralize
ZIKV in vivo, we passively transferred Z004 to IFNAR1.sup.-/- mice
one day before or one day after ZIKV infection (FIG. 4D). In 3
independent pre-exposure experiments, with a total of 14 mice
infected with ZIKV in the presence of control antibody, we found
that 93% developed clinical symptoms and 79% succumbed to
infection. In contrast, pre-exposure prophylaxis with Z004 resulted
in a significant reduction in disease symptoms and mortality. Only
12.5% of the Z004 group developed clinical symptoms and none died
(p<0.0001 for both disease and survival; FIGS. 4E and 10D).
Similar results were also obtained when the antibody was
administered one day after infection (p<0.0001 for symptoms,
p=0.0027 for survival; FIGS. 4F and 10D). We conclude that Z004 was
protective and significantly reduced both symptoms and mortality
when administered either before or after infection. Z004 also
displayed a suitable profile of low poly- and auto-reactivity (FIG.
10E). Thus, VH3-23/VK1-5 antibodies have the potential for further
pre-clinical evaluation.
[0158] VH3-23/VK1-5 Antibodies Recognize the Lateral Ridge of
ZEDIII
[0159] There are only 2 contiguous amino acids that are uniquely
shared between the EDIIIs of ZIKV and DENV1, and not by DENV2,
DENV3, DENV4, WNV or YFV (E393 and K394 in ZIKV, E384 and K385 in
DENV1; FIG. 4G). These 2 amino acids are found in the lateral ridge
region of the ZEDIII, which is a region that is associated with
virus interaction with cellular receptors (Mukhopadhyay et al.,
2005). To determine whether these 2 amino acids are essential for
interaction between VH3-23/VK1-5 antibodies and ZIKV, we made
alanine substitutions in the context of the ZIKV RVPs and tested
the recombinant RVPs for sensitivity to Z004-mediated
neutralization. Although ZIKV RVPs bearing the E393A substitution
remained sensitive to Z004, K394A mutant RVPs were resistant to the
antibody (FIG. 4H). African ZIKV strains differ from others at
position 393 carrying aspartic acid at this position. Similar to
wild type Asian/American ZIKV RVPs, African ZIKV RVPs carrying D393
instead of E393 were sensitive to Z004, and Asian/American ZIKV
RVPs with an E393D substitution were also efficiently neutralized
(FIGS. 4G and I). Thus a shared epitope in the lateral ridge region
could account for the finding that Z004 neutralizes ZIKV and DENV1,
but not other flaviviruses.
[0160] Structures of ZIKV Antibodies/EDIII Complexes Reveal a
Shared Binding Mode
[0161] To gain additional insights into the molecular basis of
ZEDIII recognition by VH3-23/VK1-5 antibodies, we solved crystal
structures of complexes of the antigen-binding fragment (Fab) of
two antibodies isolated from different donors, Z006 and Z004, with
ZIKV and DENV1 EDIII domains, respectively (FIG. 5). The Z006
Fab-ZEDIII and Z004 Fab-DENV1 EDIII structures showed a common mode
of antigen recognition, as revealed by similar orientations of Fab
V.sub.H and V.sub.L domains when the EDIII domains were
superimposed (FIG. 5A). The Z006/Z004 Fab orientation is distinct
from orientations in other crystallographically-characterized
Fab/ZIKV and Fab/DENV1 EDIII complexes (FIG. 5B). The Z006 epitope
extends over much of the EDIII lateral ridge (FIG. 5C): beyond the
E393-K394.sub.ZIKV region, the next largest parts of the interface
consist of the N-terminal region of EDIII (residues
305-311.sub.ZIKV), CC' loop residues 350-352.sub.ZIKV, and BC loop
residues 333-336.sub.ZIKV. The E393-K394.sub.ZIKV
(E384-K385.sub.DENV1) motif is central to the interface (FIG. 5C)
and contacts residues within the Fab CDRH3, CDRL3, and CDRL1 loops
in both structures (FIG. 5A, D-F). Despite the antibodies
originating from different donors and binding to two different
flavivirus EDIIIs, a number of contact interactions occur in both
complexes (Table 6). Specifically, the side chain of residue
K394.sub.ZIKV (K385.sub.DENV1) occupies a hydrophobic pocket formed
by W32.sub.LC and Y91.sub.LC(Z006)/F91.sub.LC(Z004) and forms an
H-bond with the latter residue's backbone oxygen atom (FIG. 5D).
The side chain of residue E393.sub.ZIKV (E384.sub.DENV1) interacts
with R96.sub.HC, although this interaction differs somewhat in the
two structures: in the Z006 structure, E393.sub.ZIKV forms an
H-bond with the Y91.sub.LC hydroxyl and an electrostatic
interaction with R96.sub.HC, while for Z004, the side chain of
residue F91.sub.LC lacks a hydroxyl group to form an H-bond, and
instead the side chain of E384.sub.DENV1 forms a salt bridge with
R96.sub.HC (FIG. 5E). Other common interactions include the side
chain of Y58.sub.HC forming an H-bond to the backbone oxygen of
L307.sub.ZIKV (M301.sub.DENV1) (FIG. 5F), and the side chain of
T93.sub.LC (Z006)/S93.sub.LC (Z004) forming an H-bond to the
backbone N of T335.sub.ZIKV (T329.sub.DENV1). Hence the common mode
of recognition involves using equivalent pairwise interactions as
well as binding with a similar orientation.
[0162] Pre-Existing DENV1 Reactivity is Associated with Enhanced
ZEDIII Antibody Responses
[0163] The existence of VH3-23/VK1-5 antibodies that neutralize
both DENV1 and ZIKV and are recurrently found in expanded clones
suggests that prior exposure to DENV1 primes the development of
protective ZIKV immunity. To examine this possibility, we tested
sera obtained at time points before and after introduction of ZIKV
in the Pau da Lima community in Salvador, Brazil. Anti-ZEDIII serum
IgG reactivity increased significantly between April and November
of 2015 (FIG. 6A). Interestingly, a similar increase was seen for
DENV1, although there was no documented DENV1 outbreak in this area
at this time, with only 5 DENV1 cases reported between September
2014 and July 2016 (FIG. 6A). In contrast, no significant increase
in reactivity was observed for DENV2, DENV3, DENV4, YFV, or WNV
EDIIIs (FIG. 6A). Consistent with the hypothesis that DENV1 primes
the subsequent response to ZIKV, we observed a significant positive
correlation between DENV1 EDIII-reactive IgG levels pre-ZIKV, and
ZEDIII-reactive IgG levels post-ZIKV (Pseudo-p=0.48, p<0.001,
FIG. 6B). Together, these data indicate that the exposure to ZIKV
boosted the pre-existing DENV1 antibody response, and that
individuals with pre-existing antibodies targeting the DENV1 EDIII
are more likely to develop high levels of EDIII antibodies upon
ZIKV infection.
[0164] Lateral Ridge Antibodies are Associated with ZIKV
Neutralization
[0165] To determine whether antibodies to the lateral ridge region
recognized by Z004 contribute to serologic activity against ZIKV in
the Pau da Lima cohort, we developed a competition ELISA assay. In
this assay we measure inhibition of biotin-Z004 binding to ZEDIII
in order to quantify lateral ridge-binding antibodies present in
serum (see Methods). Paired samples from April 2015 (before ZIKV)
and November 2015 (after ZIKV) showed an increase in lateral ridge
reactivity after ZIKV introduction (p=0.0007, FIG. 7A). Levels of
antibodies present in the post-ZIKV serum that are capable of
blocking Z004 binding to ZEDIII were directly correlated with the
overall reactivity of antibodies to ZEDIII (Spearman coefficient,
p=0.7319, p<0.0001 FIG. 7B), as well as with the increase in
reactivity to ZEDIII from prior to after ZIKV (p=0.8190,
p<0.0001, FIG. 7C). Finally, there was also a significant
correlation between ZIKV neutralizing activity and total ZEDIII
reactivity (p=0.5885, p=0.0012, FIG. 7D), as well as Z004 blocking
activity (p=0.6585, p=0.0002, FIG. 7E). We conclude that antibodies
that block Z004 binding to the lateral ridge make a measurable
contribution to the overall serum neutralizing activity to ZIKV in
exposed individuals.
Example 2
[0166] This Example provides a description of materials and methods
used to obtain the results discussed above.
Experimental Model and Subjects Details
[0167] Human Subjects
[0168] Samples of peripheral blood were obtained upon consent from
community participants of cohort studies in Pau da Lima (Brazil)
and Santa Maria Mixtequilla (Mexico) under protocols approved by
the ethical committees of the Rockefeller University (IRB
DRO-0898), Yale University (IRB HIC 1603017508), FIOCRUZ (CAAE
63343516.1.0000.5028), Hospital Geral Roberto Santos (1.998.103),
and National Institute of Respiratory Diseases (C16-16).
Information regarding sex and age of study participants can be
obtained upon request. Details on the size of the cohorts and time
when samples were obtained is listed in the Results section of the
manuscript.
[0169] Mice
[0170] IFNAR1.sup.-/- mice were obtained from The Jackson
Laboratory and bred and maintained in the AAALAC-certified facility
of the Rockefeller University. Mice were specific pathogen free and
maintained under a 12 hr light/dark cycle with standard chow diet.
Both male and female mice (3-4 week old) were used for all
experiments and were equally distributed within experimental and
control groups. Animal protocols were in agreement with NIH
guidelines and approved by the Rockefeller University Institutional
Animal Care and Use Committee (16855-H).
[0171] Cell Lines
[0172] Human embryonic kidney HEK-293-6E suspension cells were
cultured at 37.degree. C. in 8% CO.sub.2, shaking at 120 rpm. All
other cell lines described below were cultured at 37.degree. C. in
5% CO.sub.2, without shaking. Green monkey VERO cells and human
hepatocytes Huh-7.5 cells (Blight et al., 2002) were cultured in
Dulbecco's Modified Eagle Medium (DMEM) supplemented with 1%
nonessential amino acids (NEAA) and 5% FBS. Human Lenti-X 293T
cells (Clontech) and STAT1.sup.-/-, an SV40 large T antigen
immortalized skin fibroblast line (Chapgier et al., 2006), were
grown in DMEM 10% FBS.
[0173] Bacteria
[0174] E. coli BL21(DE3) were cultured at 37.degree. C., shaking at
250 rpm. MC1061 cells were cultured in LB medium, with 250 rpm
shaking, at 30-37.degree. C. depending on the plasmid.
[0175] Viruses
[0176] Zika virus (ZIKV), 2015 Puerto Rican PRVABC59 strain
(Lanciotti et al., 2016), was obtained from the CDC and passaged
once in STAT1.sup.-/- fibroblasts (STAT1.sup.-/--ZIKV stock, used
in mouse experiments) or twice in Huh-7.5 cells (Huh-7.5-ZIKV
stock, used in all other experiments). The Thai human isolate of
DENV1 PUO-359 (TVP-1140) was obtained from Robert Tesh and
amplified by three passages in C6/36 insect cells.
[0177] Method Details
[0178] Collection of Human Samples
[0179] Samples of peripheral blood for serum or mononuclear cells
(PBMCs) isolation were obtained from community participants and
donors and frozen at the cohorts' sites. PBMCs were purified using
the gradient centrifugation method with Ficoll and cryopreserved in
90% heat-inactivated fetal bovine serum (FBS) supplemented with 10%
dimethylsulfoxide (DMSO), prior to shipment to Rockefeller
University in liquid nitrogen. Serum aliquots were heat-inactivated
at 56.degree. C. for 1 h and stored at 4.degree. C. thereafter.
[0180] Production and Biotinylation of Flavivirus Protein
[0181] The coding sequences for the EDIII portion of flaviviruses
were preceded by sequences encoding the human CD5 signal peptide
(MPMGSLQPLATLYLLGMLVASCLG (SEQ ID NO: 119)) and followed by a
polyhistidine-AviTag (SIH-GLNDIFEAQKIEWHE (SEQ ID NO: 120)). The
following flavivirus sequences were used.
TABLE-US-00013 ZIKV (KJ776791): (SEQ ID NO: 121)
5'GTGTCATACTCCTTGTGTACCGCAGCGTTCACATTCACCAAGATCCCGG
CTGAAACACTGCACGGGACAGTCACAGTGGAGGTACAGTACGCAGGGACAG
ATGGACCTTGCAAGGTTCCAGCTCAGATGGCGGTGGACATGCAAACTCTGA
CCCCAGTTGGGAGGTTGATAACCGCTAACCCCGTAATCACTGAAAGCACTG
AGAACTCTAAGATGATGCTGGAACTTGATCCACCATTTGGGGACTCTTACA
TTGTCATAGGAGTCGGGGAGAAGAAGATCACCCACCACTGGCACAGGAGT. DENV1
(codon-optimized based on NC_001477): (SEQ ID NO: 122)
5'ATGTCATATGTGATGTGTACGGGGTCCTTTAAACTTGAAAAGGAGGTGG
CAGAAACACAGCACGGAACAGTACTTGTGCAGGTTAAATATGAGGGAACCG
ATGCTCCTTGTAAAATACCGTTTTCAAGCCAGGACGAAAAGGGTGTAACAC
AAAATGGTCGCCTGATTACAGCCAACCCAATAGTCACTGATAAGGAGAAAC
CTGTGAATATCGAGGCAGAGCCACCATTCGGCGAAAGTTATATCGTAGTTG
GTGCTGGAGAAAAGGCCCTGAAACTCTCTTGGTTTAAGAAG. DENV2 (NC001474): (SEQ
ID NO: 123) 5'ATGTCATACTCTATGTGCACAGGAAAGTTTAAAGTTGTGAAGGAAATAG
CAGAAACACAACATGGAACAATAGTTATCAGAGTGCAATATGAAGGGGACG
GCTCTCCATGCAAGATCCCTTTTGAGATAATGGATTTGGAAAAAAGACATG
TCTTAGGTCGCCTGATTACAGTCAACCCAATTGTGACAGAAAAAGATAGCC
CAGTCAACATAGAAGCAGAACCTCCATTCGGAGACAGCTACATCATCATAG
GAGTAGAGCCGGGACAACTGAAGCTCAACTGGTTTAAGAAA. DENV3 (codon-optimized
based on NC_001475.2): (SEQ ID NO: 124)
5'ATGTCATACGCAATGTGTACGAACACATTCGTTCTTAAAAAAGAGGTAA
GTGAAACCCAACATGGTACTATCCTTATAAAAGTTGAGTACAAGGGCGAGG
ACGCTCCCTGCAAAATACCGTTTTCCACAGAGGACGGGCAAGGTAAGGCAC
ACAATGGGAGACTTATAACCGCCAATCCAGTAGTGACCAAGAAAGAGGAAC
CAGTCAACATTGAAGCGGAGCCCCCTTTCGGAGAATCCAACATAGTGATAG
GCATTGGGGACAACGCTCTGAAGATCAACTGGTATAAGAAG. DENV4 (codon-optimized
based on NC_002640.1): (SEQ ID NO: 125)
5'ATGTCATATACAATGTGTAGCGGTAAATTCAGCATTGATAAAGAAATGG
CCGAGACACAGCACGGCACCACCGTGGTAAAAGTGAAATACGAAGGAGCGG
GAGCCCCGTGCAAGGTCCCCATCGAAATCAGGGATGTAAACAAAGAGAAGG
TCGTTGGTAGAATAATTTCTTCTACACCACTGGCCGAGAACACTAATTCAG
TTACGAATATAGAACTTGAGCCCCCCTTTGGTGACAGCTATATAGTTATTG
GCGTGGGAAATTCTGCACTGACTCTGCATTGGTTCCGAAAA. YFV (Asibi strain,
KF769016): (SEQ ID NO: 126)
5'ACATCCTACAAAATGTGCACTGACAAAATGTCTTTTGTCAAGAACCCAA
CTGACACTGGCCATGGCACTGTTGTGATGCAGGTGAAAGTGCCAAAAGGAG
CCCCCTGCAAGATTCCAGTGATAGTAGCTGATGATCTTACAGCGGCAATCA
ATAAAGGCATTTTGGTTACAGTTAACCCCATCGCCTCAACCAATGATGATG
AAGTGCTGATTGAGGTGAACCCACCTTTTGGAGACAGCTACATTATCGTTG
GGACAGGAGATTCACGTCTCACTTACCAGTGGCACAAAGAG YFV (17D strain,
KF769015): (SEQ ID NO: 127)
5'ACATCCTACAAAATATGCACTGACAAAATGTTTTTTGTCAAGAACCCAA
CTGACACTGGCCATGGCACTGTTGTGATGCAGGTGAAAGTGTCAAAAGGAG
CCCCCTGCAGGATTCCAGTGATAGTAGCTGATGATCTTACAGCGGCAATCA
ATAAAGGCATTTTGGTTACAGTTAACCCCATCGCCTCAACCAATGATGATG
AAGTGCTGATTGAGGTGAACCCACCTTTTGGAGACAGCTACATTATCGTTG
GGAGAGGAGATTCACGTCTCACTTACCAGTGGCACAAAGAG. WNV (KX547539.1): (SEQ
ID NO: 128) 5'ACAACCTATGGCGTCTGTTCAAAGGCTTTCAAGTTTCTTGGGACTCCCG
CAGACACAGGTCACGGCACTGTGGTGTTGGAATTGCAGTACACTGGCACGG
ATGGACCTTGCAAAGTTCCTATCTCGTCAGTGGCTTCATTGAACGACCTAA
CGCCAGTGGGCAGATTGGTCACTGTCAACCCTTTTGTTTCAGTGGCCACGG
CCAACGCTAAGGTCCTGATTGAATTGGAACCACCCTTTGGAGACTCATACA
TAGTGGTGGGCAGAGGAGAACAACAGATCAATCACCACTGGCACAAGTCT.
[0182] Gene synthesis was by Genscript. The proteins were produced
by transient transfection into HEK-293-6E cells using PEI
(polyethylenimine, branched). After 7 days of incubation, cell
supernatants were cleared by centrifugation and histidine-tagged
proteins were purified with Ni Sepharose 6 Fast Flow. Purified
ZEDIII was biotinylated using the Biotin-Protein Ligase-BIRA kit
according to manufacturer's instructions.
[0183] ELISA Assays
[0184] Serum and Recombinant Antibody
[0185] The binding of serum IgG or recombinant IgG antibodies to
the EDIII proteins was measured by standard ELBA. ELISA plates were
coated with 250 ng of EDIII protein in PBS per well and stored
overnight at room temperature. Plates were then blocked with 1%
BSA, 0.1 mM EDTA in PBS-T (PBS with 0.05% Tween20) for 1 h at
37.degree. C. Plates were washed with PBS-T in between each step
above. Serum samples were diluted 1:500 with PBS-T and added for 1
h at 37.degree. C. Secondary HRP-conjugated goat anti-human IgG
(0.16 .mu.g/ml) was added for 1 h at 37.degree. C., Plates were
then developed using ABTS substrate and read at 405 nm. The
relative binding affinity of recombinant monoclonal antibodies was
determined similarly, using serially diluted samples. The half
effective concentration (EC.sub.50) needed for maximal binding was
determined by non-linear regression analysis.
[0186] Cross-Reactivity ELISA
[0187] The binding of monoclonal antibodies to the panel of
flavivirus EDIII proteins was determined using the standard ELISA
setup described above. Antibodies were tested at 10 .mu.g/ml
alongside a control serum weakly cross-reactive to all
flaviviruses. Samples with a relative optical density ratio of
>1 compared to control were deemed reactive.
[0188] Auto- and Poly-Reactivity ELISA
[0189] To determine the auto- and poly-reactivity of recombinant
antibodies, ELISA plates were coated with 50 .mu.l PBS containing
dsDNA (10 .mu.g/ml), ssDNA (10 .mu.g/ml, obtained by denaturing
dsDNA at 95.degree. C. for 30 minutes), LIDS (10 .mu.g/ml), Insulin
(5 .mu.g/ml), or keyhole limpet hemocyanin (KLH; 10 .mu.g/ml).
After washing with PBS-T, plates were blocked with 1% BSA and 0.5
mM EDTA in 0.05% PBS-T for 2 h at room temperature. Serial
dilutions of antibody samples were then incubated for 2 h, also at
room temperature. Incubation with secondary antibody and ELISA
development were performed as described above. Previously reported
antibodies ED38 (Wardemann et al., 2003) and mG053 (Yurasov et at,
2005) were used as positive and negative control, respectively.
[0190] Competition ELISA
[0191] Competition ELISA was performed as described above for serum
EDIII binding, with the following modifications. After 1 h of
incubation with serum (diluted 1:10 in PBS-T) at room temperature,
biotinylated antibody 2004 (biotin-Z004) was added at a final
concentration of 0.16 .mu.g/ml to compete for an additional 15 min
at room temperature. After washing, streptavidin-HRP was used for
detection of bound biotin-Z004. The optimal concentration of
biotin-Z004 (0.16 .mu.g/ml) was determined by measuring its binding
to ZEDIII over a range of concentrations, and corresponds to 50% of
the Observed maximal binding. The concentration of Z004 blocking
antibodies in serum was estimated by interpolation with a standard
curve generated by competing biotin-Z004 (0.16 .mu.g/ml) with a
range of non-biotinylated Z004 concentrations, and using the stats
package nls( ) function in R 3.3.2.
[0192] Antibody Discovery and Production
[0193] Isolation of ZEDIII.sup.+ Memory B Cells
[0194] B cell purification, labeling and antibody discovery were
performed as previously described in detail (Tiller et al., 2008;
von Boehmer et al., 2016), with the following modifications.
[0195] PBMCs were resuscitated and washed in 37.degree. C. RPMI. To
enrich for B cells, PBMCs were incubated with CD19 microbeads
according to the manufacturer's instructions. Upon washing, B cells
were positively selected using LS magnetic columns, washed with PBS
3% FBS, and incubated with anti-CD20-PECy7, anti IgG-APC, and
fluorescently-labeled ZEDIII bait at 4.degree. C. for 20 min. The
fluorescently-labeled ZEDIII bait was previously prepared by
incubating 2-3 .mu.g of biotin-ZEDIII with streptavidin-PE for at
least 1 h at 4.degree. C. in the dark. After wash, single
CD20.sup.+ZEDIII.sup.+gG.sup.+ memory B cells were sorted into
96-well plates using a FACSAriaII (Becton Dickinson).
[0196] Antibody Sequencing and Production
[0197] RNA from single cells was reverse-transcribed using random
primers (von Boehmer et al., 2016), followed by nested PCR
amplifications and sequencing using the primers listed in (Tiller
et al., 2008). V(D)J gene segment assignment and determination of
the CDR3 sequences were with IgBlast (Ye et al., 2013). Sequences
that were non-productive, out of frame, or with premature stop
codons were excluded. Similarly, sequences for which a matching
light or heavy chain sequence was not identifiable were omitted.
Cloning for recombinant antibody production was by the Sequence and
Ligation-Independent Cloning (SLIC; (Li and Elledge, 2007)) method
as detailed in (von Boehmer et al., 2016). Amplicons from the first
sequencing PCR reaction were used as template for amplification
with the SLIC-adapted primers listed in Table 3, and cloned into
IG.gamma.1-, IG.kappa. or IG.lamda.-expression vectors as detailed
in (von Boehmer et al., 2016). The recombinantly expressed
antibodies correspond to the following antibody sequence IDs (see
Tables 1 and 2): Z028 (MEX84_p4-53), Z001 (MEX18_21), Z004
(MEX18_89), Z006 (MEX105_42), Z010 (MEX105_88), Z031 (BRA112_46),
Z035 (BRA112_71), Z038 (BRA12_2), Z014 (MEX18_91), Z039 (BRA12_21),
Z015 (MEX84_p2-44), Z018 (MEX84_p2-45), Z021 (MEX84_p4-23), Z024
(MEX84_p4-12), Z012 (MEX105_57), Z037 (BRA112_57), Z041
(BRA138_57), Z042 (BRA138_17), Z043 (BRA138_15). The variable
portion of the predicted germline antibody Z004-GL was
codon-optimized, synthesized by Genscript, and cloned as described
above
TABLE-US-00014 (IGH (SEQ ID NO: 129)
5'GAGGTGCAGCTGTTGGAGTCTGGGGGAGGTCTTGTTCAGCCGGGTGGAT
CATTGAGACTTTCTTGTGCTGCAAGTGGATTTACTTTCTCTTCCTACGCCA
TGTCTTGGGTTCGACAAGCTCCAGGGAAAGGACTCGAATGGGTTAGTGCGA
TATCTGGGTCTGGAGGATCTACTTACTACGCAGATTCAGTAAAAGGGCGCT
TCACAATATCACGCGATAATTCCAAGAATACGCTCTACCTTCAGATGAACA
GTCTTCGGGCAGAGGACACAGCGGTTTATTATTGTGCGAAAGATCGCGGTC
CCAGAGGCGTGGGCGAACTGTTCGACTATTGGGGACAAGGCACCCTGGTCA CCGTCTCCTCAG
and IGK (SEQ ID NO: 130)
5'GACATCCAGATGACCCAGTCACCGTCTACCTTGTCAGCGTCAGTTGGTG
ACCGGGTAACCATTACTTGCCGCGCTAGTCAGAGTATTTCCTCCTGGCTCG
CCTGGTATCAACAAAAACCAGGTAAAGCCCCCAAATTGCTGATCTATAAGG
CAAGTAGCTTGGAATCAGGAGTTCCCAGCCGCTTCTCTGGCTCAGGGTCCG
GTACTGAATTTACATTGACCATCTCTTCTCTCCAGCCAGATGACTTCGCCA
CGTACTATTGTCAACAGTATAACTCATATCCCTGGACTTTTGGACAGGGGA
CCAAGGTGGAAATCAAAC).
Recombinant antibodies were produced as previously described (Klein
et al., 2014). Briefly, HEK-293-6E cells were transiently
transfected with equal amounts of immunoglobulin heavy and light
chain expression vectors. After 7 days, the supernatant was
harvested and antibodies were purified with Protein G Sepharose 4
Fast Flow. For antibody biotinylation, 1.5 mg/ml of Z004 were used
with FluoReporter Mini-biotin-XX Protein Labeling Kit as instructed
by the manufacturer.
[0198] Mouse Experiments
[0199] All experiments involving mice were performed under
protocols approved by the Rockefeller University Institutional
Animal Care and Use Committee. 123 .mu.g of monoclonal antibodies
in 200 .mu.l of PBS were administered intraperitoneally to 3-4 week
old IFNAR1.sup.-/- mice one day prior or after infection with
1.25.times.10.sup.5 PFU ZIKV Puerto Rican strain in 50 .mu.l into
the footpad. Mice were monitored for symptoms and survival over
time.
[0200] Virus Titration
[0201] Viral titers were measured on VERO cells by plaque assay
(PA) for ZIKV virus and focus forming assay (FFA) for DENV-1
strains. For PA, 200 .mu.l of serial 10-fold virus dilutions in
OPTI-MEM were used to infect 400,000 cells seeded the day prior in
a 6-well format. After 90 minutes adsorption, the cells were
overlayed with DMEM containing 2% FBS with 1.2% Avicel and
Pen/Strep. Four days later the cells were fixed with 3.5%
formaldehyde and stained with crystal violet for plaque
enumeration. For FFA, 100 .mu.l of serial 10-fold virus dilutions
in OPTI-MEM were used to infect 250,000 cells seeded the day prior
in a 12-well format. After 90 minutes, the cells were overlayed as
described above for PA. Six to 7 days later the cells were fixed
and incubated with 2 .mu.g/ml of antibody Z004 in PBS/5% FBS/0.25%
Triton X-100 for 1 h at room temperature. Foci were enumerated
after reaction with goat anti-human IgG HRP-conjugated antibodies
and TrueBlue HRP substrate, followed by addition of a few drops of
DAB buffer solution (DAKO). Experiments with infectious ZIKV and
DENV strains were performed in a biosafety level 2 laboratory.
[0202] Plaque Reduction Neutralization Test
[0203] Antibody neutralization activity was measured using a
standard plaque reduction neutralization test (PRNT) on VERO cells.
Diluent medium consisted of medium 199 (Lonza) supplemented with 1%
BSA and Pen/Strep (BA-1 diluent). Briefly, 3- to 10-fold serial
human antibody dilutions were added to a constant amount of
Huh-7.5-ZIKV stock diluted in BA-1 diluent and incubated for 1 h at
37.degree. C. prior to application to VERO cells seeded at 400,000
cells per 6-well the day prior. After 90 min adsorption at
37.degree. C. the cells were overlayed as per PA protocol above.
After 4 days at 37.degree. C., the wells were fixed and stained to
enumerate plaques. PRNT.sub.50 values were determined as the
antibody concentration that resulted in 50% of the number of
plaques obtained with the no antibody control.
[0204] RVP Plasmid Construction West Nile virus (WNV) subgenomic
replicon-expressing plasmid pWNVII-Rep-REN-IB (Pierson et al.,
2006) and a ZIKV C-prM-E expression plasmid (pZIKV/HPF/CprME) were
obtained from Ted Pierson (NIH). Plasmid pWNVII-Rep-REN-IB encodes
a Renilla luciferase-expressing WNV replicon RNA while
pZIKV/HPF/CprME encodes the structural proteins (C-prM-E) of the
ZIKV French Polynesian strain H/PF/2013, both under the control of
a CMV promoter. Co-transfection of the two plasmids into permissive
cells allows the WNV replicon RNA to replicate, express luciferase
and be packaged by the ZIKV H/PF/2013 structural proteins to
generate RVPs that can be used for single round infection studies
(Mukherjee et al., 2014; Pierson et al., 2006). To facilitate
expression of the envelopes of a wide range of ZIKV strains,
plasmid pZIKV/HPF/CprME was engineered to have a unique BspHI
restriction enzyme site immediately upstream of the envelope region
by PCR-based site-directed mutagenesis of two other BspHI
restriction sites located in the plasmid backbone. The resulting
plasmid, pZIKV/HPF/CprM*E*, has unique BspHI and SacII restriction
sites flanking the envelope region, allowing facile manipulation.
PCR-based site-directed mutagenesis was used to introduce E393A or
K394A mutations into the envelope of H/PF/2013 in
pZIKV/HPF/CprM*E*, resulting in plasmids pZIKV/HPF/CprME(E393A) and
pZIKV/HPF/CprME(K394A). We generated pZIKV/HPF-CprM/MR766-E by
replacing the H/PF/2013 envelope in pZIKV/HPF/CprM*E* with that of
the ZIKV African strain, MR766. Because the African strains contain
a BspHI site within the E protein coding region, this site was
mutated using assembly PCR prior to swapping in the MR766-based
BspHI and SacII fragment. To generate pDENV1/PUO-359/CprME, DENV1
(strain PUO-359) virion RNA was isolated by TRIzol extraction
(Thermo Fisher Scientific), cDNA generated using Superscript II
reverse transcriptase (Thermo Fisher Scientific), and the C-prM-E
region amplified by PCR. After PCR assembly with the upstream
promoter and vector sequences, the corresponding region of
pZIKV/HPF/CprME was replaced using SnaBI/SacII enzymes. PCR
reactions utilized either PfuUltra Hotstart DNA Polymerase (Agilent
technologies), Phusion High Fidelity DNA polymerase (NEB) or KOD
DNA polymerase (Toyobo). All PCR-derived plasmid regions were
verified by sequencing. Primer sequences used for assembly PCR and
mutagenesis are listed in Table 4.
[0205] RVP Production
[0206] Reporter viral particles (RVPs) were produced in Lenti-X
293T cells, seeded the day before DNA transfection at
1.times.10.sup.6 cells/well in collagen coated 6-well plates. One
.mu.g of pWNVII-Rep-REN-IB (WNV replicon expression construct) and
3 .mu.g of the appropriate flavivirus CprME expression construct
were co-transfected using Lipofectamine 2000 (Invitrogen) according
to the manufacturer's instructions. Lipid-DNA complexes were
removed after 4-5 h incubation at 37.degree. C. and replaced with
DMEM containing 20 mM HEPES and 10% FBS. After incubation for 48-72
h at 34.degree. C., RVP-containing supernatants were harvested,
filtered through a 0.45 micron filter and frozen at -80.degree. C.
RVPs were titrated on Huh-7.5 cells to determine the dilution to
use in the RVP-based neutralization assay to achieve
.about.2-5.times.10.sup.6 RLU in the absence of serum/antibody.
[0207] RVP Neutralization Assay
[0208] The day before infection, 96-well plates were seeded with
15,000 Huh-7.5 cells/well in a volume of 100 .mu.l. RVPs were
diluted in BA-diluent (ranging from 1:4 to 1:32 depending on the
RVP stock) and 100 .mu.l were added to 100 .mu.l of triplicate
samples of 3- or 10-fold serially diluted human serum/antibody.
After incubation for 1 h at 37.degree. C., 100 .mu.l of the
RVP/antibody mixture was added to the cells. After 24 h incubation
at 37.degree. C., the medium was removed and cells were lysed in 75
.mu.l lysis buffer and 20 .mu.l used for Renilla luciferase
measurement using the Renilla Luciferase Assay System (Promega)
according to the manufacturer's instructions using a FLUOstar Omega
luminometer (BMG LabTech). Neutralization capacity of the
serum/antibody was determined by the percentage of luciferase
activity obtained relative to activity from RVPs incubated with
BA-diluent alone (no serum/antibody). NT.sub.50 values represented
the reciprocal of the serum dilution or the antibody concentration
that resulted in 50% inhibition compared to RVP alone.
[0209] Flow Cytometry-Based Neutralization Assay
[0210] The day prior to infection 5,000 VERO cells/well were seeded
in 96-well plates. Serial dilutions of antibody were mixed with
ZIKV or DENV-1 virus for 1 h at 37.degree. C. and then applied to
infect cells, using an MOI of 0.02 for ZIKV and DENV-1. After 3
days, cells were fixed with 2% formaldehyde and permeabilized in
PBS containing 1% FBS and 0.5% saponin. Cells were stained with 2
.quadrature.g/ml of the pan flavivirus anti-E protein 4G2
monoclonal antibody (Henchal et al., 1982). After incubation with
Alexa Fluor 488-conjugated anti-mouse IgG antibody (Invitrogen) at
1:1,000 dilution, the number of infected cells was determined by
flow cytometry. The percentage of infected cells relative to cells
infected with virus in the absence of antibody was calculated for
each antibody dilution to estimate the 50% reduction.
[0211] Protein Production and Crystallization
[0212] His-tagged Fabs were transiently expressed in HEK-293-6E
cells by co-transfecting with appropriate heavy and light chain
plasmids. Fabs were purified from the supernatant using Ni-NTA
affinity chromatography (GE Healthcare) and size exclusion
chromatography (Superdex 200; GE Healthcare) in 20 mM Tris pH 8.0,
150 mM NaCl, 0.02% NaN.sub.3. The Fabs were concentrated to 10-20
mg/mL for crystallography. Untagged constructs of ZEDIII and DENV1
EDIII were expressed in E. coli and refolded from inclusion bodies
as previously described (Sapparapu et al., 2016). Briefly,
BL21(DE3) E. coli were transformed with an appropriate expression
vector encoding ZIKV E protein residues 299-407 (ZIKV EDIII, strain
H/PF/2013) or DENV1 E protein residues 297-396 (DENV1 EDIII, strain
clone 45AZ5). Cells were grown to mid-log phase and induced with
isopropyl .beta.-D-1-thiogalactopyranoside (IPTG) for 4 hours. The
cells were lysed and the insoluble fraction containing inclusion
bodies was solubilized in buffer containing 6M guanidine
hydrochloride and 20 mM .beta.-mercaptoethanol, and then clarified
by centrifugation. The solubilized inclusion bodies were refolded
using rapid dilution into 400 mM L-arginine, 100 mM Tris-base (pH
8.0), 2 mM EDTA, 0.2 mM phenyl-methylsulfonyl fluoride, and 5 and
0.5 mM reduced and oxidized glutathione at 4.degree. C. The
refolded protein was filtered and concentrated, and then purified
by size exclusion chromatography (Superdex 75; GE Healthcare) in 20
mM Tris pH 8.0, 150 mM NaCl, 0.02% NaN.sub.3. Antigens were
concentrated to 2-15 mg/mL for crystallography. Complexes for
crystallization were produced by mixing Fab and antigen at a 1:1
molar ratio and incubating at room temperature for 1-2 hours.
Crystals of Z006 Fab-ZEDIII complex (space group H32; a=385.08
.ANG., b=385.08 .ANG., c=56.64 .ANG., .alpha.=90.degree.,
.beta.=90.degree., .gamma.=120.degree.; two molecules per
asymmetric unit) were obtained by combining 0.2 .mu.L of
crystallization sample with 0.2 .mu.L of 10% isopropanol, 0.1M
sodium citrate tribasic dihydrate pH 5.0, 26% PEG 400 in sitting
drops at 22.degree. C. Crystals of Z004 Fab-DENV1 EDIII complex
(space group P4.sub.32.sub.12; a=74.23 .ANG., b=74.23 .ANG.,
c=190.76 .ANG.; one molecule per asymmetric unit) were obtained by
combining 0.2 .mu.L of crystallization sample with 0.2 .mu.L of
0.1M sodium acetate trihydrate pH 4.5, 30% w/v PEG 1500 in sitting
drops at 22.degree. C.
[0213] Structure Determination and Refinement X-ray diffraction
data were collected at Stanford Synchrotron Radiation Lightsource
(SSRL) beamline 12-2 using a Dectris Pilatus 6M detector. The data
were integrated using Mosflm (Battye et al., 2011) and scaled using
CCP4 (Winn et al., 2011) (Table 5). The Z006-ZEDIII complex
structure (PDB ID 5VIG) was solved by molecular replacement with a
Z006 unbound Fab structure (data not shown) and Zika EDIII (PDB ID
SKVG) as the search models using Phaser and Molrep (CCP4) and
refined to 3.0 .ANG. using an iterative approach involving (i)
refinement in CNS and Phenix applying NCS constraints and (ii)
manual rebuilding into electron density maps using 0 and
AntibodyDatabase (Jones, 2004; West et al., 2013). The final model
(R.sub.work=21.2%; R.sub.free=25.7%) contains 7,892 protein atoms
and one citrate ion (12 atoms). 90.8, 7.6, and 1.6% of the residues
were in the favored, allowed, and disallowed regions, respectively,
of the Ramachandran plot (Table 5). Residues 1, 128-133, 214-219,
and the 6.times.-His tag of the Z006 heavy chain; residue 214 of
the LC; and residues 299-304 and 405-407 were disordered and are
not included in the model. The Z004-DENV1 EDIII complex structure
(PDB ID 5VIC) was solved by molecular replacement using the
V.sub.HV.sub.L (CDR residues removed) and C.sub.HC.sub.L domains
from PDB 3 SKJ and DENV1 EDIII from PDB 4L5F as search models in
Phenix (Adams et al., 2010). The model was refined to 3.0 .ANG.
resolution using an iterative approach involving (i) refinement in
Phenix and (ii) manual rebuilding into a simulated annealing
composite omit map using Coot (Emsley and Cowtan, 2004). The final
model (R.sub.work=23.6%; R.sub.free=28.1%) contains 3,904 protein
atoms. 93.0%, 6.8%, and 0.2% of the residues were in the favored,
allowed, and disallowed regions, respectively, of the Ramachandran
plot (Table 5). Residues that were disordered and not included in
the model were Fab HC residues 129-132, 215-219, and the
6.times.-His tag; LC residues 212-214; and DENV1 EDIII domain
residues 315-317, 341-347, 373-374, and 393-396. Structures were
superimposed, rmsd calculations done, and figures were generated
using PyMOL. Hydrogen bonds were assigned using the following
criteria: a distance of <3.5 .ANG., and an A-D-H angle of
>90.degree..
[0214] Statistical Analysis Details
[0215] Unless otherwise noted, statistical analysis was with Prism
software. The half effective concentration (EC.sub.50) needed for
maximal binding by ELISA was determined by non-linear regression
analysis (FIG. 3A). Data are the average of at least two
independent experiments. Similarly, luciferase- and flow
cytometry-based neutralization assays were performed in triplicate
wells, and the serum dilution (NT.sub.50) or antibody concentration
(IC.sub.50) that neutralized 50% of the virus or RVP inoculum was
calculated by nonlinear, dose-response regression analysis (FIG.
4A). The Mantel-Cox test was applied to analyze disease and
survival in mice infection experiments (FIG. 4D-F). The Paired t
test was used to analyze changes in sero-reactivity over time
(FIGS. 6A and 7A). Univariate associations were assessed between
log-relative optical densities of anti-ZEDIII antibodies at t=2
(November 2015) with log-relative optical densities of anti-DENV1
EDIII antibodies at t=1 (April 2015) using proc mixed in SAS v 9.4
(FIG. 6B). An individual-level random intercept was included to
account for non-independence of the two replicated measurements.
The two-tailed Spearman r test was used for the correlations in
FIG. 7B-E.
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TABLE-US-00015 [0295] TABLE 1 Antibody SEQ ID SEQ ID SEQ ID SEQ ID
Clone ID amino acids NO: VH DH JH CDR3 NO: amino acids NO: VK/L
JK/L CDR3 NO: MEX 84 - refers to an individual donor. Sequences
were analyzed with IgBlast VH3- MEX84_p2-02 GGGLIQPGGT 131 IGHV3-
IGHD3- IGHJ5*01 AKDRP 171 SASVGDRVT 211 IGKV1- IGKJ1*01 QKFNSV 251
23/VK1-5 LRLSCAASGF 23*01 10*01 RQGVG ITCRASQSIG 5*03 PWT SFTNYAMSW
ELYDS SWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSAITGD IYTASILESG GESTYYSDSV
VPSRFSGSGS KGRFTISRDN GTEFTLTINS SKNTLYLQM LQPDDFATY NSLTADDTAL
YCQKFNSVP YYCAKDRPR WTFGPGTK QGVGELYDS VEVK WGQGTLVTV SS
MEX84_p2-49 GGGLVQPGGS 132 IGHV3- IGHD3- IGHJ5*01 AKDRL 172
SASLGDRVTI 212 IGKV1- IGKJ1*01 QHYHSY 252 LRLSCAASGF 23*01 10*01
EKGIGE TCRASQSISP 5*03 PWT TFSAYAMSW LFHS WLAWYQQK VRQAPGKGL
PGKAPKFLIY EWVSSISVQS QTSILESGVP DSTYFADSVK SRFSGSGSGT GRFTISRDNS
EFTLTISSLQ KNTLYLQMN PDDFATYYC SLRAEDTALY QHYHSYPW YCAKDRLEK
TFGQGTKVE GIGELFHSWG IK QGTLVTVSS MEX84_p4-18 GGGLVQPGGS 133 IGHV3-
IGHD3- IGHJ5*02 AKDRL 173 SASIGDRVTI 213 IGKV1- IGKJ1*01 QHYHSY 253
LRLSCAASGF 23*01 10*01 RQGVG TCRASQSISP 5*03 PWT TFSAYAMSW ELFHS
WLAWYQQK VRQAPGKGL PGKAPKFLIY EWVSGISVQS QTSILESGVP DSTYLADSVK
SRFSGSGSGT GRFTTSRDNS EFTLTISSLQ KNTLYLQMN PDDLATYYC SLRVEDTALY
QHYHSYPW YCAKDRLRQ TFGQGTKVE GVGELFHSW IK GQGTLVTVSS MEX84_p4-19
GGGLVQPGGS 134 IGHV3- IGHD3- IGHJ4*01 AKDRL 174 SASVGDRVT 214
IGKV1- IGKJ1*01 QHYHSY 254 LRLSCAASGF 23*01 10*01 REGVG ITCRASQNIS
5*03 PWT TFGAYAMSW ELYQY PWLAWYQQ VRQAPGKGL KPGKAPKFL EWVSSISVHS
IYQTSILESG DSTYYADSVR VPSRFSGSGS GRFTISRDNS GTDFTLTISS KNTLYLQMN
LQPDDFATY SLRAEDTALY YCQHYHSYP YCAKDRLRE WTFGQGTK GVGELYQYW VEIK
GHGTLVTVSS MEX84_p4-53 GGGLVQPGGS 135 IGHV3- IGHD3- IGHJ5*02 AKDRL
175 SASIGDRVTI 215 IGKV1- IGKJ1*01 QHYHSY 255 LRLSCAASGF 23*01
10*01 REGIGE TCRASQSITP 5*03 PWT TFSAYAMSW LFHS WLAWYQQK VRQAPGKGL
PGKAPKFLIY EWVSSINGHS QTSILESGVP DSTYFADSVK SRFSGSGSGT GRFTISRDNS
EFTLTISSLQ KNTLYLQMN PDDFATYYC SLRAEDTALY QHYHSYPW YCAKDRLRE
TFGQGTKVE GIGELFHSWG IK QGTLVTVSS MEX84_p4-89 GGGLVQPGGS 136 IGHV3-
IGHD1- IGHJ3*01 AKDRD 176 SASVGGRVTI 216 IGKV1- IGKJ3*01 QRYDSY 256
LRLSCAGSGF 23*01 14*01 HFDGH TCRASQSISS 5*03 PFT TFSSFAMSW DV
WLAWYQQK VRQAPGKGL PGKAPKLLIS EWVSTITGIG KASNLESGV GDTYYTDSVK
PSRFSGGGS GRFTVSRDNS ETEFTLTISS KKTVFLHMN LQPDDFATY SLRAEDTAVY
YCQRYDSYP YCAKDRDHF FTFGPGTKV DGHDVWGQ TIK GTMVTVSS VH1-
MEX84_p2-13 GAGVKKPGAS 137 IGHV1- IGHD3- IGHJ5*02 ARGGP 177
SLSPGERAT 217 IGKV3- IGKJ4*01 QQYVSS 257 2/VK3-20 VKVSCKASGY 2*02
22*01 VNAPR LSCRASQEIG 20*01 PLT IFSDYYMQW GFDP SFSLGWYQQ VRQAPGQGL
KFGQPPRLLI QWMGWINP YGASSRATGI KSGFTNYAQ PDRFSGSGS KFQGRVTMT
GTDFTLTISR RDTSISTAYM LEPEDVAVY ELTGLTSDDT YCQQYVSSP AIYYCARGGP
LTFGGGTKV VNAPRGFDP EIK WGQGTLVTV SS MEX84_p2-15 GAGVKIPGAS 138
IGHV1- IGHD1- IGHJ5*02 ARGGP 178 SLSPGDRAT 218 IGKV3- IGKJ4*01
QQYVSS 258 VKVSCKASGY 2*02 26*01 VNSPL LSCRASQSIG 20*01 PLT
IFSDYYMQW GFDP SFSLAWYQQ VRQAPGQGL KFGHAPRLL EWMGWINP IYGASSRATG
KSGFSDYAQK IPDRFSGSGS FQGRVSMTR DTDYTLTIS DTAISTAYME RLEPEDFAV
LTRLTSDDTA YYCQQYVSS VYYCARGGPV PLTFGGGTK NSPLGFDPW VEIK GQGTLVTVSS
MEX84_p2-45 GPGVKKPGAS 139 IGHV1- IGHD1- IGHJ5*02 ARGGR 179
SLSPGERAT 219 IGKV3- IGKJ4*01 QQYVSS 259 VKVSCKASGY 2*02 26*01
INSPLG LSCRASQSIS 20*01 PLT IFSDYYILWV FDP TFSLAWYQQ RQAPGQGLE
KFGQAPRLL YMGWMNPIS IYGASSRATG GFTHYAQNF IPDRFSGSGS QGRVTMTRD
GTDFTLTISR TSISTAYMEL LEPEDFAVY TRLASDDTA YCQQYVSSP VYYCARGGRI
LTFGGGTKV NSPLGFDPW EIR GQGTLVTVSS MEX84_p2-51 GAEVKKPGAS 140
IGHV1- IGHD5- IGHJ5*02 ARGGQ 180 SLSPGERAT 220 IGKV3- IGKJ4*01
QQYGSS 260 VKVSCKVSGY 2*02 24*01 ISAPHG LSCRASQSVS 20*01 PLT
TFTGYYMQW FDP SIHLGWYQQ VRQAPGQGL KPGQAPRLL EWMGWINP IYGASSRATG
KTGHTNFAQ IPDRFSGSGS RDTSISTAYM GTDFTLTISR ELARLTSDDT LEPEDFAVY
AVYFCARGG YCQQYGSSP KFQGRVTMT LTFGGGTKV QISAPHGFDP EIK WGQGTLVTV SS
MEX84_p2-58 GAGMRKPGA 141 IGHV1- IGHD2- IGHJ5*02 ARGGR 181
SLSPGETAT 221 IGKV3- IGKJ4*01 QQYVSS 261 SVKVSCKASG 2*02 8*01
INAPLG LSCRASQSIG 20*01 PLR YSFNDYYIH FDP SISLGWYQQ WVRQAPGQG
KFGQAPRLL LEWMGWINP IYGASTRAT KSGFTNYAQ GTPDRFSGS RFQGRVTMT
GSETDFTLTI GDTSNSVAY SRLEPEDSA MELTRLTSD VYYCQQYVS DTAVYYCAR
SPLRFGGGT GGRINAPLGF KVEIK DPWGQGTLV TVSS MEX84_p4-65 GAEVKKPGAS
142 IGHV1- IGHD6- IGHJ5*02 ARGGPI 182 SLSPGERAT 222 IGKV3- IGKJ4*01
QQYGSS 262 VKVSCKVSGY 2*02 6*01 SAPLGF LSCRASQSVS 20*01 PLT
TFSDYYMQW DP SIHLAWYQQ VRQAPGQGL RPGQAPRLL EWMGWINP INGASSRAT
KTGHTNFAQ GIPDRFSGSG KFQGRVTVT SGTDFTLTIS RDTSITTAYM RLEPEDFAV
ELRTLTSDDT YYCQQYGSS AVYFCARGGP PLTFGGGTK ISAPLGFDPW VEIK
GQGTLVTVSS MEX84_p4-91 GAEVKKPGAS 143 IGHV1- IGHD1- IGHJ3*01 ARAAM
183 SLSPGERAT 223 IGKV3- IGKJ1*01 QQYGSS 263 VKVSCKASAY 2*02 14*01
NRISGV LSCRASQSLS 20*01 RGT SFTDYYIHWV VPPGD SNYLAWYQ RQAPGQGLQ
AFDL QKPGQAPRL WMGWINPDS LIYGASSRAT GEVNYVQKF GIPDRFSGSG QDRVTMTRG
SGTDFTLTIS TSISTAYMEL RLEPEDFAV RRLRSDDTA YYCQQYGSS VYYCARAAM
RGTFGQGTK NRISGVVPPG VEIK DAFDLWGQG TLVTVSS VH1- MEX84_p2-44
GAEVKKPGAS 144 IGHV1- IGHD2- IGHJ4*02 TRSLV 184 SLSPGERAT 224
IGKV3- IGKJ3*01 QQYGSS 264 46/VK3-20 VKLSCKSSGY 46*01 2*01 TPAAQ
LSCRASQSVS 20*01 PLT SFTSYYMHW SVQYF LSFLAWYQQ VRQAPGQGL DS
KPGQAPRLL EWMGIINPSG IYGASNRAT VFTSYAQRFQ GIPDRFSGSG GRVTMTSDT
SGTDFTLTIS ATSTVYMELS RLEPGDFAV SLRSGDTAVY YYCQQYGSS YCTRSLVTPA
PLTFGPGTK AQSVQYFDS VDIK WGQGTLITVS S MEX84_p2-55 GAEVKKPGAS 145
IGHV1- IGHD2- IGHJ4*02 ARTLV 185 SLSPGERGT 225 IGKV3- IGKJ3*01
QQYGSS 265 VKLSCKASGY 46*01 8*02 APSAQ LSCRASQYIT 20*01 PVT
TFTSYYVHW SMYYF TGHFAWYQ VRQAPGQGL DF QKPGRAPRL EWMGIINPG
LIYGASVRAT NNFVSFAQN GVPDRFSGS FYDRATMTR GAETDFTLT DTSTNTVYM
ISRLDPEDV ELTNLQSEDT GVYYCQQYG AVYYCARTLV SSPVTFGPG APSAQSMYYF
TKVEIK DFWGQGTLV TVSS MEX84_p4-33 GSEVKKPGAS 146 IGHV1- IGHD2 -
IGHJ4*02 TRTQV 186 SLSPGERAT 226 IGKV3- IGKJ3*01 QQYGSS 266
VKLSCKASGY 46*01 15*01 VPSAQ LSCRASQNIG 20*01 PVT TFTSYYIHWV SVYYF
LDYFAWYQ RQAPGQGLE DF QKPGQAPRL WVGVINPGN LIYGASIRAT VFTSYAQRFH
GIPDRFSGSG DRVTMTRDT SGTDFTLTIS STSTVYMEM RLVPEDIAV SSLRSEDTAV
YYCQQYGSS YYCTRTQVVP PVTFGPGTK SAQSVYYFDF VEVK WGQGTLVTV SS
MEX84_p4-68 GAEVKKPGTS 147 IGHV1- IGHD3- IGHJ4*02 TRTRV 187
SLSPGERAT 227 IGKV3- IGKJ3*01 QQYGSS 267 VKVSCKASGY 46*01 3*01
VPSAQ LSCRASQSV 20*01 PVT TFTSYYIHWV SVYYF TSGYFAWYQ REAPGQGLE DF
HKPGQAPRL WVGIINPGNT LIYGASIRAT FTSYAPRFHG GIPDRFSGSE RVSMTRDTS
SGTDFTLTIS TSTVYMELSS RLEPEDVAV LRSEDTAVYY YYCQQYGSS CTRTRVVPSA
PVTFGPGTK QSVYYFDFW VDIK GQGTLVTVSS MEX84_p4-85 GAEVKKPGAS 148
IGHV1- IGHD2- IGHJ4*02 TRTQII 188 SLSPGERAT 228 IGKV3- IGKJ3*01
QQYGSS 268 VKVSCKTSGF 46*01 2*01 PAAQS LSCRASQFVI 20*01 PPT
TFTSYYIHWV VYFFD SGHFAWYQ RQAPGQGLE Y QKPGQAPRL WMGFINPTS LIYGTSNRA
GFTSYTQNLH TGIPDRFSGS GRVTMTRDT ESGADFTLTI STRTVFMELR SRLEPEDFA
SLASGDTAVY VYFCQQYGS
YCTRTQIIPA SPPTFGPGT AQSVYFFDY KVDIK WGPGTLVTV SS MEX84_p4-92
GAEVAKPGTS 149 IGHV1- IGHD6- IGHJ5*02 TRTRII 189 SLSPGDRAT 229
IGKV3- IGKJ3*01 QQYGSS 269 VKVSCKASGY 46*01 6*01 AAAQS LSCRASQHIT
20*01 PVT TFTSYYIHWV VYHYD TGHFAWYQ RQAPGQGLE L QKPGQAPRL
WVGIINPGGA LIYGASIRAS FTSYAQRFHG GIPDRFSGSG RVRMTRDTS SGTDFSLTIS
ASTVYVELSS RLEPEDCAV LRSDDTAVYY YYCQQYGSS CTRTRIIAAA PVTFGPGTK
QSVYHYDLW VDIK GQGTLVTVSS VH1- MEX84_p2-21 GAEVKKPGAS 150 IGHV1-
IGHD2- IGHJ4*02 ARAQD 190 SASVGDRVT 230 IGKV1- IGKJ4*01 QQSYITP 270
46/VK1-39 VKVSCKASGY 46*01 21*02 PATAIR ITCRASQSID 39*01 LT
TFSSYYIHWV GLRWE TYLNWYQQ RQAPGQGLE Y KPGKVPAILI WMGIIKPSSG
YAASSLQSG STNYAHKFQ VPSRFSGSGS DRVTMTTDT GTDFTLTIN STSTVYMELS
SLQPEDFAT SLRYQDTAVY YYCQQSYITP YCARAQDPA LTFGGGTKV TAIRGLRWEY EIK
WGQGSLVTV SS MEX84_p4-16 GAEVKKPGAS 151 IGHV1- IGHD2- IGHJ3*02
ARGGS 191 SASVGDRVT 231 IGKV1- IGKJ4*01 QQSFST 271 VKVSCKASGY 46*01
2*02 YPVAIR ITCRASQSIS 39*01 PLT TFTTYFIHWV GVTFGI NYLNWYQQ
RQAPGQGLE KPGKAPNLL WMGIINPNS IFATSSLQSG GSTNYAQKIQ VPSRFSGSGS
GRVTMTTDT GTDFTLTISS SASTVYMELS LQPEDFATY GLRSEDTAVY YCQQSFSTP
YCARGGSYPV LTFGGGTKV AIRGVTFGIW EIR GQGTMVTVS S MEX84_p4-41
GAEVKKPGAS 152 IGHV1- IGHD2- IGHJ3*01 ARGAA 192 SASVGDRVT 232
IGKV1- IGKJ4*01 QQSYISP 272 VRVSCKASGY 46*01 2*02 YPTAIR ITCRASQSIS
39*01 LT TFTSYYMHW GVIYGF TYLNWYQQ VRQAPGQGL KPGKAPKLL EWMGIINPSS
IFAASTLQSG GSTSYAQKLH VPSRFSGSGS DRVTMTRDT GTEFTLTITS STSTVYMEM
LQPADFAIY SSLRSEDTAV YCQQSYISPL YYCARGAAYP TFGGGTKVE TAIRGVIYGF IN
WGQGTMVTV SS MEX84_p4-80 GAEVKKPGAS 153 IGHV1- IGHD6- IGHJ5*02
ATSPA 193 SASVGDRVT 233 IGKVI- IGKJS*01 HQSFSA 273 VKISCKASAD 46*01
13*01 AAGSG ITCRASQSII 39*01 PYT TFTKNYVHW HPSGW NYLNWYQQ VRQAPGQGL
FDP KPGKAPKLL EWMGIINPSS IYTASSLQSG GWTSNPQKF VPSRFSGSGS QGRVTMTRD
GTSFTLTISS TSTSTVYMEL LQPEDFAIY SSLRSDDTAL YCHQSFSAP YYCATSPAAA
YTFGQGTKL GSGHPSGWF EIK DPWGPGTLV TVSS MEX84_p4-82 GAEMKKPGA 154
IGHV1- IGHD2- IGHJ6*02 ARPPG 194 SASVGHRVT 234 IGKV1- IGKJ1*01
QQSYST 274 SVKVSCQASG 46*01 21*01 RSFLD ITCRASQSIS 39*01 PLS
YSFTNHFIH GMDV SYLNWYQQ WVRQAPGQG KPGKAPKLL LEWMGTINP IFAASSLQSG
SGGSTTFAQK VPSRFSGSGS FQGRVTMTR GTDFTLTIN DTSTSTVYME SLQPGDFAT
LSSLRSEDTA YYCQQSYST VYYCARPPGR PLSFGQGTR SFLDGMDVW VEIK GQGTTVTVSS
VH4- MEX84_p2-68 GAGLLKTSET 155 IGHV4- IGHD3- IGHJ4*02 TRVRW 195
PASVSGSPG 235 IGLV2- IGLJ1*01 CSYANS 275 34/VL2-32 LYLTCTVYGD 34*01
3*01 DGIEFT QSITIYCSGS 23*02 GTFV SFNHYYWGW MFFDS SSDVGSYNL
IRQPPGKGLE VSWYQQHP WLGEINHRG GKAPKLIIYG TTNYNPSLKS VTRRPSGVS
RVSILVDTSQ SRFSGSKSG KQFSLRVTSV NTASLTFSG TAADTSVYYC LQVEDDADY
TRVRWDGIE YCCSYANSG FTMFFDSWG TFVFGTGTK QGSLVTVSP VTV MEX84_p2-76
GAGLLKTSET 156 IGHV4- IGHD5- IGHJ4*02 ARVRW 196 PASVSGSPG 236
IGLV2- IGLJ1*01 CSYANS 276 LYLTCTVYGD 34*01 12*01 DGIEST QSITIYCSGS
23*02 GTFV SFNHYYWGW MFFDS SSDVGSYNL IRQPPGKGLE VSWYQQHP WLGEINHRG
GKAPKLIIYG TTNYNPSLKS VTRRPSGVS RVSILVDTSH SRFSGSKSG KQFSLRVTSV
NTASLTFSG TAADTSVYYC LQVEDDADY TRVRWDGIE YCCSYANSG STMFFDSWG
TFVFGTGTK QGSLVTVSP VTV MEX84_p2-83 GAGLLKTSET 157 IGHV4- IGHD5-
IGHJ4*02 TRVRW 197 PASVSGSPG 237 IGLV2- IGLJ1*01 CSYANS 277
LYLTCTVYGD 34*01 12*01 DGIEST QSITIYCSGS 23*02 GTFV SFNHYYWGW MFFDS
SSDVGSYNL IRQPPGKGLE VSWYQQHP WLGEINHRG GKAPKLIIYG TTNYNPSLKS
VTRRPSGVS RVSILVDTSQ SRFSGSKSG KQFSLRVTSV NTASLTFSG TAADTSVYYC
LQVEDDADY TRVRWDGIE YCCSYANSG STMFFDSWG TFVFGTGTK QGSLVTVSP VTV
VH4- MEX84_p4-30 GARPLKPSET 158 IGHV4- IGHD3- IGHJ6*02 ARDVV 198
SLSPGDRAT 238 IGKV3- IGKJ1*01 QIYDSSV 278 34/VK- LSLTCGVNGG 34*01
10*01 TMVEG LSCGASQSVS 20*01 RT 3-20 SFSGYHWSW LRFHY SNYLAWYQ
IRQPPGKGLE YYNYY QKLGQAPRL WIGEIDHNG GMDV LIYAASTRAT RINYNPSLKS
GIPDRFSGG RVTISIDTFKS GSGTDFTLTI QFSLRLTSIIA NKLEAEDFA ADTAVYYCA
MYYCQIYDS RDVVTMVEG SVRTFGQGT LRFHYYYNYY KVEIK GMDVWGQG TPVTVSS
MEX84_p4-37 GARPLKPSET 159 IGHV4- IGHD3- IGHJ6*02 ARDVV 199
SLSPGDRAT 239 IGKV3- IGKJ1*01 QIYDSSV 279 LSLTCGVNGG 34*01 10*01
TMVEG LSCRASQSVS 20*01 RT SFSGYHWTW LRFHY SNYLAWYQ IRQPPGKGLE YYNYY
QKLGQAPRL WIGEIDHNG GMDV LIYGASTRAT RINYNPSLKS GIPDRFSGG
RVTISIDTFKS GSGTDFTLTI QFSLRLTSIT NKLEAEDFA AADTAIYYCA VYYCQIYDSS
RDVVTMVEG VRTFGQGTK LRFHYYYNYY VEIK GMDVWGQG TPVTVSS MEX84_p4-57
GARPLKPSET 160 IGHV4- IGHD3- IGHJ6*02 ARDVV 200 SLSPGDRAT 240
IGKV3- IGKJ1*01 QIYDSSL 280 LSLTCGVNGG 34*01 10*01 TMVEG LSCGASQSVS
20*01 RT SFSGYHWSW LRFHY SNYLAWYQ IRQPPGKGLE YYNYY QKLGQAPRL
WIGEIDHNG GMDV LIYGASTRAT RINYNPSLKS GIPDRFSGG RVTMSIDTFK
GSGTDFTLTI SQFSLRLTSIT NKLEAEDFA AADTAVYYC MYYCQIYDS ARDVVTMVE
SLRTFGQGT GLRFHYYYNY KVEIK YGMDVWGQ GTPVTVSS VH4- MEX84_p4-10
GPGLVKPSET 161 IGHV4- IGHD3- IGHJ4*02 ARNQP 201 SLSPGQRAT 241
IGKV3- IGKJ1*01 QERNN 281 59/VK3-11 LSLTCTVSGG 59*01 16*01 GGRAF
LSCRASQSVS 11*01 WPLTW SISTYYWSWI DY NYFAWYQQ T RQTPGKGLE KPGQAPRLL
WIGCIYYSVD IYDTSKRAT THFNPSLESR GTPARFSGS VTISVDTSKN GSGTDFTLTI
QFSLKMTSM SSLEPEDFA TAADTAVYY VYYCQERNN CARNQPGGR WPLTWTFG
AFDYWGPGT LGTKVEIK LVTVSS MEX84_p4-23 GPGLVKPSET 162 IGHV4- IGHD3-
IGHJ4*02 ARNQP 202 SLSPGQRAT 242 IGKV3- IGKJ1*01 QERNN 282
LSLTCTVSGG 59*01 16*01 GGRAF LSCRASQSVS 11*01 WPLTW SIDTYYWSWI DY
NYFAWYQQ T RQTPGKGLE KPGQAPRLL WIGCFYYSVD IYDTSKRAT NHFNPSLESR
GTPARFSGS VTISVDTSKN GSGTDFTLTI QFSLKMTSM SSLEPEDFA TASDTAVYYC
VYYCQERNN ARNQPGGRA WPLTWTFG FDYWGPGTL LGTKVEIK VTVSS VH5-
MEX84_p2-11 GAEVKKPGES 163 IGHV5- IGHD2- IGHJ6*02 ARHDG 203
SASVGDRVT 243 IGKV1- IGKJ1*01 QQTDRT 283 51/VK1-39 LRISCKTSGY 51*03
15*01 RGYCS ITCRASQSIS 39*01 PLT TFTSHWLAW PTRCF NYLNWYQQ VRQMPGKGL
FSGMD KPGKAPNLL EWMGIIYPGD V IYAASSLQSG SDTRYSPSFQ VPSRFSGSGS
GQISISADKSI GTDFTLTISS NTAYLQWSS LQPEDYAIY LKASDTAIYY YCQQTDRTP
CARHDGRGY LTFGQGTKV CSPTRCFFSG EIK MDVWGQGT TVIVSP MEX84_p4-12
GAEVRKPGES 164 IGHV5- IGHD2- IGHJ6*02 ARHDG 204 SASVGDRVT 244
IGKV1- IGKJ1*01 QQTDRT 284 LRISCKTSGY 51*03 15*01 RGYCS ITCRASQSIS
39*01 PLT TFTSHWVAW PTRCF NYLNWYQQ VRQMPGKGL FSGMD KPGKAPNLL
EWMGIIYPGD V IYAASSLQSG SDTRYSPSFQ VPSRFSGSGS GQISISADKSI
GTDFTLTISS NTAYLQWSS LQPEDYAIY LKASDTGIYY YCQQTDRTP CARHDGRGY
LTFGQGTKV CSPTRCFFSG EIK MDVWGQGT TVIVSP VH1- MEX84_p2-38
GAEVKKPGAS 165 IGHV1- IGHD3- IGHJ2*01 ARRTY 205 SASVGDRVT 245
IGKV1- IGKJ2*01 QQSISAP 285 2/VK1-39 VRVSCKASGY 2*02 16*01 YDNRF
ITCRASQSIG 39*01 YT TFSDYYVHW PYWYF KYLNWYQQ LRQAPGQRLE DL
KPGLAPEVLI WMGWINAN SGATTLQSG TGGSDSGPKF VPSRFSGSGS YGRVTLTRDT
ETDFTLTINS SVNTAYMELS LQPEDLATY RLRSDDTAVY VCQQSISAPY FCARRTYYD
TFGPGTKLEI NRFPYWYFD K LWGRGTLVT VSS MEX84_p4-61 GAEVKKPGAS 165
IGHV1- IGHD3- IGHJ2*01 ARRTY 206 SASVGDRVT 246 IGKV1- IGKJ2*01
QQSLSA 286 VKVSCKASGY 2*02 22*01 YDTRF ITCRASQDIG 39*01 PYT
TFSGYYIHWL PYWYF SYLNWYQQ RQAPGQGLE DL KPGKAPNVL WMGWINSNS
ISAASTLQSG GGADSGPRF VPSRISGIGS HGRVTMTRD GTDFTLTISS TSINTAYLEL
LQPEDFATY TNLRSDDTA YCQQSLSAP
VYYCARRTYY YTFGQGTKL DTRFPYWYF EIK DLWGRGTLV TVSS VH1- MEX84_p2-53
GAEVKKPGSS 167 IGHV1- IGHD2- IGHJ4*02 ARSWG 207 SVSPGERAT 247
IGKV3- IGKJ2*01 QYYTN 287 69/VK3-15 VKVSCKASGG 69*05 8*02 TAATG
LSCRASHSV 15*01 WPPHV TFSSYAIIWV GSFVQ TSNLAWYQ A RQAPGQGLE
QKPGQAPRL WMGGIIPIFG LIYGASTRAT TTNYAQKFR GIPARFSGSG GRVTIATDAS
SGTEFTLTIS KSAAYMDLSS SLQSEDSAV LKSEDTAIYY YYCQYYTN CARSWGTAA
WPPHVAFG TGGSFVQWG QGTKLEIK QGTLVTVSS MEX84_p4-34 GAEVKTPGSS 168
IGHV1- IGHD2- IGHJ5*02 ARGRD 208 SVSPGERAT 248 IGKV3- IGKJ4*01
QQYNN 288 VKVSCKTSGG 69*13 21*02 SSGRLL LSCRASQTV 15*01 WPPLT
TFSNFAITWV DH NRNLAWYQ RQAPGQGLE QKPGQAPRL WMGGIIPLFG LIYAASARA
ITNYTQKFQG TGVPARFSG RVTITTDESK SGSGTEFTL TTAYMDLSG TISSLQSEDF
LRSEDTAVYF AVYYCQQYN CARGRDSSGR NWPPLTFG LLDHWGQGT GGTKVEIK LVTVSS
VH1- MEX84_p2-94 GAEVKKPGAS 169 IGHV1- IGHD6- IGHJ4*02 ARGGM 209
SASVGDRVT 249 IGKV1- IGKJ2*01 QQYQSS 289 2/VK1-5 VKVSCKASGN 2*02
13*01 LGQLW ITCRASQSIS 5*03 PYT TFMGYYFHW ALDN HWLAWYQQ VRQAPGQGL
RPGEAPKLLI EWMGWINP YQASTLESG NSGHANIAQT VPSRFSGSGS FQGRVTMTR
GTEFTLSISS DPSITTAYME LQPDDFATY LSRLRSDDTA YCQQYQSSP VFYCARGGM
YTFGQGTKL LGQLWALDN EIK WGQGTLVTV SS MEX84_p4-54 GAEVKRPGAS 170
IGHV1- IGHD2- IGHJ4*02 ARGGR 210 STFVGDRVT 250 IGKV1- IGKJ1*01
QQYMSY 290 VKVSCKASGY 2*02 21*01 INVAE ITCRASQTIG 5*03 PWT
TFADYYIHW ALRY DWLAWYQQ VRQAPGLGLE KPGKAPKLL WMGWINPK ISKATRLESG
TGFSHYEQTF VPSRFSGSGS QGRVTMARD ETEFSLTINS TSIPAAYMEL LQPDDVAAY
SSLKSDDTAI YCQQYMSYP YYCARGGRIN WTFGQGTK VAEALRYWG VEIK QGSLVIVSS
MEX 18 - refers to an individual donor. Sequences were analyzed
with IgBlast VH3- MEX18_07 GGGLVQPGGS 291 IGHV3- none IGHJ3*01
AKDRVA 315 SASVGDRVT 339 IGKV1- IGKJ1*01 QQYNSYP 363 23/VK1-5
LRLSCAASGF 23*01 FDGFHV ITCRASQSIS 5*03 WT TFSSYAMNW SWLAWYQQ
VRQAPGKGL KPGKAPKLL EWVSGIGGRG IYKASSLESG AIAGDGSIYY VPSRFSGSGS
ADSVKGRFTI GTEFSLTISS SRDNSKNTLY LQPDDFATY LQMNGLRVE YCQQYNSYP
DTAVYYCAK WTFGQGTK DRVAFDGFH VEIK VWGQGTTVT VSS MEX18_15 GGGLIQPGGS
292 IGHV3- IGHD3- IGHJ1*01 AKDRLT 316 SASVGDRVT 340 IGKV1- IGKJ1*01
QHYYSYP 364 LRLSCSASGF 23*01 10*01 MGVGEL ITCRASQNIN 5*03 WT
TFSSYAMSW FVD SWLAWYQQ VRQAPGKGL KPGKAPKFL EWVSGISPLD IYQASTLQN
GSTYYAASVK GVPSRFSGS GRFTISRDNS GSGTEFTLTI KNTLFLQMN SSLQPDDFA
SLRVEDTAIY TYYCQHYYS YCAKDRLTM YPWTFGQG GVGELFVDW TKVEIK GPGTLVSVSS
MEX18_21 GGGLVQPGGS 293 IGHV3- IGHD3- IGHJ4*02 AKDRGP 317 SASVGDRVT
341 IGKV1- IGKJ1*01 QHFHSVP 365 RRLSCATSGF 23*01 10*01 RGIGELF
ITCRASQSIS 5*03 WT SFDTYAMSW DF RWLAWYQQ LRQAPGKGLE KPGKAPKLL
WVSSFSGLD IYKTSTLKSE DSTYYADSVK VPSRFSGSGS GRFTISRDNS GTEFTLTISS
KNTLYLQMN LQPDDFATY SLRAEDTAIY YCQHFHSVP YCAKDRGPR WTFGQGTK
GIGELFDFWG VEIK QGTLVSVSS MEX18_24 GGGLVQPGGS 294 IGHV3- IGHD5-
IGHJ4*02 SKDRGP 318 SASVGDRVT 342 IGKV1- IGKJ1*01 QHFYSVP 366
LRLSCVTSGF 23*01 24*01 RGVGEL ITCRASQSIS 5*03 WT SFDTYALSW FDS
KWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSSFSGID IYTTSTLKSG DSTYYTESVK
VPSRFSGSGS GRFTMSRDN GTEFTLTISS SKSTLFLQMN LQPDDFATY GLRAEDTAM
YCQHFYSVP YYCSKDRGPR WTFGQGTK GVGELFDSW VEIK GQGTLVIFSS MEX18_27
GGGLVQPGGS 295 IGHV3- IGHD3- IGHJ4*02 AKDRGP 319 SASVGDRVT 343
IGKV1- IGKJ1*01 QHFHSVP 367 LRLSCATSGF 23*01 10*01 RGVGEL MTCRASQSI
5*03 WT TFSTYAMSW FDS NRWLAWYQ VRQAPGKGL QKPGKAPKL EWVSSFSGVD
LIYTTSTLKS DSTYYAESVK GVPSRFSGS GRFTISRDNS GSGTEFTLTI KNTVYLQMT
SSLQPDDFA RLRAEDTAV TYYCQHFHS YYCAKDRGP VPWTFGQG RGVGELFDS TKVEIK
WGQGTLVTV SS MEX18_36 GGGLVRPGGS 296 IGHV3- IGHD3- IGHJ4*02 AKDRGP
320 SASVGDRVT 344 IGKV1- IGKJ1*01 QHFYSVP 368 LTLTCATSGF 23*01
10*01 RGVGEL ITCRASQSIS 5*03 WT TFSDYAMSW FDS KWLAWYQQ VRQAPGKGL
KPGKAPKLL EWVSSYSGID IYTTSTLKSG DSTYYADSVK VPSRFSGSGS GRFTISRDNS
GTEFTLTISS KRTLSLHMN LQPDDFATY SLRAGDSALY YCQHFYSVP YCAKDRGPR
WTFGQGTK GVGELFDSW VEIK GPGTLVTVSS MEX18_38 GGGLVQPGGS 297 IGHV3-
IGHD3- IGHJ4*02 AKDRLP 321 SAAIGDRVT 345 IGKV1- IGKJ1*01 QHYYSYP
369 LRLSCAASGF 23*01 10*01 EGFGKL FTCRASQSIN 5*03 WT TFSDYAMGW FDY
TWLAWYQQ VRQAPGKGL KPGKAPKLL EWLSSMTRT MHKASTLHS GDNLYYADS
GVPSRFSGS VKGRFTISRD GSGTEFTLTI NSKNTLYLQ SSLQPDDFA MSSLRVEDT
TYYCQHYYS AIYFCAKDRL YPWTFGQG PEGFGKLFDY TKVEIK WGQGTLVTV ST
MEX18_41 GGGLVQPGGS 298 IGHV3- IGHD1- IGHJ5*02 ARDQEV 322
SVSVGDRVTI 346 IGKV1- IGKJ4*01 QQYSSFFT 370 LRLSCAASGF 23*01 26*01
IGHYPS TCRASQNIN 5*03 SFSDFAMSW DH SWLAWYQQ VRQAPNQGL KPGKAPKLL
DWVSCVSGG IYKASRLERG GDTTYYADSV VPSRFSGRG KGRFTISRDN SGTEFALTIS
SKNTVFLEM GLQPDDFAT NNLRPEDTA YYCQQYSSF VYYCARDQE FTFGGGTKV
VIGHYPSDH EIK WGQGTLVIVS S MEX18_50 GGGLVQPGGS 299 IGHV3- IGHD3-
IGHJ3*01 TKDRIL 323 SASVGDRVT 347 IGKV1- IGKJ1*01 QQYNNYP 371
LRLSCVASGF 23*01 9*01 FDAFHV ITCRASQSIS 5*03 WT TFSNYGMNW SWLAWYQQ
VRQAPGKGL KPGKAPNLL EWVSGITGSG IYKASTLESG DDTYYADSV VPSRFSGSGS
KGRFTISRDN GTEFTLTISS SRNTLYVQM LQPDDFATY NNLRAEDTAI YCQQYNNYP
YYCTKDRILF WTFGQGTK DAFHVWGQG VEIK TMVTVSS MEX18_54 GGDLVQPGGS 300
IGHV3- IGHD3- IGHJ4*02 AKDRVS 324 SASVGDRVT 348 IGKV1- IGKJ1*01
QHYYSYP 372 LRLSCVASGF 23*01 10*01 GGFGEL ITCRASQNIN 5*03 WT
TFSAYGMSW QDY SWLAWFQQ VRQAPGKGL KPGKAPELLI EWVSAMTGS YKTSTLHTG
GDSTYYADSV VPSRFRGRG KGRFTISRDN SGTEFTLTIS SKNTLYLQM SLQPDDFAT
NSLRVEDTAI YYCQHYYSY YYCAKDRVSG PWTFGQGT GFGELQDYW KVEIK GQGTLVTVSS
MEX18_58 GGGLVQPGGS 301 IGHV3- IGHD3- IGHJ5*02 AKDRGP 325 SASVGDRVT
349 IGKV1- IGKJ1*01 QHFFSVP 373 LRLSCATSGF 23*01 10*01 RGVGEL
ITCRASQSIS 5*03 WT TFTTFAMSW FDS KWLAWYQQ VRQAPGKGL KPGKAPRLL
EWVSSISGAD IYTTSTLKSG DSTYYAASVK VPSRFSGSGS GRFTISRDNS GTEFTLTISS
RSTLFLQMNS LQPDDFATY LRAEDTAVYY YCQHFFSVP CAKDRGPRG WTFGQGTK
VGELFDSWG VEIK QGTVVSVSS MEX18_65 GGGLVQPGGS 302 IGHV3- IGHD3-
IGHJ4*02 AKDRVT 326 SASIGDRVTI 350 IGKV1- IGKJ1*01 QHYYSYP 374
LTLSCAGSGF 23*01 10*01 MGFGEL TCRASQSVS 5*03 WT PFNTYALIWV FAH
GWLAWYQQ RQAPGKGLE KPGKAPKLL WVSSISYDSA IHKASTLQS STYYAESVKG
GVPSRFSGS RFTISRDNSQ GSGTEFTLTI NTLYLEMNF TSLQPDDFA LRADDTAVY
TYYCQHYYS FCAKDRVTM YPWTFGQG GFGELFAHW TKVEVK GQGTLVAVSS MEX18_79
GGGLKQPGGS 303 IGHV3- IGHD3- IGHJ4*02 AKDRVE 327 PASVGDRVT 351
IGKV1- IGKJ1*01 QHYHSYP 375 LRLSCAASGF 23*01 10*01 KGFGEL
ITCRASQNIN 5*03 WT TFRNYGMSW WAS SWLAWYQQ VRQAPGKGL TPGRPPKLLI
EWVSSISSLD YKASASLDG DSTYYADSVK VPSRFSGSGS GRSAISRDDS GTEFTLTITS
KNTLYLQIHS LQPHDFATY LRAEDTALYF YCQHYHSYP CAKDRVEKG WTFGQGTK
FGELWASWG VEIK QGTLVTVSS MEX18_80 GGGLVQPGGS 304 IGHV3- IGHD3-
IGHJ4*02 AKDRGP 328 SASVGDRVT 352 IGKV1- IGKJ1*01 QHFHSVP 376
LRLTCATSGF 23*01 10*01 RGVGEL ITCRASQSIS 5*03 WT TFSDYAMSW FDS
KWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSSYSGID IYTTSTLKSG DSTYYADSVK
VPSRFSGSGS GRFIISRDNSK GTEFTLTISS NTLSLHMNS LQPDDFATY LRAEDSALYF
YCQHFHSVP CAKDRGPRG WTFGQGTK VGELFDSWG VEIK QGTLVTVSS MEX18_83
GGGLVQPGGS 305 IGHV3- IGHD3- IGHJ4*02 AKDRGP 329 SASVGDRVT 353
IGKV1- IGKJ1*01 QHFHSVP 377 LRLTCATSGF 23*01 10*01 RGVGEL
ITCRASQSVS 5*03 WA
TFSDYAMSW FDS KWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSSYSGID IYTTSTLKSG
DSTYYADSVK VPSRFSGSGS GRFTISRDNS GTEFTLTISS RSTLSLHMNS LQPDDFATY
LRAEDSALYF YCQHFHSVP CAKDRGPRG WAFGQGTK VGELFDSWG VEIK QGTLVTVSS
MEX18_84 GGGLVQPGGS 306 IGHV3- none IGHJ3*01 AKDRVA 330 SASVGDRVT
354 IGKV1- IGKJ1*01 QQYNSYP 378 LRLSCAASGF 23*01 FDGFHV ITCRASQSIS
5*03 WT TFTSYAMNW SWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSGIGGRG
IYKASSLESG AIAGDGSIYY VPSRFSGSGS ADSVKGRFTI GTEFSLTISS SRDNSKNIVY
LQPEDFATY LQMNGLRVE YCQQYNSYP DTAVYYCAK WTFGQGTK DRVAFDGFH VEIK
VWGQGTITT VSS MEX18_86 GGGLVQPGGS 307 IGHV3- IGHD1- IGHJ4*02 AKDRGP
331 SASVGDRVT 355 IGKV1- IGKJ1*01 QHFYSVP 379 LRLTCATSGF 23*01
26*01 RGVGEL ITCRASQSIS 5*03 WT TFSDYAMSW FDS KWLAWYQQ VRQAPGKGL
KPGKAPKLL EWVSSYSGID IYTTSTLKSG DSTYYADSVK VPSRFSGSGS GRFIISRDNSK
GTEFTLTISS STLSLHMNSL LQPDDFATY RAEDSALYFC YCQHFYSVP AKDRGPRGV
WTFGQGTK GELFDSWGQ VEIK GTLVTVSS MEX18_89 GGGLVQPGGS 308 IGHV3-
IGHD3- IGHJ4*02 AKDRGP 332 SASVGDRVT 356 IGKV1- IGKJ1*01 QHFYSVP
380 LRLTCATSGF 23*01 10*01 RGVGEL ITCRASQSIS 5*03 WT TFRDYAMSW FDS
KWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSSYSGID IYTTSTLKSG DSTYYADSVK
VPSRFSGSGS GRFTISRDNS GTEFTLTISS KSTLSLHMNS LQPDDFATY LRAEDSALYF
YCQHFYSVP CAKDRGPRG WTFGQGTK VGELFDSWG VEIK QGTLVTVSS MEX18_93
GGGLVQPGGS 309 IGHV3- IGHD3- IGHJ4*02 AKDRGP 333 SASVGDRVT 357
IGKV1- IGKJ1*01 QHFFSVP 381 LRLTCATSGF 23*01 10*01 RGVGEL
ITCRASQSIS 5*03 WT TFSDYAMSW FDS KWLAWYQQ VRQAPGKGL KPGKAPKLL
EWVSSYSGID IYTTSTLKSG DSTYYADSVK VPSRFSGSGS GRFTISRDNS GTEFTLTISG
KSTLSLYMKS LQPDDFATY LRAEDSALYY YCQHFFSVP CAKDRGPRG WTFGQGTK
VGELFDSWG VESK QGTLVTVSS MEX18_94 GGGLVQPGGS 310 IGHV3- IGHD3-
IGHJ4*02 AKDRGP 334 SASVGDRVT 358 IGKV1- IGKJ1*01 QHFYSVP 382
LRLTCATSGF 23*01 10*01 RGVGEL ITCRASQSIS 5*03 WT TFSDYAMSW FDS
KWLAWYQQ VRQAPGKGL KPGKAPKLL EWVSSYSGID IYTTSTLKTG DSTYYADSVK
VPSRFSGSGS GRFTISRDNS GTEFTLTISS KSTLSLHMNS LQPDDFATY LRAEDSALYF
YCQHFYSVP CAKDRGPRG WTFGQGTK VGELFDSWG VEIK QGTLVTVSS VH3- MEX18_09
GGDLVQPGGS 311 IGHV3- IGHD3- IGHJ5*02 AKDRLV 335 SASVGDRVT 359
IGKV1- IGKJ1*01 QKYNSVP 383 23/VK1-27 LRLSCAASGF 23*01 10*01 RGFGEV
ITCRASQGIS 27*01 WT TFSSYGMSW LAS NYLAWYQQ VRQAPGKGL KPREVPKLLI
EWVSSISGFD YAASTLHSG PSTYYADSVR VPSRFSGSGS GRFTIARDNS GTDFTLTISG
KNTLYLQMK LQPEDVATY SLRVEDTAIY YCQKYNSVP YCAKDRLVR WTFGQGTK
GFGEVLASW VEMK GQGTLVTVSS MEX18_13 GGGLVQPGGS 312 IGHV3- IGHD6-
IGHJ4*02 AKDRLV 336 SASVGDRVT 360 IGKV1- IGKJ1*01 QKYNSVP 384
LRLSCAASGF 23*01 6*01 RGFAEV ITCRASQDIS 27*01 WT TFSSYAMSW LDY
KYLAWYQQ VRQAPGKGL RPGKVPNLL EWVSSFSGID IYTASTLQSG DSTWYADSV
VPSRFSGSGS KGRFTISRDN GTHFTLTISS SKSTLYLQMN LQPEDVATY SLRAEDTAVY
YCQKYNSVP YCAKDRLVR WTFGQGTK GFAEVLDYW VEIK GRGTLVTVSS MEX18_52
GGGLVQPGGS 313 IGHV3- IGHD6- IGHJ4*02 AKDRLV 337 SASVGDRVT 361
IGKV1- IGKJ1*01 QKYNSVP 385 LRLSCAASGF 23*01 6*01 RGFAEV ITCRASQDIS
27*01 WT TFSSYAMSW LEH KYLAWYQQ VRQAPGKGL RPGKVPNLL EWVSSFSGID
IYTASTLQSG DSTWYADSV VPSRFSGSGS KGRFTISRDN GTHFTLTISS SKSTLFLQMN
LQPEDVATY SLRAEDTAVY YCQKYNSVP YCAKDRLVR WTFGQGTK GFAEVLEHW VEIK
GRGTLVTVSS MEX18_91 GGDLVQPGGS 314 IGHV3- IGHD3- IGHJ4*02 AKDRLV
338 SASVGDRVT 362 IGKV1- IGKJ1*01 QKYNSVP 386 LRLSCAASGF 23*01
10*01 RGFGEV ITCRASQGIS 27*01 WT TFSSYGMSW LDS NYLAWYQQ VRQAPGKGL
KPREVPKLLI EWVSSISGFD YAASTLHSG PSTYYADSVR VPSRFSGSGS GRFTIARDNS
GTDFTLTISG KNTLYLQMK LQPEDVATY SLRVEDTAIY YCQKYNSVP YCAKDRLVR
WTFGQGTK GFGEVLDSW VEMK GQGTLVTVSS MEX 105 - refers to an
individual donor. Sequences were analyzed with IgBlast VH3-
MEX105_01 GGGLVRPGG 387 IGHV3- IGHD6- IGHJ4*02 VKDRD 416 SASVGDRVT
445 IGKV1- IGKJ1*01 QQYSTYW 474 23/VK1-5 SLRLSCKASG 23*03 19*01
TGWSS ITCRTSQTIA 5*03 T FTFRRYAMA IVD NWLAWYQQ WVRQAPGK KPGKAPKLL
GLEWVSLIY IYQASILESG NGDDSTYYA VPSRFSGSGS KSVKGRFTIS GTEFTLTIRS
RDDSQSTLS LQPEDFATY LQMNSLRAE FCQQYSTYW DTAVYYCVK TFGQGTKVG
DRDTGWSSI IK VDWGQGTL VTVSS MEX105_02 GGGLVRPGG 388 IGHV3- IGHD6-
IGHJ4*02 VKDRD 417 SASVGDTVTI 446 IGKV1- IGKJ1*01 QQYSTFW 475
SLRLSCTASG 23*03 19*01 NGWSS TCRASQTLG 5*03 T FTFRRYAMA IVD
NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY IYQASILESG NGDDSTYYS
VPSRFSGSGS KSVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMNSLRVE
FCQQYSTFW DTAVYYCVK TFGQGTKVG DRDNGWSSI IK VDWGQGTL VTVSS MEX105_04
GGGLVRPGG 389 IGHV3- IGHD6- IGHJ4*02 VKDRD 418 SASVGDRVT 447 IGKV1-
IGKJ1*01 HQYSTYW 476 SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T
FTFRRYAMA IVD SWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIF IYQASILESG
NGDDSTYYA VPSRFSGSGS ASVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY
LQMNSLRAE FCHQYSTYW DTAVYYCVK TFGQGTKVG DRDNGWSSI MK VDWGQGTL VTVSS
MEX105_05 GGGLVRPGG 390 IGHV3- IGHD6- IGHJ4*02 VKDRD 419 SASVGDRVT
448 IGKV1- IGKJ1*01 QQYSTYW 477 SLRLSCTASG 23*03 19*01 NGWSS
ITCRASHNIG 5*03 T FTFRRYALA IVD GLLAWYQQ WVRQVPGK KPGKAPKLL
GLEWVSLIY IYQASRLESG NGDDSTYYA VPSRFSGSGS ESVKGRFTIS GTEFTLTIRG
RDNSQNTLS LQPEDFATY LQMNSLRAE FCQQYSTYW DTAVYYCVK TFGQGTKVA
DRDNGWSSI IK VDWGQGTL VTVSS MEX105_09 GGGLVRPGG 391 IGHV3- IGHD6-
IGHJ4*02 VKDRD 420 SASVGDRVT 449 IGKV1- IGKJ1*01 QQYSTFW 478
SLRLSCTASG 23*03 19*01 TGWSS ITCRTSHTIG 5*03 T FTFRRYAMA IVD
NWLAWYQQ WVRQAPGK KPGRAPKLL GLEWVSLIY IYQASILESG NGDDSTYYA
VPSRFSGSGS ESVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMNSLRAE
FCQQYSTFW DTAIYYCVK TFGQGTKVG DRDTGWSSI IK VDWGQGTL VTVSS MEX105_11
GGGLVRPGG 392 IGHV3- IGHD6- IGHJ4*02 VKDRD 421 SASVGDRVT 450 IGKV1-
IGKJ1*01 HQYSTYW 479 SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T
FTFRRYAMA IVD SWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY IYQASILESG
DGEDSTYYA VPSRFSGSGS ASVKGRFTIS GTEFTLTIKS RDNSQNTLS LQPEDFATY
LQMNSLRAE FCHQYSTYW DTAIYYCVK TFGQGTKVG DRDNGWSSI IK VDWGQGTL VTVSS
MEX105_14 GGDLAQPGG 393 IGHV3- IGHD2- IGHJ3*02 AKDRL 422 SASVGDSVTI
451 IGKV1- IGKJ1*01 QQYNNYP 480 SLRLSCAVSG 23*01 8*01 MFDGF
SCRASRSISS 5*03 WT LSIGRYGMN HM WLAWYQQK WIRQAPGKG PGKAPKLLIY
LEWVSGISD TASTLETGV DGGSTYYAA PSRFSGSGSG SVKGRFTISR AEFTLTISSL
DNSKNSVYL QPDDFATYY QMSSLRAED CQQYNNYP TARYYCAKD WTFGQGTT RLMFDGFH
VEIK MWGQGTMV TVSS MEX105_15 GGGLVQPGG 394 IGHV3- IGHD3- IGHJ5
AKDRL 423 SASVGDRVT 452 IGKV1- IGKJ1*01 QHYHSYP 481 SLRLSCAASG
23*01 16*01 *02 QLGVG ITCRASQNIN 5*03 WT FTFRTYAMS ELYES SWLAWYQQ
WVRQPPGK KPGKAPKLL GLEWVSSIS IYMASSLQS AREDSTYFA GVPSRFSGS
ASVRGRFTIS GSGTEFTLT RDNSKNTLY VSSLQPDDF LQMNNLRA ATYYCQHYH
EDTALYYCA SYPWTFGQG KDRLQLGVG TKLEIK ELYESWGQG TLVTVSS MEX105_23
GGGLVRPGG 395 IGHV3- IGHD6- IGHJ4*02 VKDRD 424 SASVGDRVT 453 IGKV1-
IGKJ1*01 QQYSTFW 482 SLRLSCTASG 23*03 19*01 TGWSS ITCRASQNV 5*03 T
FTFRRYAMA IVD DNWLAWYQ WVRQAPGK QKPGKAPKL GLEWVSLIY LIYQASILEN
NADDSTYYA GVPSRFSGS
ESVKGRFTIS GSGTEFTLTI RDNSQNTLS RSLQPEDVA LQMNSLRAE TYFCQQYST
DTAVYYCVK FWTFGQGT DRDTGWSSI KVGIK VDWGQGTL VTVSS MEX105_25
GGGLVRPGG 396 IGHV3- IGHD6- IGHJ4*02 VKDRD 425 SASVGDRVT 454 IGKV1-
IGKJ1*01 QQYSTFW 483 SLRLSCSASG 23*03 19*01 TGWSS ITCRASQTIS 5*03 T
FTFRRYAMA IVD HWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLLY IYQASVLETG
NGDDSTYYA VPSRFSGSGS ESVKGRFIIS GTEFTLTIRS RDNSLNTLS LQPEDFGTY
LQMNSLRAE FCQQYSTFW DTAVYYCVK TFGQGTKVE DRDTGWSSI IK VDWGRGTL VTVSS
MEX105_27 GGGLVRPGG 397 IGHV3- IGHD6- IGHJ4*02 VKDRD 426 SASVGDTVTI
455 IGKV1- IGKJ1*01 QQYSTYW 484 SLRLSCTASG 23*03 19*01 NGWSS
TCRASRTIGS 5*03 T FTFRRYAMA IVD WLAWYQQK WVRQAPGK PGKAPKLLIY
GLEWVSLIY QASILESGVP DGHDTTYYA SRFSGSGSGT DSVKGRFTIS EFTLTIRSLQ
RDNSQNTLS PEDFATYFC LQMNSLRAE QQYSTYWTF DTAVYYCVK GQGTTVGVK
DRDNGWSSI VDWGQGTL VAVSS MEX105_28 GGGLVRPGG 398 IGHV3- IGHD6-
IGHJ4*02 VKDRD 427 SAFVGDRVT 456 IGKV1- IGKJ1*01 QQYSTFW 485
SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T FNFRRYAMA IVD
NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLLY IYQASILESG NGDDSTYYA
VPSRFSGSGS KSVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMNSLRAE
FCQQYSTFW DTAVYYCVK TFGQGTKVE DRDNGWSSI IK VDWGQGTL VTVSS MEX105_33
GGGLVRPGG 399 IGHV3- IGHD6- IGHJ4*02 VKDRD 428 SASVGDRVT 457 IGKV1-
IGKJ1*01 QQYSTYW 486 SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T
FTFRRYAMA IVD NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIW IYQASILESG
NGDDSTYYA VPSRFSGSGS SSVKGRFTIS GTEFTLTIRG RDNSQNTLS LQPEDFATY
LQMNSLRAE FCQQYSTYW DTAVYYCVK TFGQGTKVG DRDNGWSSI IK VDWGQGTL VTVSA
MEX105_37 GGGLVRPGG 400 IGHV3- IGHD2- IGHJ4*02 VKDRD 429 SASVGDRVT
458 IGKV1- IGKJ1*01 QQYSTYW 487 SLRLSCTASG 23*03 15*01 TGRSSI
ITCRASQTIG 5*03 T FTFRRYAMA VE NWLAWYQQ WVRQAPGK KPGKAPKLL
GLEWVSLLY IYQASILESG NGDDSTYYA VPSRFSGSGS ESVKGRFTIS GTEFTLTIRS
RDNSQNTLS LQPEDFATY LQMNSLRAE FCQQYSTYW DTAVYYCVK TFGQGTKVE
DRDTGRSSI IK VEWGQGTW VTVSS MEX105_39 GGGLVQPGG 401 IGHV3- IGHD3-
IGHJ4*02 AKDRL 430 SASVGDRVT 459 IGKV1- IGKJ1*01 QHYYSYP 488
SLRLSCAASG 23*01 10*01 ELGVG ITCRASQNIN 5*03 WT FTFRTYAMS ELYEF
SWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSSIS IYKASSLQSG ASDDSTYFA
VPSRFSGSGS ASVRGRFTIS GTEFTLTVS RDNSKNTLY SLQPDDFAT LQMNNLRA
YYCQHYYSY EDTALYYCA PWTFGQGT KDRLELGVG KVEIK ELYEFWGQG TLVTVSS
MEX105_42 GGGLVQPGG 402 IGHV3- IGHD2- IGHJ4*02 VRDRS 431 SASVGDRVT
460 IGKV1- IGKJ1*01 QQYSTFW 489 SLRLSCAASG 23*03 15*01 NGWSS
MTCRASQTI 5*03 T FTFKNYAMA INL SGWLAWYQ WVRQAPGK QKPGKAPKL
GLEWVSLLY LIYQASRLES NSEESTYYA GIPSRFSGSG DSVKGRFTIS SGTEFTLTIS
RDNSKNTLF SLQPDDVAT LQMNRLRVE YYCQQYSTF DTAVYFCVR WTFGLGTR
DRSNGWSSI VEIK NLWGRGTL VTVSS MEX105_45 GGGLVRPGG 403 IGHV3- IGHD6-
IGHJ4*02 VKDRD 432 SASVGDRVT 461 IGKV1- IGKJ1*01 QQYSTYW 490
SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T FNFRRYAMA IVD
SWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSQIY IYQASILESG NGEDSTYYA
VPSRFSGSGS ESVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMNGLRAE
FCQQYSTYW DTAIYYCVK TFGQGTKVG DRDNGWSSI IK VDWGQGTL VTVSS MEX105_48
GGGLVRPGG 404 IGHV3- IGHD6- IGHJ4*02 VKDRD 433 SASVGDRVT 462 IGKV1-
IGKJ1*01 QHYHSYP 491 SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTL 5*03 WT
FTFRRYAMA IVD NVWLAWYQ WVRQAPGK QQPGKAPKL GLEWVSLIY LIYKASTLQS
DGDDSTYYA GVPSRFSGS ESVKGRFTIS GSGTEFTLTI RDNSQNTVS NSLQPEDFA
LQMTSLRAE TYYCQHYHS DTALYYCVK YPWTFGQG DRDNGWSSI TKVEIK VDWGQGTL
VTVSS MEX105_50 GGGLVRPGG 405 IGHV3- IGHD6- IGHJ4*02 VKDRD 434
SASVGDRVT 463 IGKV1- IGKJ1*01 QQYSTFW 492 SLRLSCTASG 23*03 19*01
NGWSS ITCRASHSIS 5*03 T FTFRRYAMA IVD GWLAWYQQ WVRQAPGK KPGKAPKLL
GLEWVSLIY IYQASILESG DGDDSTYYA VPSRFSGSGS KSVKGRFAIS GTEFTLTIGS
RDNSKNTLS LQPEDFATY LQMNSLRAE FCQQYSTFW DTAVYYCVK TFGQGTKVE
DRDNGWSSI IK VDWGQGTL VTVSS MEX105_51 GGGLVRPGG 406 IGHV3- IGHD6-
IGHJ4*02 VRDRD 435 SASVGDRVT 464 IGKV1- IGKJ1*01 QQYSTFW 493
SLRLSCTASG 23*03 19*01 NGWSS ITCRASQTIG 5*03 T FTFRRYAMA IVD
SWLAWYQQ WVRQAPGK KPGKAPRLL GLEWVSLLY IYQASILESG NGDDSTYYA
VPSRFSGSGS KSVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMNSLRAE
FCQQYSTFW DTAVYYCVR TFGQGTKVG DRDNGWSSI IK VDWGQGTL VTVSS MEX105_54
GGGLVRPGG 407 IGHV3- IGHD6- IGHJ4*02 VKDRD 436 SASVGDRVT 465 IGKV1-
IGKJ1*01 QQYSTYW 494 SLRLSCTASG 23*03 19*01 TGWSS ITCRASRTIG 5*03 T
FTFRRFAMA IVD NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY IYQASILESGI
NGDDSTYYA PSRFSGSGSG QSVKGRFTIS TEFTLTIRGL RDNSQNTLS QPEDFGTYF
LQMNSLRVE CQQYSTYWT DTAVYYCVK FGQGTKVGI DRDTGWSSI K VDWGQGTL VTVSS
MEX105_60 GGGLVRPGG 408 IGHV3- IGHD6- IGHJ4*02 VKDRD 437 SVGDRVTIT
466 IGKV1- IGKJ1*01 QQYSTFW 495 SLRLSCTASG 23*03 19*01 NGWSS
CRASQTIGN 5*03 T FTFRRFAMA IVD WLAWYQQK WVRQAPGK PGKAPKLLIY
GLEWVSLIW QASVLESGV NGDDSTYYA PSRFSGSGSG ESVRGRFTIS TEFTLTISSL
RDNSHNTLS QPEDFATYF LQMRSLRAE CQQYSTFWT DTAIYYCVK FGQGTKVGI
DRDNGWSSI K VDWGQGTL VTVSS MEX105_64 GGGLVRPGG 409 IGHV3- IGHD6-
IGHJ4*02 VRDRD 438 SASVGDRVT 467 IGKV1- IGKJ1*01 QQYSTFW 496
SLRLSCTASG 23*03 19*01 NGWSS ITCRASRTIG 5*03 T FTFRRYAMA IVD
SWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY IYQASILEGG NGDDSTYYA
VPSRFSGSVS ESVKGRFTV GTEFTLTIRS SRDNSQNTL LQPEDFATY SLQMNSLRA
FCQQYSTFW EDTAIYYCV TFGQGTKVE RDRDNGWS IK SIVDWGQGT LVTVSS
MEX105_66 GGGLARPGG 410 IGHV3- IGHD6- IGHJ4*02 VKDRD 439 SASVGDRVT
468 IGKV1- IGKJ1*01 QQYSTFW 497 SLRLSCTASG 23*03 19*01 TGWSS
ITCRASQTIA 5*03 T FTFRRYAMA IVD NWLAWYQQ WVRQAPGK KPGQPPKLL
GLEWVSLIW IYQASILESG NGDDSTYYA VPSRFSGSGS ESVKGRFTIS GTEFTLTIRS
RDNSQNTLS LQPEDFATY LQMNSLRAE FCQQYSTFW DTAVYYCVK TFGQGTKVG
DRDTGWSSI IK VDWGQGTL VTVSS MEX105_78 GGGLVRPGG 411 IGHV3- IGHD6-
IGHJ4*02 VKDRD 440 SASVGDRVT 469 IGKV1- IGKJ1*01 QQYSTYW 498
SLRLSCTASG 23*03 19*01 TGWSS ITCRASHTIG 5*03 T FTFRRYAMA IVD
NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY IYQASILESG NAYDSTYYA
VPSRFSGSGS ESVKGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFATY LQMSSLRAE
FCQQYSTYW DTAVYYCVK TFGQGTKVG DRDTGWSSI IK VDWGQGTL VTVSP MEX105_87
GGGLVRPGG 412 IGHV3- IGHD6- IGHJ4*02 VKDRD 441 SASVGDRVT 470 IGKV1-
IGKJ1*01 QQYSTFW 499 SLRLSCTASG 23*03 19*01 TGWSS ITCRASHTIS 5*03 T
FTFRRYAMA IVD NWLAWYQQ WVRQAPGK KPGKAPKLL GLEWVSLIY VYQASILETG
NGDDSTYYA VPSRFSGSGS ESVRGRFTIS GTEFTLTIRS RDNSQNTLS LQPEDFGTY
LQMNSLRAE FCQQYSTFW DTAVYYCVK TFGQGTKVE DRDTGWSSI IK VDWGQGTL VTVSS
MEX105_88 GGGLVQPGG 413 IGHV3- IGHD2- IGHJ4*02 VKDRG 442 SASVGDRVT
471 IGKV1- IGKJ1*01 QQYSTYW 500 SLRLSCAASG 23*03 15*01 TGWSS
ITCRASQTIS 5*03 T FTFSNYAMA IVH NWLAWYQQ WVRQAPGK KPGKAPKLL
GLEWVSLIYS IYQASSLESG
GDDSTYYAD VPSRFSGSGS FVKGRFTISR GTEFTLTISS HNSKNTLSL LQPDDFATY
QMNSLRAED YCQQYSTYW TAIYYCVKD TFGQGTKVE RGTGWSSIV IK HWGQGTLV TVSS
VH1- MEX105_40 GAEVKRPGA 414 IGHV1- IGHD4- IGHJ6*02 ARGKA 443
SASVGDRVT 472 IGKV1- IGKJ2 QQANSFP 501 46/VK1-12 SVKVSCKAS 46*01
23*01 HQTTV ITCRASQGIS 12*01 *01 YT GYTFTSYYM VILSW SWLAWYQQ
HWVRQAPG YYGMD KPGKAPKLL QGLEWMGII V ISAASSLQSG NPRGGSTTY
VPSRFSGSGS AQKFQGRVA GTDFTLTISS LTGDTSTST LQPEDFATY VYMELTSLR
YCQQANSFP SDDTAVYYC YTFGQGTKL ARGKAHQTT EIK VVILSWYYG MDVWGQGT
TVTVSS MEX105_57 GAEVKKSGA 415 IGHV1- IGHD4- IGHJ6*02 ARGKN 444
SASVGDRVT 473 IGKV1- IGKJ2*01 QQANSFP 502 SVKVSCKAS 46*01 23*01
HQTTV ITCRASQGIS 12*01 YT GYSFTTNYIH AVLSW SWLAWYQQ WVRQAPGQ YYGMD
KPGKAPKLL GPEWMGIIN V ISAASSLQSG PRGGSTTYA VPSRFSGSGS QKFQGRVLM
GTDFTLTIS TSDTSTSTV NLQPEDFAT YMELSSLRS YFCQQANSF EDRAVYYCA
PYTFGQGTK RGKNHQTTV LEIK AVLSWYYG MDVWGQGT TVTVSS BRA112 - refers
to an individual donor. Sequences were analyzed with IgBlast VH3-
BRA112_08 GGGLVQPGG 503 IGHV3- IGHD3- IGHJ4*02 ARDRGI 527
SASVGDRVTI 551 IGKV1- IGKJ1*01 QHYYSYP 575 23/VK1-5 SLKLSCSAAG
23*03 10*01 EGLGEL TCRASQSINS 5*03 WT FNFRSYAMS YSH WVAWYQQK
WIRQAPGKG PGKAPKFLIY LEWVSSLGT KASTLESGVP RGTETTYYA SRFSGSGSGT
ASVKGRFTIS EFTLTITSLQP RDNSKNILY DDFATYYCQ LQMNILGAE HYYSYPWTF
DTAVYYCAR GQGTKVEIK DRGIEGLGEL YSHWGQGT LVTVSS BRA112_09 GGGLAQPGG
504 IGHV3- IGHD5- IGHJ4*02 VRDRIQ 528 SASVGDRVT 552 IGKV1- IGKJ1*01
QHYHGYP 576 SLRLSCETSG 23*05 18*01 GGFGEL MTCRASQSV 5*03 WT
FTFRSYGMG YRY NKWLAWYQ WVRQAPGK QKPGKAPKLL GLEWVSSIYI IYETSILESGV
SGDSTYYAA SSRFSGSGSGT SVKGRFTISR EFTLTISSLQP DNSKSTLYL DDFATYYCQ
QMDRLTAE HYHGYPWTF DTAVYYCVR GQGTKVEIR DRIQGGFGE LYRYWGQG TLVTVSS
BRA112_21 GGGLAQPGG 505 IGHV3- IGHD3- IGHJ4*02 AKDRD 529 SAAVGDSVTI
553 IGKV1- IGKJ3*01 QKYNSYP 577 SLRLSCAASG 23*01 3*01 HFDGHD
TCRASQSISS 5*03 FT FTFSSYAMT F WLAWYQQK WVRQAPGK PGRAPKLLIS
GLEWVSTIT KASNVESGVP GRDGSTYYA SRFSGSGSGT DSVKGRFTIS EFTLTISSLQP
RANSKNTLY DDFATYYCQK LQMNGLRAE YNSYPFTFGP DTAVYFCAK GTKLDIK
DRDHFDGH DFWGQGAL VTVSS BRA112_24 GGRLVQPGG 506 IGHV3- IGHD3-
IGHJ4*02 AKDRLH 530 SASVGDRVNI 554 IGKV1- IGKJ1*01 QHYFSYP 578
SLTLSCAASG 23*01 10*01 SGLGEL TCRASQSINQ 5*03 WT FPFSTYAMS FSY
WLAWYQQK WLRQAPGK PGKAPKFLM GLEWVSGIT YKASTLETGV GDSGSTYYA
PSRFSGSGSG ASVKGRFTIS TEFTLTISSLQ RDNSKNTLY PDDFATYYCQ LQMNSLTAD
HYFSYPWTF DTAVYYCAK GQGTKVEIK DRLHSGLGE LFSYWGQGT LVTVSS BRA112_33
GGGLVQPGG 507 IGHV3- IGHD3- IGHJ5*02 AKDRLA 531 SASVGDRVTI 555
IGKV1- IGKJ1*01 QHYHSYP 579 SLRLSCAASG 23*01 10*01 SGIGELF
TCRASQNIDM 5*03 WT FSFRTYGMS SS WLAWYQQK WVRQAPGK PGRAPKFLIH
GLEWVSSISS KASTLESGVP VDDSTYYAD SRFSGSGSGT SVKGRFTISR EFTLTISSLQP
DNSKNTLYL DDFATYYCQ QMHNLSAK HYHSYPWTF DTALYYCAK GQGTKVDIK
DRLASGIGEL FSSWGQGTL VTVAS BRA112_37 GGGLVQPGG 508 IGHV3- IGHD3-
IGHJ5*02 AKDRMS 532 SASVGDRVTI 556 IGKV1- IGKJ1*01 QHYFSYP 580
SLRLSCAASG 23*01 10*01 GGFGEL TCRASQSISG 5*03 WT FTFRTYGMN NES
WLAWYQQK WVRQAPGK PGRAPNLLIY GLEWVAGIS QASALHSGVP SVDPSTYYA
SRFSGSGSGT GSVKGRFTIS EFSLTISSLQP RDNSKNML DDFATYYCQ YLQMNSLTA
HYFSYPWTF DDSAVYYCA GQGTKVEIK KDRMSGGFG ELNESWGQG TRVTVSS BRA112_46
GGGLVQPGG 509 IGHV3- IGHD3- IGHJ4*02 AKDRLN 533 SASVGDSVTI 557
IGKV1- IGKJ1*01 QHYHSYP 581 SLRLSCVASG 23*01 10*01 GGFGEL
TCRASQSISS 5*03 WT FTFGSYGMA FAS WLAWYQQK WVRQAPGK PGKAPKFLIH
GLEWISSISSI KASSLESGIPS DPSTYYADS RFSGSGSGTE VKGRFTVSR FTLTINNLQP
DNSENTLYL DDFATYYCQ HMSSLKVED HYHSYPWTF TAVYFCAKD GQGTKVEIK
RLNGGFGEL FASWGQGTL VTVSS BRA112_48 GGGLGQPGG 510 IGHV3- IGHD3-
IGHJ4*02 ARDRIK 534 SASVGDRVTII 558 IGKV1- IGKJ2*03 QHYFSSPY 582
SLRLSCAASG 23*01 10*01 GGLGEL CRASRSIDSW 5*03 S FPFSDFGMS FHL
LAWYQQKPG WVRQAPGK KAPRLLIHKA GLEWVSSISG STLHSGVPSR PGFDTYYAD
FSGSGSGTEF SVKGRFTISR TLTISSLQPD DNSKDTLFL DFATYFCQHY QMSRLRVED
FSSPYSFGQG TAVYYCARD TKLEIK RIKGGLGELF HLWGQGAL VTVSS BRA112_51
GGGLVQPGG 511 IGHV3- IGHD3- IGHJ4*02 AKDRLA 535 SASVGDRVTI 559
IGKV1- IGKJ1*01 QHYHSYP 583 SLRLSCAASG 23*01 16*01 AGLGEL
TCRAGQNINS 5*03 WT FTFNTHAM FSH WLAWYQQK AWLRQAPG PGKAPKFLIH
KGLEWVSSV KASTLESGVS TANGGDSW SRFSGSGSGT YADSVKGRF EFTLTINNLQ
TISRDNSRNI PDDFATYYCQ LYLQMSSLR HYHSYPWTF VEDTAVYYC GQGTKVEIK
AKDRLAAGL GELFSHWGQ GTLVSVSS BRA112_56 GGGLVQPGG 512 IGHV3- IGHD3-
IGHJ4*02 TRDRLP 536 SASVGDRVSI 560 IGKV1- IGKJ1*01 QHYHSYP 584
SLRLSCAASG 23*01 10*01 NGIGEL TCRASQNIDM 5*03 WT FTFSTYAMS HDH
WLAWYQQK WVRQAPGK PGKAPKFLIY GLKWVSGIT KASNLKSGVP GDSGSTYYA
SRFSGSGSGT RSVKGRFTIS EFTLTISSLQP RDNSKNTLY DDFATYYCQ LEISSLRAED
HYHSYPWTF TAFYFCTRD GQGTKVEIK RLPNGIGEL HDHWGQGT LVTVSS BRA112_65
GGGLVQPGG 513 IGHV3- IGHD3- IGHJ5*02 TKDRLS 537 SASIGARVTIT 561
IGKV1- IGKJ1*01 QHYHSYP 585 SLRLSCAASG 23*01 10*01 GAFGEL
CRASQDISGW 5*03 WT FTFRTYGMN NES LAWYQQKPG WVRQAPGK RAPKLLIYQA
GLEWVSGIS STLYNGVPPR GIDPSTYYA FSGSGSGTEF DSVKGRFTIS TLTISGLQPD
RDNSKNILF DFATYYCQHY LQMNSLTAD HSYPWTFGQ DTAVYYCTK GTKVEIK
DRLSGAFGE LNESWGQG TMVIVSS BRA112_69 GGALVQPGG 514 IGHV3- IGHD3-
IGHJ5*02 TKDRVQ 538 SASVGDRVTI 562 IGKV1- IGKJ1*01 QQYHSYP 586
SLRLSCAASG 23*01 10*01 GGFGEL TCRASQNINS 5*03 WT FTFRNYGVS FHS
WLAWYQQK WVRQAPGK PGQAPKFLM GLEWVSSIN HKASILESGV TDGGSTYYA
PSRFSGSGSG ASVKGRFTIS TEFTLTISSLQ RDNSRNTLY PDDFASYFCQ LQMDGLTVA
QYHSYPWTF DTAMYFCTK GPGTKVEIK DRVQGGFGE LFHSWGQGT LVTVSP BRA112_71
GGGLIQPGGS 515 IGHV3- IGHD3- IGHJ4*02 AKDRLS 539 AASVGDRVTI 563
IGKV1- IGKJ2*01 QHYYSYP 587 LRLSCAASGF 23*01 10*01 GGFGEL
TCRASQNINS 5*03 YT TFSSYAMSW FQK WLAWYQQK VRQAPGKGL PGKAPKFLIY
EWVSGISGS KASTLESGAP GGASDNGAS SRFSGSGSGT RYYADSVKG EFTLTISSLQP
RFSISRDNSK DDFATYYCQ NTVYLQMNS HYYSYPYTFG LRAEDTAVY QGTKLEIK
YCAKDRLSG GFGELFQKW GQGTLVTVS S BRA112_91 GGDLVQPGG 516 IGHV3-
IGHD3- IGHJ4*02 AKDRIP 540 SASVGDRVTI 564 IGKV1- IGKJ2 QHYHSYP 588
SLRLSCAASG 23*01 16*01 HGLGEL TCRASQSISG 5*03 *01 YT FTFSTYGMA YAN
WLAWYQQK WVRQAPGK PGKAPRLLM GLEWLSSISS HKASILYRGV VDDSKYYAA
PSRFSGSGSG SVKGRFTISR TEFTLTISSLQ DNSRNTLYL PDDFATYYCQ HMNSLRVD
HYHSYPYTFG DTAVYYCAK QGTKLEIK DRIPHGLGE LYANWGQG TLVAVSS BRA112_94
GGDLVQPGG 517 IGHV3- IGHD3- IGHJ4*02 AKDRSP 541 SASVGDRVTI 565
IGKV1- IGKJ2*01 QHYFSYP 589 SLRLSCAASG 23*01 16*01 HGLGEL
TCRASQSISS 5*03 YT FTFRTYGMT YGD WLAWYQQK WVRQAPGK PGKAPKLLM
GLEWVSSISS HKASNLHVG VDDSTYYAK VPSRFSGSGS SVKGRFTISR GTEFTLTITSL
DNSKNTLYL QPDDFATYYC HITNLRVDD QHYFSYPYTF TAMYYCAKD GQGTKVEIK
RSPHGLGEL
YGDWGQGT LVTVSS VH3- BRA112_23 GGGLVKPGG 518 IGHV3- IGHD3- IGHJ4*02
VNGGFS 542 SLSPGERATL 566 IGKV3- IGKJ4*01 QQRSNWL 590 23/VK3-11
SLRLSCAASG 23*01 22*01 GYYSDY SCRASQSVSN 11*01 T LTFSTYAMS
YLAWYQQKP WVRQAPGK GQAPRLLIYD GLEWVSAIS ASNMAPGIPA PGSGDNIYY
RFSGSGSGTD GDSVKGRFT FTLTISSLEPE ISRDNSKNT DFAVYYCQQR LYLQMNSLR
SNWLTFGGG AEDTAVYYC TKIEIK VNGGFSGYY SDYWGQGTL VAVSS BRA112_52
GGGLGQPGG 519 IGHV3- IGHD3- IGHJ6*03 AKVKDS 543 SLSPGERTTL 567
IGVK3- IGKJ4*01 QQRGKW 591 SLRLSCGASG 23*01 22*01 SGYMYY
SCRASQSISNY 11*01 PPS FTFSTYAMT YYMDV LAWYQQKPG WVRQAPGK QAPRLLIYDA
GLEWVSDIS SNRAAGIPAR ADSDTTSYA FSGSGSGIDFT DSVKGRFTIS LTISSLEPEDF
RDNSKNTLY GVYYCQQRG LQMNSLRAE KWPPSFGGG DSAVYYCAK TKVEIK VKDSSGYMY
YYYMDVWG KGTTVTVSS BRA112_63 GGGLVLPGG 520 IGHV3- IGHD1- IGHJ4*02
AKDLYN 544 SLSPGERATL 568 IGKV3- IGKJ4*01 QQRGNW 592 SLRLSCAASG
23*01 14*01 GYFDY SCRASQSVRN 11*01 PPAT FTFSTHAMT FLAWYQQKP
WVRQAPGK GQAPRLLIYD GLEWVSVIS ASNRATGIPA HSGTTTYYA FTLTISSLEPE
DSFRGRFTIS RFSGSGSGTD RDNSKNTVY DFAVYYCQQR LQMNRLRVE GNWPPATFG
DTAVYYCAK GGTKVEIK DLYNGYFDY WGQGTLVT VSS VH3- BRA112_36 GGGVVQPGR
521 IGHV3- IGHD1- IGHJ2*01 ARGEVG 545 SLSPGERATL 569 IGKV3-
IGKJ5*01 QQRSNW 593 30/VK3-11 SLRLSCAASG 30*04 26*01 YFDL
SCRASQSVSS 11*01 PPIT FTFSISTIHW FLAWYQQKP VRQAPGKGL GQPPRLLIYD
EYVVVISHD ASTRATGIPA GNTKYYADS RFSGSGSGTD VKGRFIISRD FTLTISSLEPE
NSKNTVFLQ DFAVYYCQQR MNSLRPVDT SNWPPITFGQ AVYYCARGE GTRLEIK
VGYFDLWGR GTLVTVSS BRA112_70 GGGVVQPGR 522 IGHV3- IGHD5- IGHJ1*01
AREVDG 546 SLSPGERATL 570 IGKV3- IGKJ5*01 QQRSYSIT 594 SLRLSCAASG
30*07 24*01 IYGYLHY SCRARQNVR 11*01 FSFSSHAMY NFLAWYQQK WVRQAPGK
PGQAPRLLIY GLEWVAIVS DASNRATDIP YDGSTKNYA ARFSGSGSGT DSVKGRFTIS
DFTLTISSLEP RDNSKNTIY EDFAVYYCQQ LHLNSLRAE RSYSITFGQG DTAVYFCAR
TRLEMK EVDGIYGYL HYWGQGTL VTVSS BRA112_75 GGGVVQPGR 523 IGHV3-
IGHD4- IGHJ6*03 ARDGTT 547 SLSPGERATL 571 IGKV3- IGKJ4*01 QQRSNGP
595 SLRLSCAASG 30*03 17*01 VTNFYL SCRASQSVSN 11*01 LT FTFSNYGMH DV
YLAWYQQKP WVRQAPGK GQAPRLLIYD GLEWVAIISY ASSRATGIPA DGNTKYYAD
RFSGSGSGTD SVKGRFTISR FSLTISSLEPE DNSKNTLYL DFAVYYCQQR QLNSLRAED
SNGPLTFGGG TAIYYCARD TKVEIK GTTVTNFYL DVWGKGST VTVSS BRA112_76
GGGVVQPGR 524 IGHV3- IGHD5- IGHJ4*02 ARDFHG 548 SLSPGERATL 572
IGKV3- IGKJ4*01 QQRSNW 596 SLRLSCAASG 30*10 18*01 YLDS SCRASQSVSN
11*01 PPLT FTFNTYAVH FFAWYQQKP WVRQAPGK GQAPRLLIYD GLDWVTVLS
ASKRATGIPA HDGNSKYYT RFSGSGSGTD DSVRGRFTIS FTLTISSLEPE RDSSKKTVF
DFAVYYCQQR LQMDNLRTE SNWPPLTFG DTAVYYCAR GGTKVEIK DFHGYLDS WGQGTLVT
VSS VH4- BRA112_20 GPGLVKPSE 525 IGHV4- IGHD3- IGHJ3*02 ARTETI 549
SLSPGERATL 573 IGKV3- IGKJ4*01 QQYGTSP 597 38-2/VK3-20 TLSLTCGVSG
38-2*01 10*01 TIRGAV SCRASQSVSSS 20*01 PEFT YSLTSGYYW SFDI
YLAWYQQKP SWIRQPPGK GQAPRLLIYG GLEWIGSIYH AYNRATGIPD TGNTYYNPS
RFSGSGSGTD LKSRVTILVD FTLTINRLEP TSKNHFSLK EDFAVYYCQQ LTSVTAADT
YGTSPPEFTF AMYYCARTE GRGTKVEIK TITIRGAVSF DIWGQGRM VTVSS BRA112_57
GPGLVKPSE 526 IGHV4- IGHD6- IGHJ5*02 ARDARS 550 SLSPGERATL 574
IGKV3- IGKJ2*02 QQYGSSW 598 TLSLTCSVSG 38-2*02 13*01 RSWDR
SCRASQSLSSS 20*01 GT YFISSGHYW TGFFGP FLAWYQQKP GWIRQSPGK
GQSPRLLIYG GLEWIASIYQ TSSRDTGIPD SGSKFQTGN RFSGSGSGTD TYYNPSLES
FTLTISRLEPE RVTISMDTS DSAVYYCQQY KNQFSLKLS GSSWGTFGQ SVTAADTAV
GTKLEIK YFCARDARS RSWDRTGFF GPWGQGILV TISS BRA 12 - refers to an
individual donor. Sequences were analyzed with IgBlast VH3-
BRA12_08 GGALVQPGG 599 IGHV3- IGHD6- IGHJ4*02 VKHLRG 603 SLSPGERAT
607 IGKV3 IGKJ2*01 QQFGSSP 611 23/VK3-20 SLRLSCAASG 23*01 19*01
WYTFEI LSCRASQSVS 20*01 RYT FTFNYYAMT GSYLAWYQ WVRQAPGR QKPGQAPRL
GLEWVSTIT LIYGASRRA DNGGTTYLA TGIPDRFSGS DSVKGRFTIS GSGTDFTLTI
RDNSQNTQS SRLEPEDFA LQMNNLRA VYYCQQFGS DDTAVYFCV SPRYTFGQG KHLRGWYT
TKLEIK FEIWGQGTL VTVSS BRA12 21 GGGLVQPGG 600 IGHV3- IGHD3- IGHJ4
AKSPYV 604 SLSPGERAT 608 IGKV3- IGKJ4*01 QQYGDS 612 SLRLSCAASG
23*01 16*01 *02 GGYGLP LSCRASQTIF 20*01 PPT YIFDNYAMS GDS FNYLAWYQ
WVRQAPGK KKPGQAPRL GLEWVSYIN LVHGASTRA GGGYGTDYA TGIPDRFSGS
DSVKGRFTIS GSGTDFTLTI RDNSKRILY NSLDPEDFA LQMNSLRVG VYYCQQYGD
DTAVYYCAK SPPTFGGGT SPYVGGYGL KVDIK PGDSWGQG TLVTVSS VH4- BRA12_06
GPGLVKPSE 601 IGHV4- IGHD3- IGHJ6*02 ARGPHY 605 SLSPGERAT 609
IGKV3- IGKJ5*01 QQYGSSP 613 59/VK3-20 TLSLTCTVX 59*01 22*01 YDSSAY
LSCRVSQSVS 20*01 PVT GGSISRYFXS FTYNGM SNSLAWYQ WIRQPPGKG DV
QKPGQAPRL LEWIGYIYYT LIYGASSRAT GSTNYNPSL GIPDRFSGSG KSRVIILVDT
SGTDFTLTIS SKNQFSXKL RLEPEDFAV SSVTXADTA YYCQQYGSS VYYCARGPH
PPVTFGQGT YYDSSAYFT RLEIK YNGMDVWG QGTTVTVSS BRA12_58 GPGLVKPSE 602
IGHV4- IGHD3- IGHJ4*02 ARGDYY 606 SLSPGERAT 610 IGKV3- IGKJ4*01
QQYGTS 614 TLSLTCTVSG 59*01 22*01 YDSSGY LSCRASQSVS 20*01 VT
GSISSYYWS LYYFDY SSSLAWYQQ WIRQPPGKG KPGQAPRLL LEWIGFIYYS IYGASNRAT
GSTNYNPSL GIPDRFSGSG KSRVTISVDT SGTDFTLTIS SKNQFSLKL RLEPEDFAV
SSVTAADTA YYCQQYGTS VYYCARGDY VTFGGGTKV YYDSSGYLYY EIK FDYWGQGT
LVTVSS BRA 138 - refers to an individual donor. Sequences were
analyzed with IgBlast VH1- BRA138_23 GAEVKKPGSS 615 IGHV1- IGHD2-
IGHJ5*02 ARQKCT 627 SGRAIESVSGX 639 IGKV3- IGKJ4*01 HQSIKWP 651
69/VK3-11 VRVSCKASGD 69*06 8*02 GGSCYS LAWYQQKPG 11*01 PT
TFSNYAISWV GNFDP QAPRLLIYDA RQAPGQGLE SNRATGIPPR WMGGIIPIFG
FSGSGXGTEF TASYAQRFQD TLTISSAEPED RVTITADKST FAVYYCHQSI GTVYMELSSL
KWPPTFGGG RSEDTAVFYC SKVEIK ARQKCTGGSC YSGNFDPWG QGTLVTVSS
BRA138_28 GAEVKKPGSS 616 IGHV1- IGHD3- IGHJ4*02 ARFRYY 628
ERVTLSCRAS 640 IGKV3- IGKJ4*01 QQRSNW 652 VKVSCKAPGG 69*01 22*01
YESGGY QSVSSYLAWY 11*01 PLT TFSRYSIAWV SDASPY QQKPGQAPR RQAPGQGLE
YLDY LLIYDASNRA WMGGINPTF TGIPARFTGS TTPNYAQKFQ GSGTDFTLTIS
GRVTITADES SLEPEDFAVY TNTAYLDLSS YCQQRSNWP LRSEDTAVYY LTFGGGTKVE
CARFRYYYES IK GGYSDASPYY LDYWGQGTL VTVSS VH4- BRA138_59 GPGLVKPSQT
617 IGHV4- IGHD1- IGHJ5*02 ARAWC 629 SLSPGERATL 641 IGKV3- IGKJ2*01
QQYGRSP 653 31/VK3-20 LSLTCTVSGV 31*03 EYAAYC SCRASQSVTS 20*01 FT
SISSGGYYYS 26*01 WFDP SYLAWYQHK WFRQLPGKG PGQAPRLLIY LEWIGHIYYT
GASSRAPGIP GNTHYNPSLR DRFSGSGSGT SRLTISVDTSK DFTLTISRLEP NQFSLKLSSV
EDFAVYWCQ TAADTARYYC QYGRSPFTFG ARAWCEYAA QGTNLEIK YCWFDPWGR
GTLVTVSS BRA138_62 GPGLVKPSQT 618 IGHV4- IGHD4- IGHJ3*02 ARAGFD 630
SLSPGERATL 642 IGKV3- IGKJ2*01 QQYAHSP 654 LSLTCTVSGG 31*03 17*01
YGSPVS SCRASQSVSS 20*01 RGYT SITGGVYYWN AFDI TYLVWYQQK WIRHHPGKG
PGQAPRLLIY LEWIGYMFYS GASSRATGIP GDTDYNPSLR DRFSGSGSGT SRVTISGDTS
DFTLTISRLEP KNKFSLNLNS EDFAVYFCQQ VTAADTAVYY YAHSPRGYTF CARAGFDYGS
GQGTKLEIK PVSAFDIWGQ GTMVTVSS VH4- BRA138_65 GPGLVKPSET 619 IGHV4-
IGHD3- IGHJ2*01 ARHGPG 631 SLSPGERATL 643 IGKV3- IGKJ4*01 QQRSTWL
655
39/VK3-11 LSLTCTVSGG 39*01 16*01 MGHNW SCRASQSISSY 11*01 T
SISSYNYYWG YFDL LAWYQQKPG WIRQPPGKGL QAPRLLIYDA EFIGSIYYTGS
SNRAPGIPAR TYYNPSLRSR FSGSGSGTDF VTISVDTSKN TLTISSLEPED QFSLKLTSVT
FAVYYCQQRS AADTAVYYCA TWLTFGGGT RHGPGMGHN KVEIK WYFDLWGRG TLVTVSS
BRA138_94 GPRLVKPSET 620 IGHV4- IGHD6- IGHJ4*02 AKHLYS 632
SLSPGERATL 644 IGKV3- IGKJ2*01 QQGSKWP 656 LFLTCTVSGD 39*01 13*01
SSWNIG SCRASQSVSX 11*01 VYT SISSSSYFWG SSFDS YLAWYQQKP WIRQPPGKGL
GQAPRLLXYD EWIGSISYSGS ASSRATGIPA TYYNPSLKSR RFSGSGSGTD VTISVDTSKN
FTLTISSLEPE QFSLKLSSVT DFAVYYCQQG AADTVVYYCA SKWPVYTFG KHLYSSSWNI
QGTKLEIK GSSFDSWGPG TLVTVSS VH4- BRA138_17 GPGLVKPSET 621 IGHV4-
IGHD3- IGHJ4*02 ARGPDN 633 SVSPGERVTL 645 IGKV3- IGKJ3*01 QQYNNW
657 59/VK3-15 LSLSCTVSSGS 59*1 16*02 RY SCRASQSVSY 15*01 PPVFT
ISNYYWNWIR NLAWHQQKP QPPGKGLEWI GQAPRLLIYG GYIYYSGSISY ASTRATGIPA
NPSLKSRVTIS RFSGSGSGTE VDTSKNQLSL FTLTISNMQS KLNSVTAADT EDFAVYYCQQ
AVYYCARGPD YNNWPPVFT NRYWGQGTL FGPGTKVDIK VTVSS BRA138_79
GPGLVKPSET 622 IGHV4- IGHD3- IGHJ4*02 ARGPDN 634 SVSPGERVTL 646
IGKV3- IGKJ3*01 QQYNNW 658 LSLTCTVSGG 59*1 16*02 RY SCRASQSVSY
15*01 PPVFT SISNYYWNWI NLAWHQQKP RQPPGKGLE GQAPRLLIYS WIGYIYYSGSI
ASTRATGIPA SYNPSLKSRV RFSGSGSGTE TISVDTSKNQ FTLTISNMQS LSLKLNSVTA
EDFAVYYCQQ ADTAVYYCAR YNNWPPVFT GPDNRYWGQ FGPGTKVDIK GTLVTVSS VH1-
BRA138_49 GAEVKKPGSS 623 IGHV1- IGHD6- IGHJ4*02 ATPDW 635
PVTPGEPASIS 647 IGKV2- IGKJ3*01 MQALQTP 659 69/VK2-28 VRLSCKASGG
69*11 25*01 QYSSAY CRSSQSLLHS 28*01 FT SYSTYAISWV SLDH TGYNYLDWY
RQAPGQGLE LQKPGQSPQL WMGRIIPSLG LIYLGSNRAS KTHLAQKFQ GVPDRFSGSG
GRVTFTADES SGTDFTLKIS TTTVYMVLSS RVEAEDVGVY LKSDDTALYY YCMQALQTP
CATPDWQYS FTFGPGTKVD SAYSLDHWG IK QGTLVTVSS BRA138_57 GAEVKKPGSS
624 IGHV1- IGHD6- IGHJ4*02 ATPDW 636 PVTPGEPASIS 648 IGKV2-
IGKJ3*01 MQALQTP 660 VRLSCKASGG 69*11 25*01 QYSSAY CRSSQSLLHS 28*01
FT SYSTYAISWV SLDH TGYNYLDWY RQAPGQGLE LQKPGQSPQL WMGRIIPSLG
LIYLGSNRAS KTHLAQKFQ GVPDRFSGSG GRVTFTADES SGTDFTLKIS TTTVYMILSS
RVEAEDVGVY LKSEDTALYY YCMQALQTP CATPDWQYS FTFGPGTKVD SAYSLDHWG IK
QGTLVTVSS VH1- BRA138_15 GAEVKKPGAS 625 IGHV1- IGHD5- IGHJ4*02
GRDSKG 637 PASVSGSPGQ 649 IGLV2- IGLJ1*01 CSYAGSST 661 46/VL2-23
VKVSCKTSGY 46*01 24*01 WLQLR SITISCAGTSS 23*02 YV TFTSYYMNW GDIDY
DVGNYNLVS VRQAPGQGLE WYQQHPGKA WMGIIKPSDG PKLLIYEVSK STNYAQKFQG
RPSGVSNRFS RVTMTRDTS GSKSGNTASL TSTVYMELRS TISGLQAEDE LRSEDTAVYY
ADYYCCSYAG CGRDSKGWL SSTYVFGTGT QLRGDIDYW EVTV GQGTLVTVSS BRA138_46
GAEVKKPGAS 626 IGHV1- IGHD6- IGHJ3*02 ARDFGG 638 PASVSGSPGQ 650
IGLV2- IGLJ1*01 CSYAGSSR 662 VKVSCKASGY 46*01 6*01 YSSSSVS
SITISCTGTSS 23*02 FV TFTSTYIHWV DAFDI DVGSFNLVS RQAPGQGLE WYQQHPGKA
WMGIINPSSS PKLIIYEVSKR NTNYAQKFQ PSGVSNRFSG GRVTMTRDT SKSGNTASLT
STSTVYMELS ISGLQAEDEV SLRSEDTAVY HYYCCSYAGS YCARDFGGYS SRFVFGTGTK
SSSVSDAFDI VTV WGQGTMVTV SS
TABLE-US-00016 TABLE 2 IgH IgL Antibody SEQ ID SEQ ID ID VH DH JH
CDR3 NO: VK/L JK/L CDR3 NO: MEX 84-refers to an individual donor.
Sequences were analyzed with IgBlast MEX84_ IGHV4- IGHD6- IGHJ6
ARTAGDYGMDV 663 IGLV3-1*01 IGLJ2*01 QAWDSSTAVV 707 p2_03 39*01
13*01 *02 MEX84_ IGHV3- IGHD2- IGHJ3 YRVVAFDDPVNI 664 IGLV3-25*02
IGLJ2*01 QSADTNGSSWI 708 p2_04 30*03 15*01 *02 MEX84_ IGHV5- IGHD3-
IGHJ4 ARLPAYYDILTG 665 IGKV4-1*01 IGKJ1*01 QQYYTTPQT 709 p2_07
51*03 9*01 *02 HIKGGYFDY MEX84_ IGHV4- IGHD3- IGHJ6 ARLGGFSRTLYS
666 IGKV3-20*01 IGKJ1*01 QQSGSLPWT 710 p2_09 30-4*01 10*01 *02
YYSMNV MEX84_ IGHV3- IGHD5- IGHJ6 ARGDYRSSYGYR 667 IGLV3-25*03
IGLJ2*01 QSADTNGSSWI 711 p2_12 11*01 18*01 *02 YYGFDV MEX84_ IGHV3-
IGHD6- IGHJ4 AKDLYSSGWYMG 668 IGLV1-40*01 IGLJ1*01 QSYDSSLSGYV 712
p2_19 30*02 19*01 *02 PDY MEX84_ IGHV3- IGHD6- IGHJ3 ARDLWDKYSSSL
669 IGKV3D-15*01 IGKJ4*01 QQYNNWPLH 713 p2_20 30-3*01 13*01 *02
GAFHI MEX84_ IGHV4- IGHD1- IGHJ4 ARNQPGGRAFDF 670 IGKV3-11*01
IGKJ1*01 QERDNWPLTWP 714 p2_27 4*07 14*01 *02 MEX84_ IGHV4- IGHD5-
IGHJ6 ARKKGGYGSHYY 671 IGKV3/ IGKJ1*01 QQDYSLPTT 715 p2_30 34*01
12*01 *01 YGMDV OR2-268*02 MEX84_ IGHV4- IGHD3- IGHJ4 GRTFTSAPFVDQ
672 IGKV4-1*01 IGKJ2*01 QQYYSTPYT 716 p2_32 30-4*01 10*01 *02
MEX84_ IGHV4- None IGHJ6 ARHLPYYYGMDV 673 IGKV3-15*01 IGKJ2*01
QQYNNWPPT 717 p2_34 59*08 *02 MEX84_ IGHV3- IGHD2/OR1 IGHJ6
ARGRRRIQGVGE 674 IGKV2-28*01 IGKJ4*01 MQSLQTPRALT 718 p2_36 13*01
5-2a*01 *02 YSGMDV MEX84_ IGHV3- IGHD4- IGHJ4 ASHDYGGNFRV 675
IGKV3-20*01 IGKJ1*01 QQYGSSPRT 719 p2_46 7*01 23*01 *02 MEX84_
IGHV4- IGHD2- IGHJ5 ARVGGRVWWFDP 676 IGKV1-39*01 IGKJ1*01 QQTYSTPWT
720 p2_48 59*01 21*01 *02 MEX84_ IGHV3- IGHD3- IGHJ3 AKYRDLWSGYDA
677 IGKV3-20*01 IGKJ4*01 QQYGSSLT 721 p2_56 23*01 10*01 *02 FDI
MEX84_ IGHV4- IGHD3- IGHJ4 ATVIRHFDN 678 IGKV1-33*01 IGKJ3*01
QQYDNLPGFT 722 p2_59 39*01 22*01 *02 MEX84_ IGHV3- IGHD3- IGHJ3
AKVQTFVGAFDL 679 IGKV1-33*01 IGKJ3*01 QHYDSLPLLIS 723 p2_61 9*01
16*01 *01 MEX84_ IGHV3- IGHD3- IGHJ6 ARDYGNMRYGMDG 680 IGKV1-39*01
IGKJ1*01 QQNDDARALT 724 p2_64 30*04 16*01 *02 MEX84_ IGHV4- IGHD3-
IGHJ6 ARGLRFLYGMDV 681 IGKV3-20*01 IGKJ5*01 QHYDSSIT 725 p2_66
61*02 3*01 *02 MEX84_ IGHV4- IGHD2- IGHJ6 ASENLISQGHCTG 682
IGKV1-39*01 IGKJ1*01 QQSYTVPRT 726 p2_71 4*02 8*02 *02 AICYSTYGMDV
MEX84_ IGHV4- IGHD3- IGHJ4 ARDSPYYYDATGS 683 IGKV1-5*03 IGKJ1*01
QQYNSYPRT 727 p2_73 31*03 22*01 *02 PLLGPGTLVTVSS MEX84_ IGHV3-
IGHD5- IGHJ4 ANHWGSAVMVTGY 684 IGKV1-8*01 IGKJ1*01 QQYYSYPRT 728
p2_88 23*01 18*01 *02 FDY MEX84_ IGHV4- IGHD5- IGHJ4 TRVRWDGIESTMF
685 IGLV2-8*01 IGLJ2*01 SSYAGSNNFEVV 729 p2_89 34*01 12*01 *02 FDS
MEX84_ IGHV1- IGHD5- IGHJ4 ARVKMANGAIPPY 686 IGKV1-9*01 IGKJ3*01
QQLISYPPT 730 p2_92 2*02 24*01 *02 FDH MEX84_ IGHV3- IGHD1- IGHJ4
VRVNRLHSGSYFS 687 IGLV2-23*02 IGLJ2*01 CSYAAGSTFV 731 p4_01 64D*06
26*01 *02 FDY MEX84_ IGHV4- IGHD5- IGHJ6 ARLGLIQSLRNYY 688
IGLV3-1*01 IGLJ2*01 QAWDSRSVV 732 p4_02 59*08 18*01 *02 YGLDV
MEX84_ IGHV3- IGHD3- IGHJ6 TTAIRVTGMDV 689 IGLV1-40*01 IGLJ1*01
QSYDSSHYV 733 p4_04 15*07 10*01 *02 MEX84_ IGHV3- IGHD2- IGHJ6
ARGWSDNSMDV 690 IGKV3-20*01 IGKJ5*01 QQYGSSPIT 734 p4_07 20*01 2*01
*02 MEX84_ IGHV4- IGHD4- IGHJ4 VTLLHDYGDYSFDY 691 IGKV1-39*01
IGKJ2*01 QQSSSIPYT 735 p4_26 31*06 17*01 *02 MEX84_ IGHV4- IGHD5-
IGHJ4 ARGNITHYDLLPCDS 692 IGKV4-1*01 IGKJ2*01 QQYYSTPHT 736 p4_27
31*03 12*01 *02 MEX84_ IGHV3- IGHD3- IGHJ4 SLGRINYFFDY 693
IGKV1-9*01 IGKJ4*01 QQLNSYPLT 737 p4_28 23*01 10*01 *02 MEX84_
IGHV4- IGHD6- IGHJ4 ARASQLVPDY 694 IGKV3-11*01 IGKJ4*01 QQRSNWLT
738 p4_32 30-4*01 6*01 *02 MEX84_ IGHV1- IGHD3- IGHJ5
ARGGPINVPLGFDP 695 IGKV3-20*01 IGKJ4*01 HQYVSSPLT 739 p4_35 2*02
10*02 *02 MEX84_ IGHV1- IGHD2- IGHJ6 ARDEGGPNCSGGNC 696 IGKV1-33*01
IGKJ4*01 NNMILSLQL 740 p4_43 69*06 15*01 *02 YYYYGMDV MEX84_ IGHV3-
IGHD2- IGHJ5 ANGGWQVPHWFDP 697 IGKV1-39*01 IGKJ4*01 QQSYSIPLT 741
p4_44 23*01 15*01 *02 MEX84_ IGHV4- IGHD5- IGHJ4 ARARSGYSLGYYFD 698
IGKV1-33*01 IGKJ4*01 QQYDDLLT 742 p4_46 61*02 18*01 *02 Y MEX84_
IGHV3- IGHD3- IGHJ5 AKVSRPKGAQASFDP 699 IGKV1-6*01 IGKJ1*01
LQDYDYPLS 743 p4_47 30*18 16*01 *02 MEX84_ IGHV3- IGHD5- IGHJ4
ATPKGGYSGYDQLDY 700 IGKV1-39*01 IGKJ4*01 QQSYNFPRT 744 p4_52 15*07
12*01 *02 MEX84_ IGHV1- IGHD3- IGHJ6 ARPGYTFGYHSYYY 701 IGKV3-11*01
IGKJ5*01 QQRAGT 745 p4_59 69*01 22*01 *02 AMDV MEX84_ IGHV3- IGHD6-
IGHJ4 ARGIDY 702 IGKV2-24*01 IGKJ1*01 TQATQFPWT 746 p4_66 23*01
13*01 *01 MEX84_ IGHV1- IGHD6- IGHJ6 ARGSLRGTNGWHS 703 IGKV1-39*01
IGKJ2*01 HQSFSSPDT 747 p4_69 2*02 19*01 *02 HLGYYGMDV MEX84_ IGHV3-
IGHD6- IGHJ4 ARSRLRYSSSWYFDY 704 IGKV4-1*01 IGKJ5*01 QQYYSTPRIT 748
p4_72 48*03 6*01 *02 MEX84_ IGHV3- IGHD1- IGHJ2 ARDILPHGTHGWYF 705
IGKV3-11*01 IGKJ2*01 QHRRDWPRYT 749 p4_73 48*01 7*01 *01 DV MEX84_
IGHV3- IGHD2- IGHJ4 ARAKGMIAELDY 706 IGKV4-1*01 IGKJ2*01 QQYRDTPSYT
750 p4_75 53*01 21*01 *02 MEX 18-refers to an individual donor.
Sequences were analyzed with IgBlast MEX18_01 IGHV3- IGHD5-
IGHJ6*02 TTEIGLGGPNTPSAQ 751 IGLV1-47*01 IGLJ3*02 VAWDDSLSGRV 773
15*01 24*01 LYYYGIDV MEX18_06 IGHV3- IGHD1- IGHJ3*02 ASFRSGAFEI 752
IGKV3-20*01 IGKJ3*01 QQYGSSAVS 774 11*06 26*01 MEX18_08 IGHV4-
IGHD3- IGHJ4*02 ARVRYEYDSGGYYY 753 IGLV2-11*01 IGLJ1*01 CSYAGSYV
775 59*01 22*01 VYDFEY MEX18_12 IGHV4- IGHD6- IGHJ6*02
ARVALSSSSFGEHY 754 IGKV3-20*01 IGKJ3*01 QQYGGSPLFT 776 31*03 6*01
YGVDV MEX18_14 IGHV3- IGHD4- IGHJ6*02 ARAGTVFAGHYGMDV 755
IGKV1-16*02 IGKJ4*01 QQYKSYPLT 777 72*01 17*01 MEX18_17 IGHV3-
IGHD3- IGHJ4*02 AKDPRRDYYDSSGYY 756 IGLV2-8*01 IGLJ3*02 SSYAGSRTWV
778 23*01 22*01 YPSRGHFDY MEX18_18 IGHV4- IGHD1-14*01 IGHJ3*02
ARIITRNGDAFDI 757 IGLV2-11*01 IGLJ2*0 CSYAGSYT 779 61*01 MEX18_25
IGHV3- IGHD1-20*01 IGHJ4*02 AKFQSSNWSPFDS 758 IGKV3-20*01 IGKJ1*01
QQYGNLPRT 780 23*01 MEX18_26 IGHV4- IGHD3- IGHJ4*02 ARGVWFGEFAVGY
759 IGKV3-15*01 IGKJ3*01 QQYNNWPPRGAT 781 30-4*01 10*01 MEX18_31
IGHV3- IGHD1-1*01 IGHJ4*02 ITGIFKSTWKTDY 760 IGKV3-11*01 IGKJ1*01
QQRSNGWT 782 15*01 MEX18_32 IGHV4- IGHD4/OR15- IGHJ4*02
ARESDFNYGAVDH 761 IGKV3-15*01 IGKJ2*01 QQYNNWPYT 783 31*03 4a*01
MEX18_35 IGHV5- IGHD1-1*01 IGHJ4*02 AKTQGYNPNWPHDF 762 IGKV1-9*01
IGKJ2*01 QQLNGHPRT 784 51*01 MEX18_37 IGHV3- IGHD3-10*01 IGHJ4*02
AKDGRGSIDY 763 IGKV2D-29*02 IGKJ5*01 MQSIQLPPIT 785 30*18 MEX18_43
IGHV3- IGHD2-15*01 IGHJ4*02 ERDIVWGVAGTDY 764 IGKV3-20*01 IGKJ1*01
QYYGDSPRP 786 7*03 MEX18_44 IGHV4- IGHD6-19*01 IGHJ3*02 ARENIAVFFDI
765 IGKV1-33*01 IGKJ4*01 QQHDNLQVI 787 61*03 MEX18_51 IGHV4-
IGHD6-19*01 IGHJ4*02 ARDKRYSSGWYYFES 766 IGKV3-11*01 IGKJ1*01
QHRANWPT 788 30-4*01 MEX18_59 IGHV3- IGHD4-17*01 IGHJ4*02
VKPSVTTHYFDY 767 IGKV3-11*01 IGKJ2*01 QQRSNWPPFT 789
64D*06 MEX18_61 IGHV4- IGHD1-1*01 IGHJ6*02 ARDHSPGTTWGNYN 768
IGKV1-39*01 IGKJ2*01 QQSYSTPQT 790 31*03 YGMDV MEX18_74 IGHV1-
IGHD3-22*01 IGHJ6*02 ARDSRYYDSRSSYYY 769 IGKV2-28*01 IGKJ1*01
MQALQTPKT 791 18*04 YGMDV MEX18_75 IGHV3- IGHD5-12*01 IGHJ4*02
ARVARPGGYGRTFDE 770 IGKV1-39*01 IGKJ4*01 QQSYSDFS 792 11*01
MEX18_88 IGHV3- None IGHJ6*02 ARVRERYYYFYGLDV 771 IGKV2-28*01
IGKJ5*01 MQALQTFT 793 33*05 MEX18_92 IGHV3- IGHD6-19*01 IGHJ4*02
AKGVAAPGYFEY 772 IGKV3-11*01 IGKJ5*01 QQRSNWPPIT 794 30*18 MEX
105-refers to an individual donor. Sequences were analyzed with
IgBlast MEX105_10 IGHV1- IGHD3-10*01 IGHJ4*02 ARGNSYGSGNLGY 795
IGLV1-44*01 IGLJ3*02 STWDDSLNGPV 809 46*01 YLDF MEX105_21 IGHV1-
IGHD3-22*01 IGHJ4*02 ARGPDYNDTPGYY 796 IGKV3-20*01 IGKJ3*01 HHYGRT
810 69*01 GNY MEX105_29 IGHV1- IGHD3-22*01 IGHJ6*02 ARGAHYYDSSGYRQ
797 IGKV3-11*01 IGKJ4*01 QQRANWPALT 811 18*01 LYGLDV MEX105_35
IGHV3- IGHD2-21*01 IGHJ4*02 ARANVATRYFDY 798 IGKV1-9*01 IGKJ5*01
QHLSTYPIT 812 72*01 MEX105_44 IGHV4- IGHD3-10*01 IGHJ3*01
ARLRVRGAGWAFDL 799 IGKV3-11*01 IGKJ5*01 QQRSNWPPAIT 813 39*01
MEX105_47 IGHV3- IGHD3-10*01 IGHJ4*02 AKSDYYGSGHYTTI 800
IGKV3D-15*01 IGKJ3*01 QQYNNWPLT 814 23*03 PSSFED MEX105_55 IGHV5-
IGHD3-22*01 IGHJ5*02 ARHPTQNYASGDYYT 801 IGKV1-9*01 IGKJ4*01
QQLTTYPGT 815 51*03 MEX105_61 IGHV1- IGHD3-3*01 IGHJ6*02
AKGARITVFGGLDV 802 IGKV1-5*03 IGKJ2*03 QQYMSLPYS 816 2*02 MEX105_69
IGHV1- IGHD4-11*01 IGHJ4*02 ARPYFDGRSNSNLI 803 IGKV3-15*01 IGKJ1*01
QQYNTWPPALT 817 46*01 FFDY MEX105_72 IGHV1- IGHD2-15*01 IGHJ5*02
ARVIVVVVAATSDLP 804 IGKV1-5*03 IGKJ1*01 QHYHSYPWT 818 18*01 VGFDP
MEX105_79 IGHV3- IGHD5-18*01 IGHJ4*02 ARWLDNGIQGKY 805 IGKV3-11*01
IGKJ2*01 QQRHEWPV 819 21*01 DY MEX105_84 IGHV4- IGHD3-10*01
IGHJ5*02 ARGPVWFGEYGG 806 IGKV3-20*01 IGKJ5*01 SNMLGHRSP 820 59*01
AFDP MEX105_93 IGHV5- IGHD3-10*02 IGHJ5*02 ARAKGRGLQNWFDP 807
IGKV3D-20*01 IGKJ5*01 QQYGSSPPIT 821 51*01 MEX105_94 IGHV4-
IGHD3-10*01 IGHJ6*02 ARVSPLWDYYDSG 808 IGKV3-15*01 IGKJ2*01 QQHMYT
822 31*03 PYYNDFYYGMDV BRA 112-refers to an individual donor.
Sequences were analyzed with IgBlast BRA112_01 IGHV4- IGHD5-24*01
IGHJ4*02 ARGGDGYTTRW 823 IGKV1-NL1*01 IGKJ4*01 QQYYSAPLT 842 31*01
FYFNH BRA112_04 IGHV4- IGHD3-22*01 IGHJ4*02 ARLGAEYYVDSS 824
IGKV2-28*01 IGKJ4*01 MQALQTLSLT 843 31*03 GYRGIDH BRA112_11 IGHV1-
IGHD3-10*01 IGHJ6*02 ARVERGHTYGLNY 825 IGLV1-47*01 IGLJ3*02
AAWDDSLRGHWV 844 8*01 YYYYGMDV BRA112_12 IGHV4- IGHD3-22*01
IGHJ4*02 ARDSSNTFHHDS 826 IGLV4-69*01 IGLJ3*02 QTWGTGIRV 845 31*03
SGYFDN BRA112_15 IGHV4- IGHD6-19*01 IGHJ4*02 ARLIPGSGWRKGG 827
IGKV3-15*01 IGKJ1*01 QHYKNWPGT 846 31*03 FDY BRA112_22 IGHV1-
IGHD3-10*01 IGHJ4*02 ARDSGWSGITTVR 828 IGKV3-15*01 IGKJ2*01
LHYNNWPPRYT 847 46*01 GVPPDF BRA112_29 IGHV1- IGHD3-10*01 IGHJ4*02
ARGYFYTSSNYYN 829 IGKV1-16*02 IGKJ3*01 QQYKSYPFT 848 8*01 TDH
BRA112_31 IGHV1- IGHD3-10*01 IGHJ6*02 ARDRFSRHYGSGS 830 IGLV2-14*01
IGLJ1*01 GSYTSTSTCV 849 2*04 LHYAMDV BRA112_32 IGHV3- IGHD4-23*01
IGHJ3*02 ATGYGGNFAFDM 831 IGKV2-28*01 IGKJ1*01 MQALQTPPT 850 7*01
BRA112_34 IGHV3- IGHD4-17*01 IGHJ4*02 ASGGYGVYGFDY 832 IGKV1-5*03
IGKJ1*01 HQYNAYPWT 851 7*01 BRA112_39 IGHV4- IGHD3-10*02 IGHJ6*03
ARAHSYYVYYYMDV 833 IGKV3-15*01 IGKJ5*01 QQYNNWLPIT 852 39*07
BRA112_42 IGHV4- IGHD3-10*01 IGHJ4*02 VRHGPHPGVLVWFG 834 IGKV4-1*01
IGKJ5*01 QQYYTTPLT 853 39*01 EQSKIDY BRA112_53 IGHV3- IGHD6-13*01
IGHJ6*02 AKDIGNIAGVAQGI 835 IGKV1-9*01 IGKJ4*01 QRLNSYPRVT 854 9*01
YFYFGMDV BRA112_54 IGHV3- IGHD4-17*01 IGHJ4*02 ARKSYGDPFFDY 836
IGLV2-14*01 IGLJ3*02 SSYTSRSTWV 855 21*01 BRA112_58 IGHV4-
IGHD2-15*01 IGHJ4*02 ASSVMVVAQFDS 837 IGKV3-20*01 IGKJ1*01
QQYGNSPWT 856 31*03 BRA112_59 IGHV1- IGHD5-18*01 IGHJ6*02
ATGAGYSYPVAMDV 838 IGKV2-28*01 IGKJ2*01 MQALQTPYT 857 3*01
BRA112_68 IGHV4- IGHD3-10*01 IGHJ4*02 ARIIINRGQSFDY 839 IGLV2-11*01
IGLJ1*01 CSYAGKYV 858 59*01 BRA112_87 IGHV3- IGHD3-10*01 IGHJ5*02
ARNAPKVFGSGSYY 840 IGKV3-11*01 IGKJ5*01 QQRLYWPVT 859 20*01 SNWFDP
BRA112_89 IGHV4- IGHD3-22*01 IGHJ4*01 ARSYSEVLVGYD 841 IGKV3-11*01
IGKJ4*01 QQRSNWLT 860 31*03 BRA 12-refers to an individual donor.
Sequences were analyzed with IgBlast BRA12_02 IGHV3- IGHD6-19*01
IGHJ4*02 AKDRTGNIGAGTG 861 IGKV1-5*03 IGKJ1*01 QQYNNYPWT 895 23*01
YFDK BRA12_03 IGHV1- IGHD5-24*01 IGHJ1*01 ARTPREYIAEYFQH 862
IGKV3-15*01 IGKJ5*01 QQYNNWLIT 896 18*01 BRA12_05 IGHV3-
IGHD6-13*01 IGHJ3*02 ARVKLRDGSSWYHA 863 IGKV4-1*01 IGKJ1*01
QQYYTTPPWT 897 53*01 FDI BRA12_11 IGHV1- IGHD6-19*01 IGHJ4*02
ARWGLSSAWVAPLG 864 IGKV4-1*01 IGKJ3*01 QQYYTTPFT 898 3*01 FDY
BRA12_13 IGHV1- IGHD1-26*01 IGHJ6*02 ARELLYSGRQTYYY 865 IGLV2-14*01
IGLJ3*02 SSYTSDNTRV 899 2*04 SYYGMDV BRA12_14 IGHV5- IGHD1-26*01
IGHJ6*02 ARRQGAHGRDLGFH 866 IGLV2-11*01 IGLJ3*02 CSYAGSYSWV 900
51*03 YAMDV BRA12_16 IGHV1- IGHD6-13*01 IGHJ4*02 ARDGAAAGDY 867
IGKV1-8*01 IGKJ3*01 QQYYDYPLT 901 18*01 BRA12_19 IGHV4- IGHD1-26*01
IGHJ6*02 GNLATVGATAPYY 868 IGLV1-47*01 IGLJ1*01 AAWDDSLNGRV 902
34*01 NYYGMYV BRA12_31 IGHV1- IGHD5-24*01 IGHJ4*02 ARGMATPALLN 869
IGKV3-15*01 IGKJ4*01 HQYNNWPLT 903 3*01 BRA12_36 IGHV4- IGHD5-24*01
IGHJ6*02 ARGHNKWLQLN 870 IGKV3-11*01 IGKJ5*01 QQRINWPIT 904 34*01
FYAMDV BRA12_37 IGHV4- IGHD6-19*01 IGHJ4*03 LVQLQQWGAGLL 871
IGKV1-39*01 IGKJ2*03 QQSYSRPYS 905 34*01 KPSETL BRA12_38 IGHV3-
IGHD6-19*01 IGHJ6*02 VKGGYNSVWSNS 872 IGKV1-33*01 IGKJ2*01
QQYDNVPYT 906 9*01 YGMDV BRA12_40 IGHV1- IGHD3-10*01 IGHJ6*02
ARALYVRGYNYG 873 IGKV3-20*01 IGKJ3*01 QQYDNSRFT 907 69*01 FLYGMDV
BRA12_42 IGHV1- IGHD1-1*01 IGHJ4*02 AKGGPTARVLSGQ 874 IGKV2-29*03
IGKJ1*01 MQGIHLWT 908 2*02 LYYFDY BRA12_46 IGHV4- IGHD6-19*01
IGHJ6*02 ARGPSGLAVAGTVG 875 IGLV2-8*01 IGLJ1*01 SSYAGTSYV 909 34*01
ERDRNYHYYYGMDV BRA12_51 IGHV1- IGHD3-9*01 IGHJ6*02 ARLGDILTGYVDY
876 IGLV1-44*01 IGLJ1*01 AAWDDSLNGLYV 910 8*02 GMDV BRA12_54 IGHV1-
IGHD4-17*01 IGHJ5*02 ARSPIYGDYGFDP 877 IGKV2-28*01 IGKJ1*01
MQALQIPPT 911 3*01 BRA12_55 IGHV1- IGHD2-15*01 IGHJ4*01
ARTHCTGGSCFSS 878 IGKV1-16*02 IGKJ4*01 QQYNSYPPT 912 69*01 SFDY
BRA12_56 IGHV3- IGHD3-10*01 IGHJ6*02 ARDRDYGSGSQPL 879 IGKV1-39*01
IGKJ2*03 QQSYSTPYS 913 21*01 YYYYAMDV BRA12_60 IGHV1- IGHD7-27*01
IGHJ4*02 ARVLGNWGFDY 880 IGKV1-9*01 IGKJ3*01 QQLNSYPFT 914 69*06
BRA12_63 IGHV3- IGHD3-16*02 IGHJ6*02 ARGGKRLGELSLF 881 IGKV2-28*01
IGKJ1*01 MQALHTPWT 915 48*03 HYYGMDV BRA12_67 IGHV5- IGHD3-22*01
IGHJ4*02 ARHRRGYYDSSG 882 IGLV2-14*01 IGLJ2*01 SSYTRSSTVV 916 51*01
YYYDY BRA12_70 IGHV4- IGHD5-18*01 IGHJ4*02 TRYSYGFSYFDY 883
IGKV3-11*01 IGKJ4*01 QQRSNWPLT 917
39*01 BRA12_71 IGHV3- IGHD6-6*01 IGHJ6*02 ARAPTRSIGHGMDL 884
IGLV8-61*01 IGLJ3*02 VLYVGAAISL 918 30*04 BRA12_75 IGHV3-
IGHD2/OR15- IGHJ6*02 ARENNNIALPYYYY 885 IGKV3-11*01 IGKJ4*01
QQSSNWPIT 919 48*03 2a*01 GMDV BRA12_77 IGHV4- IGHD1-1*01 IGHJ6*01
ARDIRYTYGPMWGG 886 IGKV3-20*01 IGKJ2*01 QQYGGSPYT 920 39*07 DYGMDV
BRA12_79 IGHV4- IGHD1-1*01 IGHJ6*02 ARRPPLLRSHNYNY 887 IGKV3-20*01
IGKJ5*01 QQYGSSPLIT 921 34*01 LGMDV BRA12_81 IGHV3- IGHD1-20*01
IGHJ6*02 AKSSGGHNWNYVDY 888 IGKV1-9*01 IGKJ3*01 QQLNSYPVT 922 23*01
YYGMDV BRA12_82 IGHV1- None IGHJ6*02 ASTHLGGLDV 889 IGKV2-30*01
IGKJ4*01 MQGTHWPLT 923 46*01 BRA12_84 IGHV3- IGHD3-10*01 IGHJ4*02
SRATNYYALGY 890 IGLV2-14*01 IGLJ3*02 SSYTSSATWV 924 49*04 BRA12_86
IGHV4- None IGHJ6*02 ARDWPVMDV 891 IGKV2-30*01 IGKJ1*01 MQGTHWPPWT
925 39*07 BRA12_88 IGHV1- IGHD2-15*01 IGHJ4*02 ARVVGTTLYSMGY 892
IGKV4-1*01 IGKJ1*01 QQYYNTWT 926 3*01 BRA12_93 IGHV3- IGHD6-13*01
IGHJ4*02 ARVAAWYAGSFDS 893 IGLV2-18*02 IGLJ1*01 SSYTSTSAF 927 21*01
BRA12_94 IGHV3- IGHD2-21*02 IGHJ4*02 AKAGAYCGGDCYS 894 IGKV1-5*03
IGKJ3*01 QQYQSDLFT 928 33*06 YLQY BRA138_02 IGHV4- IGHD4-11*01
IGHJ3*02 ARLLIDYTNYKSV 929 IGKV3-15*01 IGKJ4*01 QQYHNWPPRLT 953
38-2*02 ASAFDI BRA 138-refers to an individual donor. Sequences
were analyzed with IgBlast BRA138_05 IGHV4- IGHD3-22*01 IGHJ4*02
ASSPGYDTRGYYI 930 IGKV1-5*03 IGKJ4*01 QQYNRYVS 954 30-4*01 AGQYYFVN
BRA138_06 IGHV3- IGHD4-17*01 IGHJ4*02 ARDGTIPGYGDY 931 IGKV3-11*01
IGKJ1*01 QQRSNWPPWT 955 30-3*01 BRA138_09 IGHV4- IGHD6-19*01
IGHJ6*02 ARMPVAAHYFYD 932 IGKV3-20*01 IGKJ5*01 QQYGSSPIT 956 61*01
GMDV BRA138_12 IGHV3- IGHD6-13*01 IGHJ4*02 AKFPHRSTSWYY 933
IGLV1-40*01 IGLJ1*01 QSYDSSLSGSFYV 957 9*01 FDS BRA138_22 IGHV5-
IGHD1-1*01 IGHJ4*01 ARGLRVEIPIFAY 934 IGKV3-20*01 IGKJ3*01
QQYGGSPPRFT 958 51*01 BRA138_26 IGHV1- IGHD3-9*01 IGHJ3*02
TRDTIVGATYAFDI 935 IGKV4-1*01 IGKJ3*01 QQHYSTPFT 959 69*01
BRA138_27 IGHV3- IGHD6-13*01 IGHJ6*02 AREPDSSSWYQDYY 936
IGLV2-23*02 IGLJ1*01 CSYAGSRTRV 960 21*01 CAMDV BRA138_34 IGHV4-
IGHD3-16*02 IGHJ6*03 TRDLGNFIAYMDV 937 IGLV1-44*01 IGLJ2*01
ASWDDNLNSRV 961 61*02 BRA138_35 IGHV3- IGHD3-22*01 IGHJ4*02
SRGSYYYDSRGYY 938 IGKV2-29*02 IGKJ5*01 MQGIIFPPIT 962 49*05
FRPPSAGPFDY BRA138_51 IGHV3- IGHD1-26*01 IGHJ4*02 VKIAVGGSWSS 939
IGLV2-14*01 IGLJ2*0 SSYTSSSTLV 963 64D*06 EALDY BRA138_54 IGHV3-
IGHD1-26*01 IGHJ6*02 ARGHLVGATSY 940 IGKV1-9*01 IGKJ1*01 QQLNSYPET
964 7*02 YYGMDV BRA138_63 IGHV4- IGHD3-10*01 IGHJ4*02 ARVSLLWFGELG
941 IGKV1-9*01 IGKJ3*01 LQVNSYPLT 965 34*01 AVPYYFDY BRA138_66
IGHV1- IGHD6-19*01 IGHJ6*02 ARDRHRAGAL 942 IGLV2-14*01 IGLJ2*01
SSYTTSTTVI 966 69*01 RYGMDV BRA138_68 IGHV3- IGHD6-19*01 IGHJ5*02
AKGGTSVAIGWN 943 IGLV2-11*01 IGLJ1*01 CSYGGTYSPYV 967 9*01 WFDP
BRA138_70 IGHV4- IGHD3-9*01 IGHJ4*02 ARGYRGNILTG 944 IGKV1-33*01
IGKJ1*01 QQYAKYPLT 968 30-2*01 RLGYFDY BRA138_71 IGHV3- IGHD3-22*01
IGHJ4*02 TTAGNYYDSRGY 945 IGKV3-20*01 IGKJ4*01 QQYATSSLT 969 49*04
YFSRPRHSFDY BRA138_77 IGHV3- IGHD3-10*01 IGHJ4*02 ARAPQNYYGSGR 946
IGLV1-51*01 IGLJ1*01 GTWDSSLSAYV 970 33*01 YYSGCDY BRA138_78 IGHV4-
IGHD6-19*01 IGHJ6*03 ARTAVDRYSSGW 947 IGLV1-51*01 IGLJ2*01
GTWDSSLSAGV 971 59*01 YGEYYYYSMDV BRA138_84 IGHV1- IGHD3-22*01
IGHJ4*02 ARRPLTSYYDSGA 948 IGLV6-57*01 IGLJ1*01 QSFDSSNQEV 972
18*01 YYPYYFDY BRA138_87 IGHV3- IGHD3-22*01 IGHJ4*02 TRDTTYFYDNSGY
949 IGLV1-40*01 IGLJ2*01 QSYDRSLSGSRV 973 49*04 YGWASKGGYFDY
BRA138_89 IGHV4- IGHD6-25*01 IGHJ6*02 ARQPVRGRHSSS 950 IGKV1-13*02
IGKJ1*01 QQFNSYPQT 974 39*01 GYRHYYYGMDV BRA138_90 IGHV4-
IGHD3-16*01 IGHJ4*02 ARVETYDHVWGA 951 IGKV3-15*01 IGKJ1*01 HHYNNWT
975 31*03 FRFGEGGYFDH BRA138_91 IGHV4- IGHD3-22*01 IGHJ4*01
ARGGHYYDSRG 952 IGKV3-15*01 IGKJ1*01 QQYHDWPLWT 976 30-2*01
YFTLAGPIDY
TABLE-US-00017 TABLE 3 List of primers for cloning recombinant
antibodies by the SLIC method. Related to Methods of this example.
Best V or J gene SEQ Primer ID Primer sequence segment match ID NO:
Human antibody heavy chain (forward) p1355DFR
5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTGCAGCTGGTGCAG VH 1 977
p1356DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCCGAGGTGCAGCTGGTGCAG VH 1/5
978 p1357DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTTCAGCTGGTGCAG VH
1-18 979 p1358DFR
5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTCCAGCTGGTACAG VH 1-24 980
p1359DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCTGAGGTGCAGCTGGTGGAG VH 3
981 p1360DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCTCAGGTGCAGCTGGTGGAG VH
3-11 982 p1361DFR
5'CTAGTAGCAACTGCAACCGGTGTACATTCTGAGGTGCAGCTGTTGGAG VH 3-23 983
p1362DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCTCAGGTGCAGCTGGTGGAG VH 3-33
984 p1363DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCTGAAGTGCAGCTGGTGGAG VH
3-9 985 p1364DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTGCAGCTGCAGGAG
VH 4 986 p1365DFR
5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTGCAGCTACAGCAGTG VH 4-34 987
p1366DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGCTGCAGCTGCAGGAG VH 4-39
988 p1367DFR 5'CTAGTAGCAACTGCAACCGGTGTACATTCCCAGGTACAGCTGCAGCAG VH
6-1 989 Human antibody heavy chain (reverse) p1370DFR
5'CCGATGGGCCCTTGGTCGACGCTGAGGAGACGGTGACCAG JH 1/2 990 p1371DFR
5'CCGATGGGCCCTTGGTCGACGCTGAAGAGACGGTGACCATTG JH 3 991 p1372DFR 5
'CCGATGGGCCCTTGGTCGACGCTGAGGAGACGGTGACCAG JH 4/5 992 p1373DFR
5'CCGATGGGCCCTTGGTCGACGCTGAGGAGACGGTGACCGTG JH 6 993 Human antibody
light chain kappa (forward) p1379DFR
5'GTAGCAACTGCAACCGGTGTACATTCTGACATCCAGATGACCCAGTC VK 1-5 994
p1380DFR 5'GTAGCAACTGCAACCGGTGTACATTCAGACATCCAGTTGACCCAGTCT VK 1-9
995 p1381DFR 5'GTAGCAACTGCAACCGGTGTACATTGTGCCATCCGGATGACCCAGTC VK
1D-43 996 p1382DFR
5'GTAGCAACTGCAACCGGTGTACATGGGGATATTGTGATGACCCAGAC VK 2-2 997
p1383DFR 5'GTAGCAACTGCAACCGGTGTACATGGGGATATTGTGATGACTCAGTC VK 2-28
998 p1384DFR 5'GTAGCAACTGCAACCGGTGTACATGGGGATGTTGTGATGACTCAGTC VK
2-30 999 p1385DFR 5'GTAGCAACTGCAACCGGTGTACATTCAGAAATTGTGTTGACACAGTC
VK 3-11 1000 p1386DFR
5'GTAGCAACTGCAACCGGTGTACATTCAGAAATAGTGATGACGCAGTC VK 3-15 1001
p1387DFR 5'GTAGCAACTGCAACCGGTGTACATTCAGAAATTGTGTTGACGCAGTCT VK 3-20
1002 p1388DFR 5'GTAGCAACTGCAACCGGTGTACATTCGGACATCGTGATGACCCAGTC VK
4-1 1003 Human antibody light chain kappa (reverse) p1390DFR
GAAGACAGATGGTGCAGCCACCGTACGTTTGATYTCCACCTTGGTC JK 1/4 1004 p1391DFR
GAAGACAGATGGTGCAGCCACCGTACGTTTGATCTCCAGCTTGGTC JK 2 1005 p1392DFR
GAAGACAGATGGTGCAGCCACCGTACGTTTGATATCCACTTTGGTC JK 3 1006 p1393DFR
GAAGACAGATGGTGCAGCCACCGTACGTTTAATCTCCAGTCGTGTC JK 5 1007 Human
antibody light chain lambda (forward) p1402DFR
CTAGTAGCAACTGCAACCGGTTCCTGGGCCCAGTCTGTGCTGACKCAG VL 1 1008 p1403DFR
CTAGTAGCAACTGCAACCGGTTCCTGGGCCCAGTCTGCCCTGACTCAG VL 2 1009 p1404DFR
CTAGTAGCAACTGCAACCGGTTCTGTGACCTCCTATGAGCTGACWCAG VL 3 1010 p1405DFR
CTAGTAGCAACTGCAACCGGTTCTCTCTCSCAGCYTGTGCTGACTCA VL 4/5 1011
p1406DFR CTAGTAGCAACTGCAACCGGTTCTTGGGCCAATTTTATGCTGACTCAG VL 6 1012
p1407DFR CTAGTAGCAACTGCAACCGGTTCCAATTCYCAGRCTGTGGTGACYCAG VL 7/8
1013 Human antibody light chain lambda (reverse) p1409DFR
GGCTTGAAGCTCCTCACTCGAGGGYGGGAACAGAGTG Constant L 1014
TABLE-US-00018 TABLE 4 List of primers for the generation of RVP
expression constructs. Related to Methods of this example. Primer
ID Primer sequence Comments SEQ ID NO: Mutation of BspHI sites in
pZIKV/HPF/CprME to generate pZIKV/HPF/CprM*E* RU-O-24303
GTTAAGGGATTTTGGACATGAGATTATC BspHI at nt 6419 forward 1015
RU-O-24304 GATAATCTCATGTCCAAAATCCCTTAAC BspHI at nt 6419 reverse
1016 RU-O-24309 CTTGGTTGAGTACTCACCAGTCA Reverse outer (for 6419)
1017 RU-O-24310 GAAGACTACAGCGTCGCCAG Forward outer (for 6419) 1018
RU-O-24305 GTTATTGTCTCATGCGCGGATAC BspHI at nt 7427 forward 1019
RU-O-24306 GTATCCGCGCATGAGACAATAAC BspHI at nt 7427 reverse 1020
RU-O-24307 CTTCATGCAATTGTCGGTCAAGCC Reverse outer (for 7427) 1021
RU-O-24308 TGACTGGTGAGTACTCAACCAAG Forward outer (for 7427) 1015
Generation of E mutations in pZIKV/HPF/CprM*E* RU-O-24998
AGGAGTCGGGGCGAAGAAGATCAC E393A forward 1022 RU-O-24999
GTGATCTTCTTCGCCCCGACTCCT E393A reverse 1023 RU-O-25000
AGGAGTCGGGGAGGCGAAGATCAC K394A forward 1024 RU-O-25001
GTGATCTTCGCCTCCCCGACTCCT K394A reverse 1025 RU-O-24379
ACTTGGTCATGATACTGCTGATTGCCCCGGCATACAGCATCAGGTGCATAGGAGT Forward
outer 1026 RU-O-24380
TTCGAACCGCGGCTGGGTCCTATTAAGCAGAGACAGCTGTGGATAAGAAGATC Reverse outer
1027 Generation of pDENV1/PUO-359/CprME RU-O-24611
CTTGACCGACAATTGCATGAAG Upstream of SnaBI site 1029 forward
RU-O-24610 GTCTTTTTCCGTTGGTTGTTCATAGCCTGCTTTTTTGTACAAAC CMV
promoter-Capsid 1030 fusion reverse RU-O-24608
GTTTGTACAAAAAAGCAGGCTATGAACAACCAACGGAAAAAGAC CMV promoter-Capsid
1031 fusion forward RU-O-24609
TTCGAACCGCGGCTGGGTCCTATTACGCCTGAACCATGACTCCTAGGTAC E
C-terminus-SacII 1032 site reverse Generation of
pZIKV/HPF-CprM/MR766-E RU-O-24994 CAAAGAGTGGTTCCATGACATCCCATTG
BspHI site mutation 1033 forward RU-O-24995
CAATGGGATGTCATGGAACCACTCTTTG BspHI site mutation 1034 reverse
RU-O-24379 ACTTGGTCATGATACTGCTGATTGCCCCGGCATACAGCATCAGGTGCATAGGAGT
Forward outer 1035 RU-O-24380
TTCGAACCGCGGCTGGGTCCTATTAAGCAGAGACAGCTGTGGATAAGAAGATC Reverse outer
1036
TABLE-US-00019 TABLE 5 Data collection and refinement statistics.
Related to Figure 5. Z006-ZIKV EDIII Z004-DENV1 EDIII Data
Collection Resolution Range (.ANG.) 29.75-3.0 (3.107-3.0) 37.11-3.0
(3.107-3.0) Space group R32:H P4.sub.32.sub.12 Cell dimensions
.alpha., .beta., .chi. (.sym.) 385.08, 385.08, 56.64 74.23, 74.23,
190.76 .alpha., .beta., .gamma. (.ident.) 90, 90, 120 90, 90, 90
Total reflections 170795 (25781) 121867 (20556) Unique reflections
31520 (3151) 11154 (1101) Multiplicity 5.4 (5.6) 10.9 (11.6)
Completeness (%) 98.71 (99.78) 98.30 (99.73) Mean I/.sigma.(I) 8.2
(2.3) 11.1 (3.3) Wilson B-factor (.ANG..sup.2) 77.8 58.7
R.sub.merge 0.120 (0.598) 0.179 (0.829) R.sub.pim 0.083 (0.410)
0.079 (0.358) CC1/2 0.992 (0.779) 0.994 (0.869) Refinement
R.sub.work/R.sub.free 0.210/0.256 0.258/0.315 Number of atoms 7878
3759 Protein residues 1050 492 RMS (bonds) (.ANG.) 0.013 0.005 RMS
(angles) (.degree.) 1.42 0.97 Clashscore 15.93 13.28 Average
B-factor (.ANG..sup.2) 103.02 56.59 Number of TLS groups 6 17
Statistics for the highest-resolution shell are shown in
parentheses.
TABLE-US-00020 TABLE 6 Antibody-antigen contacts. Related to FIG.
5. Z006 ZIKV Closest Z004 DENV1 Closest Chain Fab EDIII distance
Fab EDIII distance Description Origin Count in clones HC N31 Q350,
T351 Y52 T351 I53 P336, A382 D54 M301 E55 K340, S306, L307, Y305
S56 L307 S56 M301, V300 T57 S306 Y58 L307, S306, 3.07 Y58 M301,
V300, 2.54 Tyr-OH w/ antigen V Germline 62 Y, 1 W T309 T303
backbone oxygen R96 E393 3.44 R96 E384 2.55 electrostatic/salt N
addition 62 R, 1 H bridge S97 K395, G392, E393 N98 L352, G392,
V391, K395 G99 G392 R99 G383, S338, A382 W100 T309, K394 G100 G383
S100A G392 V100A T303 S100B E393 E100C E384, G383, K385, A382 L100D
E384 LC Q27 T335 3.28 Q27 T329 3.96 V Germline 58 Q, 6 H, 5 R S30
E327 W32 K394, A311 3.08 W32 K385, S305, 3.37 hydrophobic (plus V
Germline 68 W, 1 L E327 cation-pi) Y49 E393 Q50 E393 Y91 K394, E393
2.45 F91 K385 2.28 hydrophobic (plus V Germline/ 57 Y, 12 F
Tyr-OH/Glu H-bond SHM for ZIKV) S92 A310, K394, 3.03 Y92 G328,
K385, T309 327, G304, T303 T93 T335, G334, 3.22 S93 T329, T303,
2.68 H-bond to antigen V 42 S, 23 T, 3 N D336, A310, G328 backbone
nitrogen Germline/SHM T309 antigen sidechain F94 T309, D336 3.42
V94 T303, T329 3.1 H-bond to LC 43 Y, 13 F, 12 V D330 backbone plus
vDW for antibody sidechain W96 T303
[0296] Contacts are defined as residues in which any atom is within
4 .ANG. of an atom from a residue on the interacting partner using
AntibodyDatabase (West et al., 2013). Table 6 is organized by
antibody residue, listing all antigen residues contacted by each
antibody residue (ordered by contact distance). Antibody residues
are highlighted when corresponding interactions occur in both
complexes. For the highlighted interactions additional information
is listed including the antibody residue's origin in V(D)J
recombination and the residue distribution at that antibody
position in the sequenced antibody clones.
Example 3
[0297] This Example extends the disclosure of Examples 1 and 2
above. Zika virus (ZIKV) infection causes severe neurologic
complications and fetal aberrations.sup.1. As discussed in Examples
1 and 2, human monoclonal antibody Z004 is a VH3-23/VK1-5 antibody
that recognizes the lateral ridge of the Envelope Domain III
(EDIII) of ZIKV, is a potent neutralizer in vitro, and prevents
disease in mice. In this Example we demonstrate that when Z004 is
administered to macaques for prophylaxis, it leads to emergence of
resistant ZIKV variants bearing mutations in the antibody target
site. As discussed above, Z021 has a structure in complex with the
antigen that reveals a distinct although overlapping epitope on
EDIII. Z021 potently neutralizes ZIKV in vitro and prevents disease
in mice. This Example shows that in a clinically relevant macaque
model, prophylactic co-administration of Z004 with Z021 is
protective and suppresses emergence of resistant variants. Thus, a
combination of two potent human monoclonal antibodies to EDIII is
sufficient to suppress infection and thwart viral escape in
macaques, a natural host for ZIKV.
[0298] In more detail, to determine whether human monoclonal
antibodies are efficacious against ZIKV in primates, who are
natural hosts for infection, we administered Z004 to rhesus
macaques 24 hours before intravenous challenge with high dose
(10.sup.5 PFU) of a Brazilian strain of ZIKV. Infection was
monitored by PCR to detect viral RNA in the plasma (FIG. 11A). All
four control animals developed viremia, which peaked on day 3 with
plasma viral loads ranging between 10.sup.5-10.sup.7 RNA copies/ml
(FIG. 11A, in black). Similar to previous reports, viremia cleared
spontaneously beginning on day 7 (FIGS. 11A, and .sup.19). In
contrast, viremia was either undetectable or below 10.sup.4 RNA
copies/ml in the Z004-treated macaques on day 3. However, the
Z004-treated macaques showed delayed viremia peaking on day 7-10 at
3.times.10.sup.2-5.times.10.sup.5 RNA copies/ml (FIG. 11A, in
grey). Thus, Z004 alone alters the course of ZIKV infection and
leads to prolonged but lower levels of viremia.
[0299] To determine whether the viremia in Z004-treated animals was
associated with viral escape mutations, we sequenced the EDIII from
the virus found in the plasma of the treated macaques on day 7 and
10. In both animals the circulating viruses carried mutations in
the Z004 target site; K394R in one animal and E393D or K394R in the
other (FIGS. 11B and 11C). We were unable to find these mutant
viruses at earlier time points in the same animals, in untreated
controls, or in the inoculum (data not shown). While D393 is
present in ZIKV strains of African origin, no ZIKV sequences with
R394 were found out of 704 ZIKV sequences that were analyzed (ViPR
database, Oct. 9, 2017). ELISA assays using ZIKV EDIII.sub.E393D
and EDIII.sub.K394R mutant proteins confirmed that these mutations
interfere with Z004 binding (FIG. 11D). In contrast to the macaque,
antibody resistance mutations were rare in Ifnar1.sup.-/- mice
treated with Z004; nevertheless, the only mouse that developed
mutations had the same K394R as observed in macaque (n=8; FIG. 17).
Therefore, when administered prophylactically to macaques prior to
a high-dose intravenous ZIKV inoculation, Z004 selects for
resistant viral mutants.
[0300] We tested whether a second antibody could help prevent the
development of resistance. Z021 is a human monoclonal antibody
that, like Z004, was isolated from an individual with exceptional
serum neutralizing activity against ZIKV.sup.5. Z021 binds to the
EDIII of both ZIKV and DENV1, it neutralizes ZIKV reporter viral
particles (RVPs) bearing Asian/American or African lineage E
proteins with an IC.sub.50 of 1 ng/ml and 0.7 ng/ml, respectively
(FIG. 12 and FIG. 18), and has strong activity in plaque reduction
neutralization assays using an infectious Puerto Rican strain of
ZIKV (PRNT; IC.sub.50 of 4 ng/ml, FIG. 12A). Z021 is also a potent
neutralizer of DENV1 (IC50 of 10.1 ng/ml; FIG. 12B).
[0301] To determine whether Z021 neutralizes ZIKV in vivo, we
administered Z021 to Ifnar1.sup.-/- mice either 24 hours before or
24 hours after ZIKV challenge (FIG. 12C). Whereas 100% of control
mice developed symptoms and died (n=11, FIG. 12D), only 15% did so
when Z021 was administered before infection (n=13; p=0.0002 for
disease and p<0.0001 for survival; FIG. 12D). Moreover, only 42%
developed symptoms and 33% succumbed to disease when the antibody
was administered 1 day after infection (n=12; p=0.0006 for disease
and p=0.0002 for survival; FIG. 12E). Thus, Z021 is efficacious
against ZIKV in vitro and in Ifnar1.sup.-/- mice. Z004 binding and
neutralization of ZIKV and DENV1 is dependent on ZIKV EDIII residue
K394 and also partially dependent on E393 (DENV1 residues K385 and
E384, respectively; FIGS. 11D and .sup.5). To determine whether
Z004 and Z021 recognize distinct neutralizing epitopes on EDIII, we
performed ELISA assays (FIG. 13A and see Methods of this Example).
Each monoclonal antibody was incubated with saturating amounts of
either wild type ZIKV EDIII, or an EDIII bearing mutations in the
Z004 target site that interfere with its binding and neutralizing
activity (EDIII.sub.E393A/K394A). Residual binding to wild type
EDIII was measured by ELISA. Whereas, Z004 binding to ZIKV EDIII
was only blocked by wild type ZIKV EDIII, binding of Z021 was
blocked by both wild type and ZIKV EDIII.sub.E393A/K394A,
indicating that residues E393 and K394 are critical for Z004 but
dispensable for Z021 binding (FIG. 13A). In agreement with this
finding, Z004 failed to neutralize ZIKV RVPs that were altered to
bear the E393A/K394A mutations but Z021 remained active against the
mutant RVPs in vitro (FIG. 13B). To determine whether the Z004 and
Z021 epitopes overlap, we performed competition ELISA assays, which
showed that Z004 prevented binding by Z021, and vice-versa (FIG.
13C and see Methods of this Example). Thus, Z021 binds to a
neutralizing epitope on the EDIII that does not require E393/K394
but is close to or overlapping with the epitope recognized by
Z004.
[0302] Structural analysis of Z004 and of the related VH3-23/VK1-5
antibody Z006 with the EDIII of DENV1 and ZIKV, respectively,
revealed that VH3-23/VK1-5 antibodies bind to these two different
flaviviruses in a very similar manner, with E393/K394.sub.ZIKV and
E384/K385.sub.DENV1 being central to the epitope.sup.5. To gain
structural insights into how Z021 recognizes its epitope, we
crystallized Z021 in complex with the EDIII of ZIKV and of DENV1
(FIG. 14). Z021 recognizes the EDIII of both flaviviruses in a
similar fashion, and makes no contacts with the E393/K394.sub.ZIKV
and E384/K385.sub.DENV1 residues (FIG. 14A). Similar to Z004, Z021
recognizes the lateral ridge region of DENV1 EDIII, but its epitope
is distinct. Compared to the Z004 Fab, the Z021 Fab is rotated
.about.48.degree. around an axis near the complementarity
determining region 2 (CDRH2), positioning the heavy chains in
similar regions, while the light chains exhibit divergent
footprints (FIG. 14B). Z021 uses both its heavy and light chains to
contact the N-terminal region and the BC loop of DENV EDIII, makes
light chain contacts to the DE loop, and heavy chain contacts to
the FG loop. Notably, when compared to Z004 Fab, Z021 Fab makes
unique contacts to the N-terminal region of DENV1 EDIII and shows
no ordered contacts with K385.sub.DENV1 (FIG. 14C). Thus,
consistent with the ELISA and neutralization results (FIG. 13),
Z021 recognizes a distinct but overlapping epitope on EDIII from
that of Z004.
[0303] Since Z021 binding and neutralizing activity is resistant to
mutations in EDIII E393 and K394, and its epitope is distinct from
Z004 (FIGS. 13 and 14), we co-administered the two antibodies to
macaques 24 hours before challenge with ZIKV. Two out of three
macaques developed low viremia, with approximately 10.sup.2 or
lower RNA copies/ml at around day 5 or 13 after infection. The
third macaque developed viremia below 10.sup.3 RNA copies/ml
starting on day 13 (FIG. 15). Viremia was not a consequence of
rapid clearance of Z004 and Z021, as high levels of human
antibodies were detectable in the macaque plasma (FIG. 19). In
contrast to macaques treated with Z004 alone (FIG. 11), no
mutations in the EDIII region of the circulating virus were
detected in animals treated with the combination of Z004 with Z021
(data not shown). We conclude that treatment of non-human primates
with the combination of Z004 and Z021, two antibodies that target
distinct but overlapping epitopes, suppresses and delays viremia
and prevents the emergence of ZIKV escape mutants upon high-dose
intravenous ZIKV challenge.
[0304] Viremia in the absence of viral escape could result from
antibody Z004 and Z021 promoting ZIKV infection through
antibody-dependent enhancement (ADE). ADE depends on the ability of
antibodies to engage Fc-gamma receptors. We modified the fragment
crystallizable (Fc) region of both antibodies to preclude Fc-gamma
receptor binding (GRLR or GRLR/LS mutations. These modifications
prevented Fc binding and ADE in vitro, while maintaining
neutralization potentcy against ZIKV in vitro and in mice (FIGS. 20
and 21). To determine whether the late-onset low-level plasma
viremia of macaques treated with the combination of Z004 and Z021
was dependent on Fc-gamma receptors, we administered to macaques
Z004-GRLR and Z021-GRLR antibodies and challenged them with ZIKV.
Human antibody levels were comparable in macaques treated with the
wild type or GRLR version of Z004 and Z021 (FIG. 19). Low plasma
viremia was detected in all three animals (FIG. 15): one macaque
had a single viral blip less than 10.sup.2 RNA copies/ml on day 3,
one had viremia below 10.sup.3 RNA copies/ml between days 2-4, and
one was viremic between days 6-13 (peak viremia of 10.sup.4 RNA
copies/ml). No mutations were identified in the EDIII region of the
emerging viruses. We conclude that the low-level viremia that
develops in the presence of Z004 and Z021 is not dependent on
Fc-gamma receptor engagement.
[0305] The most common mean of ZIKV transmission is through the
bite of an infected mosquito. To determine whether the combination
of Z004-GRLR and Z021-GRLR was protective against subcutaneous
challenge, we infected macaques with 10.sup.3 PFU of a Puerto Rican
strain of ZIKV by this route. As the size of the inoculum during
mosquito feeding is uncertain, we chose this dose of virus because
it is similar to recent vaccination experiments in non-human
primates.sup.18,20,21. None of the challenged macaques developed
viremia during the observation period (FIG. 16). Without intending
to be bound by any particular viewpoint, we conclude that combining
Z004-GRLR with Z021-GRLR prevents viremia altogether after
subcutaneous infection with ZIKV.
[0306] Those skilled in the art will recognize that although the
error rate of the ZIKV polymerase has not been determined,
flaviviruses are RNA viruses that are generally assumed to undergo
high rates of error prone replication thereby producing mutant
forms that can be selected for antibody resistance.sup.29-31.
Antibody evasion by flaviviruses such as DENV.sup.32-34,
WNV.sup.35-36, YFV.sup.37, Japanese encephalitis virus.sup.38,
tick-borne encephalitis virus.sup.39, and recently ZIKV.sup.40, has
been amply documented using cell culture experiments. Resistant
virus also emerged upon administration of a single monoclonal
antibody to mice challenged with WNV.sup.41 or to Rhesus monkeys
challenged with DENV.sup.42,43. In macaques, a combination of 3
antibodies (including 2 VH3-23/VK1-5 antibodies) is effective
against subcutaneous challenge with 10.sup.3 PFU of ZIKV.sup.18,
but whether escape occurs with single antibodies, or whether fewer
than 3 antibodies might be sufficient to protect was not
determined. The present disclosure demonstrates that in contrast to
in Ifnar1.sup.-/- mice escape is a significant problem upon
challenge with 10.sup.5 PFU of ZIKV in single-antibody treated
primates, which are a natural host for the virus. Moreover, it is
demonstrated herein that prophylaxis with 2 antibodies to the EDIII
is sufficient to prevent escape.
[0307] The Z004 and Z021 antibodies share a number of important
features including potent neutralizing activity against both ZIKV
and DENV1 but no binding to any of the other flaviviruses
tested.sup.5. The overlapping activity can be attributed to
distinct but overlapping target sites. Although the epitopes are
similar, Z021 makes unique contacts to the N-terminal region of
DENV1 EDIII with both its heavy and light chains, while Z004 makes
more extensive contacts to the FG loop, including the
E384/K385.sub.DENV1 motif. Because the E384/K385.sub.DENV1 motif is
peripheral to the Z021 epitope, viruses with mutations at these
positions will likely remain sensitive to Z021. These differences
account for the efficacy of the combination of the two antibodies
despite the similarities in their target sites.
[0308] Method for this Example.
[0309] Reagents.
[0310] Antibodies. Z021, Z004, Z015 and 10-1074 were prepared by
transient transfection of mammalian HEK-293-6E cells and purified
as previously described.sup.5. LPS was removed with TritonX-114 and
the antibodies concentrated to 4.6 to 19 mg/ml in PBS. The GRLR, LS
and combined (GRLR/LS) modifications in the Fc portion of Z004 and
Z021 human IgG1 expression plasmids were generated with Q5
site-directed mutagenesis kit (New England Biolabs) according to
the company's instructions and primers: DFRp1455 5'
TGAACTCCTGaGGGGACCGTCAGTC (SEQ ID NO: 1037) and DFRp1456 5'
GGTGCTGGGCACGGTGGG (SEQ ID NO: 1038); DFRp1457
5'AACAAAGCCCgCCCAGCCCCC (SEQ ID NO: 1039) and DFRp1458
5'GGAGACCTTGCACTTGTACTCCTTG (SEQ ID NO: 1040); DFRp1459
5'ATGCTCCGTGcTGCATGAGGC (SEQ ID NO: 1041) and DFRp1460
5'GAGAAGACGTTCCCCTGC (SEQ ID NO: 1042); DFRp1461
5'GCTCTGCACAgCCACTACACG (SEQ ID NO: 1043) and DFRp1462
5'CTCATGCAGCACGGAGCATG (SEQ ID NO: 1044).
[0311] Virus. For in vitro experiments, ZIKV 2015 Puerto Rican
PRVABC59.sup.44 was obtained from the CDC and passaged twice in
human Huh-7.5 cells, and the Thai isolate of DENV1 PUO-359
(TVP-1140) was obtained from Robert Tesh and amplified by three
passages in C6/36 insect cells. For mouse experiments, ZIKV 2015
Puerto Rican PRVABC59 was passaged once in STAT1.sup.-/- human
fibroblasts. For macaque experiments, a 2015 isolate of ZIKV from
Brazil (strain Zika virus/H.sapiens-tc/BRA/2015/Brazil_SPH2015;
genbank accession number KU321639.1) was used. The strain was
isolated from the plasma of a transfusion recipient and was
passaged twice in mycoplasma free Vero cells. The Puerto Rican ZIKV
strain (PRVABC59; KU501215) was used for subcutansous challenge.
Virus titration was as previously described.sup.5,19.
[0312] Reporter viral particles (RVPs). Wild type ZIKV RVPs with E
proteins corresponding to Asian/American or African lineage were
previously reported.sup.5. A plasmid for expression of ZIKV CprME
with E393A/K394A mutations was generated from plasmid
pZIKV/HPF/CprM*E*.sup.5, a derivative of pZIKV/HPF/CprME, a ZIKV
C-prM-E expression construct provided by Ted Pierson (NIH),
engineered to contain unique BspHI and SacII restriction sites
flanking the envelope region, allowing facile manipulation.
Assembly PCR-based site-directed mutagenesis was used to introduce
the E393A/K394A double mutation into the envelope of ZIKV H/PF/2013
in pZIKV/HPF/CprM*E*, resulting in plasmid
pZIKV/HPF/CprME(E393A/K394A). All PCR-derived plasmid regions were
verified by sequencing. Primers used for assembly PCR and
mutagenesis were: Forward outer (RU-O-24379)
5'ACTTGGTCATGATACTGCTGATTGCCCCGGCATACAGCATCAGGTGCATAGGA GT (SEQ ID
NO: 1045); Reverse outer (RU-O-24380) 5'
TTCGAACCGCGGCTGGGTCCTATTAAGCAGAGACAGCTGTGGATAAGAAGATC (SEQ ID NO:
1046); E393A/K394A forward (RU-O-25002)
5'AGGAGTCGGGGCGGCGAAGATCACCCAC (SEQ ID NO: 1047); and E393A/K394A
reverse (RU-O-25003) 5' GTGGGTGATCTTCGCCGCCCCGACTCCT (SEQ ID NO:
1048). RVPs bearing the ZIKV E protein with E393A/K394A mutations
were generated by cotransfection of Lenti-X-293T cells with
plasmids pZIKV/HPF/CprME(E393A/K394A) and pWNVII-Rep-REN-IB.sup.45
as previously described.sup.5.
[0313] EDIII proteins. Expression plasmids encoding the ZIKV mutant
proteins EDIII.sub.E393A/K394A, EDIII.sub.E393D and EDIII.sub.K394R
were generated by QuikChange site-directed mutagenesis (Agilent
Technologies) and confirmed by DNA sequencing. Primers used for
mutagenesis are the following: E393A/K394A 5'
TTGTCATAGGAGTCGGGGCGGCGAAGATCACCCACCACTG (SEQ ID NO: 1049); E393D
5' CATAGGAGTCGGGGACAAGAAGATCACCCAC (SEQ ID NO: 1050); and K394R:
5'GTCATAGGAGTCGGGGAGCGTAAGATCACCCACCACTGG (SEQ ID NO: 1051).
[0314] Mutant ZIKV EDIII proteins were expressed in E. coli,
refolded from inclusion bodies, and purified as described
previously.sup.5,13.
[0315] Animal Care and Experiments.
[0316] Mice. Interferon-.alpha..beta. receptor knock-out mice were
obtained from The Jackson Laboratory (Ifnar1.sup.-/-; B6.129
S2-Ifnar 1.sup.tm1Agt/Mmjax) and were bred and maintained in the
animal facility at the Rockefeller University. Mice were specific
pathogen free and on a standard chow diet. Both male and female
mice (3-4 week old) were used for experiments and were equally
distributed within experimental and control groups. 125 .mu.g of
monoclonal antibodies in 200 .mu.l of PBS were administered
intraperitoneally to Ifnar1.sup.-/- mice one day before or one day
after footpad infection with 1.25.times.10.sup.5 plaque forming
units (PFU) of ZIKV Puerto Rican strain in 50 .mu.l. Mice were
monitored for symptoms and survival over time. Animal protocols
were in agreement with NIH guidelines and approved by the
Rockefeller University Institutional Animal Care and Use
Committee.
[0317] Macaques. Macaques were from the conventional colony at the
California National Primate Research Center (CNPRC), and were type
D retrovirus-free, SIV-free and simian lymphocyte tropic virus type
1 antibody negative. Animals were housed in accordance with
Association for Assessment and Accreditation of Laboratory Animal
Care Standards. We strictly adhered to Guide for the Care and Use
of Laboratory Animals prepared by the Institute for Laboratory
Animal Research. The study was approved by the Institutional Animal
Care and Use Committee of the University of California Davis. Z004
and Z021 antibodies were administered to macaques at doses of 15
mg/kg body weight each by slow intravenous (i.v.) infusion (2
ml/minute) 24 hours before saphenous vein i.v. inoculation with
ZIKV Brazilian strain (10.sup.5 PFU in 1 ml of RPMI-1640 medium).
Macaques were evaluated twice daily for clinical signs of disease
including poor appetence, stool quality, dehydration, diarrhea, and
inactivity. When necessary, macaques were immobilized with 10 mg/kg
ketamine hydrochloride (Parke-Davis) injected intramuscularly after
overnight fasting. Animals were sedated at time zero (time of virus
inoculation), daily for 7 to 8 days, and then every few days for
sample collection. EDTA-anti-coagulated blood samples were
collected using venipuncture. Complete blood counts and separation
of plasma for cryopreservation of aliquots were performed as
described earlier.sup.19.
[0318] Neutralization and ADE Assays In Vitro.
[0319] Plaque reduction neutralization test with ZIKV PRVABC59, and
flow cytometry-based neutralization assay with DENV1 PUO-359 were
used to measure antibody neutralization activity in Vero cells, as
described.sup.5. Neutralization of luciferase-encoding RVPs by
antibodies using the ZIKV wild type, E393A/K394A, and African
mutant RVPs was performed as previously described.sup.5. Antibody
dependent enhancement (ADE) assays using antibodies or macaque
plasma were similar to neutralization assays with RVPs, except that
Fc-receptor bearing K562 cells were used, and that the cells were
in 96-well plates coated with 0.01% poly-L-lysine (Sigma).
[0320] ELISA Assays.
[0321] ELISA after antibody blocking, Serial dilutions of Z004 or
Z021 antibody were incubated overnight with nutation at 4.degree.
C. in V-bottom 96-well plates in the presence of saturating
concentrations of either wild type EDIII, EDIII.sub.E393A/K394A, or
no protein control. In preliminary experiments, the saturating
concentration of EDIII protein was determined as being
approximately 1 .mu.g/ml, and was increased to 10 .mu.g/ml for the
actual experiment. After overnight incubation the samples were
added to ELISA plates that had been pre-coated with wild type EDIII
and the residual antibody binding to EDIII was detected as
previously described.sup.5, with the exception that the signal was
enhanced by two amplification steps. First, after incubating with
goat anti-human IgG-HRP (Jackson ImmunoResearch Cat #109-035-098; 1
hour, room temperature) and washing with PBS containing Tween-20
0.05%, anti-goat IgG-biotin was added (Jackson ImmunoResearch Cat
#705-065-147; 1 hour, room temperature). Second, after washing,
streptavidin-HRP was added (Jackson ImmunoResearch Cat
#016-030-084; 1 hour, room temperature). After the final washes,
the reaction was developed with ABTS substrate (Life
Technologies).
[0322] Competition ELISA. Z004 or Z021 IgG (5 .mu.g/mL) was
adsorbed overnight at 4.degree. C. in a Nunc MaxiSorp 384-well
ELISA plate. The ELISA plate was blocked with 3% bovine serum
albumin (BSA) in TRIS buffered saline with 0.05% Tween-20 (TBS-T),
and then 5 .mu.g/mL EDIII (ZIKV EDIII or DENV1 EDIII) was added and
incubated for 3 hours at room temperature. The plate was washed
with TB S-T to remove excess antigen, and serial dilutions of Fab
were then added and incubated for 3 hours at room temperature.
Bound His-tagged Fab was detected using THE His Tag Antibody
(Genscript Cat #A00186; 1 hour, room temperature), followed by
goat-anti mouse IgG-HRP (Jackson ImmunoResearch Cat #115-035-003; 1
hour, room temperature), and developed with SuperSignal ELISA Femto
Substrate (Thermo Fisher). Relative light units (RLU) were plotted
as a function of Fab concentration for each IgG-antigen pair.
[0323] Fab ELISA. 5 .mu.g/mL EDIII antigen (WT ZIKV EDIII,
E393A/K394A ZIKV EDIII, E393D ZIKV EDIII, or K394R ZIKV EDIII) was
adsorbed to a Nunc MaxiSorp 384-well ELISA plate overnight at
4.degree. C. The ELISA plate was blocked with 3% BSA in TBS-T,
washed with TBS-T, and then serial dilutions of Fab were added and
incubated for 3 hours at room temperature. After washing the plate
with TBS-T, bound Fab was detected using goat-anti-human IgG-HRP
(GenScript Cat #A00166; 1 hour, room temperature) and developed
with SuperSignal ELISA Femto Substrate (Thermo Fisher).
[0324] ELISA for human IgG detection in macaque plasma. Neutravidin
(ThermoScientific 31000; 2 .mu.g/ml in PBS) was absorbed to high
binding 96-well plates for overnight at 4.degree. C. After washing
the plate using PBS with 0.05% Tween-20 (PBS-T), the biotinylated
anti-human IgG capture antibody was added (ThermoScientific
7103322100; 2 .mu.g/ml in PBS-T, 1 hour at room temperature). Upon
washes, the plates were blocked with 2% BSA in PBS-T (2 hours at
room temperature), blotted, and then serial dilutions of the
macaque plasma were added to the wells (5 steps of 1:4 dilutions in
PBS-T, starting with 1:10). Each plate included two dilution series
of the standard (Z004 IgG, 11 steps of 1:3 dilutions in PBS-T,
starting with 10 .mu.g/ml). Plates were incubated for 1 hour at
room temperature and washed prior to adding the detection reagent
anti-human IgG-HRP (Jackson Immunoresearch 109-036-088; 1 hour at
room temperature). After the final washes, the reaction was
developed with ABTS substrate (Life Technologies).
[0325] Surface Plasmon Resonance.
[0326] Fc.gamma.R and FcRn binding affinity of the Z004 Fc domain
variants was determined by surface plasmon resonance (SPR), using
previously described protocols.sup.46,47. All experiments were
performed on a Biacore T200 SPR system (GE Healthcare) at
25.degree. C. in EMS-EP.sup.+ buffer (GE Healthcare; pH 7.4 for
Fc.gamma.Rs, pH 6.0 for FcRn). Recombinant protein G (Thermo
Fisher) was immobilized to the surface of a CMS sensor chip (GE
Healthcare) using amine coupling chemistry at a density of 500
resonance units (RU). Fc variants of the Z004 antibody were
captured on the Protein G-coupled surface (250 nM injected for 60s
at 20 .mu.l/min) and recombinant human Fc.gamma.R ectodomains
(7.8125-2000 nM; Sinobiological) or FcRn/.beta.2 microglobulin
(1.95-500 nM; Sinobiological) were injected through flow cells at a
flow rate of 20 .mu.l/min. Association time was 60 s followed by a
600-s dissociation step. At the end of each cycle, the sensor
surface was regenerated with 10 mM glycine, pH 2.0 (50 .mu.l/min;
40 s). Background binding to blank immobilized flow cells was
subtracted and affinity constants were calculated using BIAcore
T200 evaluation software (GE Healthcare) using the 1:1 Langmuir
binding model.
[0327] Crystallization and Structure Determination.
[0328] Crystallization and structure determination. The complex for
crystallization was produced by mixing Z021 Fab and DENV1 EDIII at
a 1:1 molar ratio, incubating at room temperature for 1-2 hours,
and concentrating to 12.25 mg/mL. Crystals of Z021 Fab-DENV1 EDIII
complex (space group C2221; a=60.54 .ANG., b=91.60 .ANG., c=187.14
.ANG.; one molecule per asymmetric unit) were obtained by combining
0.2 .mu.L of crystallization sample with 0.2 .mu.L of 0.1M sodium
citrate pH 4.8, 28% Jeffamine.RTM. ED-2001 pH 7.0 in sitting drops
at 22.degree. C. Crystals were cryoprotected with Fomblin Y
oil.
[0329] X-ray diffraction data were collected at Stanford
Synchrotron Radiation Lightsource (SSRL) beamline 12-2 using a
Dectris Pilatus 6M detector. The data were integrated using
Mosflm.sup.48 and scaled using CCP4.sup.49. The Z021-DENV1 DIII
complex structure was solved by molecular replacement using the
V.sub.HV.sub.L and C.sub.HC.sub.L domains from PDB 4YK4 and DENV1
DIII from PDB 4L5F as search models in Phenix.sup.50. The model was
refined to 2.07 .ANG. resolution using an iterative approach
involving refinement in Phenix and manual rebuilding into a
simulated annealing composite omit map using Coot.sup.51. The final
model (R.sub.work=18.8%; R.sub.free=23.0%) contains 532 protein
residues and 120 water molecules. 95%, 4%, and 1% of the protein
residues were in the favored, allowed, and disallowed regions,
respectively, of the Ramachandran plot. Residues that were
disordered and not included in the model were: HC residues 215-219
and the 6.times. His tag; LC residues 1 and 213-214.
[0330] Isolation and Quantitation of Viral RNA.
[0331] Zika virus RNA was isolated from plasma and measured by
qRT-PCR according to methods described previously.sup.52 and
modified to increase the initial volume of sample tested from 140
to 300 .mu.l (when available) to increase sensitivity. The limit of
detection for plasma viral RNA copies was typically 1.1
log.sub.10.
[0332] Virus Sequencing
[0333] For detection of virus escape mutations in macaques, ZIKV
RNA was extracted from plasma using the Qiaamp viral RNA mini kit
following the manufacturer's recommendations with elution of RNA in
water. Qiagen One-Step RT-PCR was performed using either of 2
primer sets targeting sequences surrounding the ZIKV EDIII region:
1618p 5'ACAAGGAGTGGTTCCATGACA (SEQ ID NO: 1052) and 2204n
5'TTTTCCGATGGTGCTGCCAC (SEQ ID NO: 1053) or 1970p
5'GTATGCAGGGACAGATGGACC (SEQ ID NO: 1054) and 2537n
5'ACCGCATCTCGTTTCCTTCTT (SEQ ID NO: 1055) with 50.degree. C. for 30
m, 95.degree. C. for 15 m. Next, 40 cycles of each of the 3 steps
were performed: 94.degree. C. for 1 m, 58.degree. C. for 1 m,
72.degree. C. for 1m15.degree. s, followed by final extension of
72.degree. C. for 10 m. RT-PCR amplicons were visualized on 1%
agarose gels stained with ethidium bromide and sequenced after
purification using the Qiaquick PCR purification kit. Sequences
were called based on clean chromatograms sequenced with the primers
used for amplification. Viral sequences in mice were from blood.
RNA was extracted from TRIzol-LS (Life Technologies) and reverse
transcribed with Superscript III RT (Thermo Fisher Scientific) and
random primers according to the company's protocol prior to PCR
amplification of the ZIKV EDIII region with primers DFRp1284
5'GGATGATCGTTAATGACACAG (SEQ ID NO: 1056) and DFRp1469
5'ACCATCTTCCCAGGCTTG (SEQ ID NO: 1057) followed by PCR clean-up
with Nucleospin (Macherey-Nagel) and direct sequencing with primer
DFRp1283 5'GGATCCTGATTTGAAAGCTGC (SEQ ID NO: 1058). Where
necessary, a second round of nested PCR was performed with primers
DFRp1472 5' TTCCACGACATTCCATTACC (SEQ ID NO: 1059) and DFRp1470
5'ATCTACGGGGGGAGTCAGGATG (SEQ ID NO: 1060).
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not an indication that any of the references are material to
patentability of any invention encompassed by this disclosure
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[0387] While the invention has been described through specific
embodiments, routine modifications will be apparent to those
skilled in the art and such modifications are intended to be within
the scope of the present invention.
Sequence CWU 1
1
107018PRTHomo sapiens 1Gly Phe Thr Phe Arg Asp Tyr Ala1 528PRTHomo
sapiens 2Tyr Ser Gly Ile Asp Asp Ser Thr1 5315PRTHomo sapiens 3Ala
Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser1 5 10
1546PRTHomo sapiens 4Gln Ser Ile Ser Lys Trp1 559PRTHomo sapiens
5Gln His Phe Tyr Ser Val Pro Trp Thr1 568PRTHomo sapiens 6Gly Gly
Ser Ile Asp Thr Tyr Tyr1 577PRTHomo sapiens 7Phe Tyr Tyr Ser Val
Asp Asn1 5812PRTHomo sapiens 8Ala Arg Asn Gln Pro Gly Gly Arg Ala
Phe Asp Tyr1 5 1096PRTHomo sapiens 9Gln Ser Val Ser Asn Tyr1
51011PRTHomo sapiens 10Gln Glu Arg Asn Asn Trp Pro Leu Thr Trp Thr1
5 1011122PRTHomo sapiens 11Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Thr Cys Ala Thr Ser
Gly Phe Thr Phe Arg Asp Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Tyr Ser Gly Ile Asp
Asp Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Ser Thr Leu Ser65 70 75 80Leu His Met Asn
Ser Leu Arg Ala Glu Asp Ser Ala Leu Tyr Phe Cys 85 90 95Ala Lys Asp
Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser Trp 100 105 110Gly
Gln Gly Thr Leu Val Thr Val Ser Ser 115 12012107PRTHomo sapiens
12Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Lys
Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45Tyr Thr Thr Ser Thr Leu Lys Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His
Phe Tyr Ser Val Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 10513118PRTHomo sapiens 13Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys
Thr Val Ser Gly Gly Ser Ile Asp Thr Tyr 20 25 30Tyr Trp Ser Trp Ile
Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Cys Phe Tyr
Tyr Ser Val Asp Asn His Phe Asn Pro Ser Leu Glu 50 55 60Ser Arg Val
Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys
Met Thr Ser Met Thr Ala Ser Asp Thr Ala Val Tyr Tyr Cys Ala 85 90
95Arg Asn Gln Pro Gly Gly Arg Ala Phe Asp Tyr Trp Gly Pro Gly Thr
100 105 110Leu Val Thr Val Ser Ser 11514109PRTHomo sapiens 14Glu
Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10
15Gln Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Tyr
20 25 30Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
Ile 35 40 45Tyr Asp Thr Ser Lys Arg Ala Thr Gly Thr Pro Ala Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Glu Arg
Asn Asn Trp Pro Leu 85 90 95Thr Trp Thr Phe Gly Leu Gly Thr Lys Val
Glu Ile Lys 100 10515451PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 15Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Thr
Cys Ala Thr Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30Ala Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Tyr
Ser Gly Ile Asp Asp Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Ser65 70 75
80Leu His Met Asn Ser Leu Arg Ala Glu Asp Ser Ala Leu Tyr Phe Cys
85 90 95Ala Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser
Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro 115 120 125Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr 130 135 140Ala Ala Leu Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr145 150 155 160Val Ser Trp Asn Ser Gly
Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175Ala Val Leu Gln
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190Val Pro
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 195 200
205His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu225 230 235 240Arg Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu 245 250 255Met Ile Ser Arg Thr Pro Glu Val Thr
Cys Val Val Val Asp Val Ser 260 265 270His Glu Asp Pro Glu Val Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285Val His Asn Ala Lys
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 290 295 300Tyr Arg Val
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn305 310 315
320Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Arg Pro Ala Pro
325 330 335Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
Pro Gln 340 345 350Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
Lys Asn Gln Val 355 360 365Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
Pro Ser Asp Ile Ala Val 370 375 380Glu Trp Glu Ser Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro385 390 395 400Pro Val Leu Asp Ser
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415Val Asp Lys
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 420 425 430Leu
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440
445Ser Pro Gly 45016214PRTArtificial SequenceDescription of
Artificial Sequence Synthetic polypeptide 16Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Lys Trp 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Tyr Ser Val Pro Trp
85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala
Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200
205Phe Asn Arg Gly Glu Cys 21017447PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
17Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asp Thr
Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu
Trp Ile 35 40 45Gly Cys Phe Tyr Tyr Ser Val Asp Asn His Phe Asn Pro
Ser Leu Glu 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn
Gln Phe Ser Leu65 70 75 80Lys Met Thr Ser Met Thr Ala Ser Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Asn Gln Pro Gly Gly Arg Ala Phe
Asp Tyr Trp Gly Pro Gly Thr 100 105 110Leu Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125Leu Ala Pro Ser Ser
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 130 135 140Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn145 150 155
160Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
Ser Ser 180 185 190Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
His Lys Pro Ser 195 200 205Asn Thr Lys Val Asp Lys Arg Val Glu Pro
Lys Ser Cys Asp Lys Thr 210 215 220His Thr Cys Pro Pro Cys Pro Ala
Pro Glu Leu Leu Arg Gly Pro Ser225 230 235 240Val Phe Leu Phe Pro
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 245 250 255Thr Pro Glu
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 260 265 270Glu
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 275 280
285Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
Glu Tyr305 310 315 320Lys Cys Lys Val Ser Asn Lys Ala Arg Pro Ala
Pro Ile Glu Lys Thr 325 330 335Ile Ser Lys Ala Lys Gly Gln Pro Arg
Glu Pro Gln Val Tyr Thr Leu 340 345 350Pro Pro Ser Arg Glu Glu Met
Thr Lys Asn Gln Val Ser Leu Thr Cys 355 360 365Leu Val Lys Gly Phe
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 370 375 380Asn Gly Gln
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp385 390 395
400Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu His
Glu Ala 420 425 430Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser Pro Gly 435 440 44518216PRTHomo sapiens 18Glu Ile Val Leu Thr
Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Gln Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Tyr 20 25 30Phe Ala Trp
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp
Thr Ser Lys Arg Ala Thr Gly Thr Pro Ala Arg Phe Ser Gly 50 55 60Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Glu Arg Asn Asn Trp Pro Leu
85 90 95Thr Trp Thr Phe Gly Leu Gly Thr Lys Val Glu Ile Lys Arg Thr
Val 100 105 110Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
Gln Leu Lys 115 120 125Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn Phe Tyr Pro Arg 130 135 140Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln Ser Gly Asn145 150 155 160Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200
205Lys Ser Phe Asn Arg Gly Glu Cys 210 21519122PRTHomo sapiens
19Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Arg Arg Leu Ser Cys Ala Thr Ser Gly Phe Ser Phe Asp Thr
Tyr 20 25 30Ala Met Ser Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ser Phe Ser Gly Leu Asp Asp 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 Ile Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Gly Pro Arg Gly Ile
Gly Glu Leu Phe Asp Phe Trp 100 105 110Gly Gln Gly Thr Leu Val Thr
Val Ser Ser 115 12020107PRTHomo sapiens 20Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Arg Trp 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Lys Thr
Ser Thr Leu Lys Ser Glu Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe His Ser Val Pro Trp
85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
10521120PRTHomo sapiens 21Glu 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 Lys Asn Tyr 20 25 30Ala Met Ala Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Leu Tyr Asn Ser Glu
Glu 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 Phe65 70 75 80Leu Gln Met Asn
Arg Leu Arg Val Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Val Arg Asp
Arg Ser Asn Gly Trp Ser Ser Ile Asn Leu Trp Gly Arg 100 105 110Gly
Thr Leu Val Thr Val Ser Ser 115 12022106PRTHomo sapiens 22Asp Ile
Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp
Arg Val Thr Met Thr Cys Arg Ala Ser Gln Thr Ile Ser Gly Trp 20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45Tyr Gln Ala Ser Arg Leu Glu Ser Gly Ile Pro Ser Arg Phe Ser
Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu
Gln Pro65 70 75 80Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser
Thr Phe Trp Thr 85 90 95Phe Gly Leu Gly Thr Lys Val Glu Ile Lys 100
10523120PRTHomo sapiens 23Glu 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 Ala Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Tyr Ser Gly Asp
Asp Ser Thr Tyr Tyr Ala Asp Phe Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg His Asn Ser Lys Asn Thr Leu Ser65
70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr
Cys 85 90 95Val Lys Asp Arg Gly Thr Gly Trp Ser Ser Ile Val His Trp
Gly Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115
12024106PRTHomo sapiens 24Asp Ile Gln Met Thr Gln Ser Pro Ser Thr
Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Thr Ile Ser Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Ser Leu Glu
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Tyr Trp Thr 85 90 95Phe Gly Gln
Gly Thr Lys Val Glu Ile Lys 100 10525128PRTHomo sapiens 25Gln Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Ser Gly Ala1 5 10 15Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Asn 20 25
30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Met
35 40 45Gly Ile Ile Asn Pro Arg Gly Gly Ser Thr Thr Tyr Ala Gln Lys
Phe 50 55 60Gln Gly Arg Val Leu Met Thr Ser Asp Thr Ser Thr Ser Thr
Val Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Arg Ala
Val Tyr Tyr Cys 85 90 95Ala Arg Gly Lys Asn His Gln Thr Thr Val Ala
Val Leu Ser Trp Tyr 100 105 110Tyr Gly Met Asp Val Trp Gly Gln Gly
Thr Thr Val Thr Val Ser Ser 115 120 12526107PRTHomo sapiens 26Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45Ser Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn
Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ala
Asn Ser Phe Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
Lys 100 10527122PRTHomo sapiens 27Glu Val Gln Leu Leu Glu Ser Gly
Gly Asp 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 Ser Ile Ser Gly
Phe Asp Pro Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60Arg Gly Arg Phe
Thr Ile Ala Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln
Met Lys Ser Leu Arg Val Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95Ala
Lys Asp Arg Leu Val Arg Gly Phe Gly Glu Val Leu Asp Ser Trp 100 105
110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12028107PRTHomo
sapiens 28Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
Ser Asn Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Arg Glu Val Pro
Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu His Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Gly Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys
Gln Lys Tyr Asn Ser Val Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 100 10529124PRTHomo sapiens 29Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu
Ser Cys Lys Ser Ser Gly Tyr Ser Phe Thr Ser Tyr 20 25 30Tyr Met His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile
Ile Asn Pro Ser Gly Val Phe Thr Ser Tyr Ala Gln Arg Phe 50 55 60Gln
Gly Arg Val Thr Met Thr Ser Asp Thr Ala Thr Ser Thr Val Tyr65 70 75
80Met Glu Leu Ser Ser Leu Arg Ser Gly Asp Thr Ala Val Tyr Tyr Cys
85 90 95Thr Arg Ser Leu Val Thr Pro Ala Ala Gln Ser Val Gln Tyr Phe
Asp 100 105 110Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
12030108PRTHomo sapiens 30Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Ser Val Ser Leu Ser 20 25 30Phe Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Asn Arg
Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Gly Asp Phe
Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Leu Thr Phe
Gly Pro Gly Thr Lys Val Asp Ile Lys 100 10531121PRTHomo sapiens
31Gln Val Gln Leu Val Gln Ser Gly Pro Gly Val Lys Lys Pro Gly Ala1
5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Asp
Tyr 20 25 30Tyr Ile Leu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Tyr Met 35 40 45Gly Trp Met Asn Pro Ile Ser Gly Phe Thr His Tyr Ala
Gln Asn Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile
Ser Thr Ala Tyr65 70 75 80Met Glu Leu Thr Arg Leu Ala Ser Asp Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Arg Ile Asn Ser Pro
Leu Gly Phe Asp Pro Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 12032108PRTHomo sapiens 32Glu Ile Val Leu Thr Gln Ser
Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser
Cys Arg Ala Ser Gln Ser Ile Ser Thr Phe 20 25 30Ser Leu Ala Trp Tyr
Gln Gln Lys Phe Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala
Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Val Ser Ser Pro 85 90
95Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10533128PRTHomo sapiens 33Glu Val Gln Leu Val Gln Ser Gly Ala Glu
Val Arg Lys Pro Gly Glu1 5 10 15Ser Leu Arg Ile Ser Cys Lys Thr Ser
Gly Tyr Thr Phe Thr Ser His 20 25 30Trp Val Ala Trp Val Arg Gln Met
Pro Gly Lys Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Tyr Pro Gly Asp
Ser Asp Thr Arg Tyr Ser Pro Ser Phe 50 55 60Gln Gly Gln Ile Ser Ile
Ser Ala Asp Lys Ser Ile Asn Thr Ala Tyr65 70 75 80Leu Gln Trp Ser
Ser Leu Lys Ala Ser Asp Thr Gly Ile Tyr Tyr Cys 85 90 95Ala Arg His
Asp Gly Arg Gly Tyr Cys Ser Pro Thr Arg Cys Phe Phe 100 105 110Ser
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120
12534107PRTHomo sapiens 34Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Ser Ile Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Tyr Ala
Ile Tyr Tyr Cys Gln Gln Thr Asp Arg Thr Pro Leu 85 90 95Thr Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 100 10535122PRTHomo sapiens 35Glu
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 Ala Tyr
20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45Ser Ser Ile Asn Gly His Ser Asp Ser Thr Tyr Phe 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 Leu Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Leu Arg Glu Gly Ile Gly
Glu Leu Phe His Ser Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 12036107PRTHomo sapiens 36Asp Ile Gln Met Thr Gln Ser
Pro Ser Thr Leu Ser Ala Ser Ile Gly1 5 10 15Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Ser Ile Thr Pro Trp 20 25 30Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Gln Thr Ser
Ile Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser
Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Tyr Pro Trp 85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10537122PRTHomo
sapiens 37Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro
Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe
Gly Ser Tyr 20 25 30Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Ile 35 40 45Ser Ser Ile Ser Ser Ile Asp Pro Ser Thr Tyr
Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Val Ser Arg Asp Asn
Ser Glu Asn Thr Leu Tyr65 70 75 80Leu His Met Ser Ser Leu Lys Val
Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Lys Asp Arg Leu Asn Gly
Gly Phe Gly Glu Leu Phe Ala Ser Trp 100 105 110Gly Gln Gly Thr Leu
Val Thr Val Ser Ser 115 12038107PRTHomo sapiens 38Asp Ile Gln Met
Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Ser Val
Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25 30Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45His
Lys Ala Ser Ser Leu Glu Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Asn Leu Gln Pro65
70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Tyr Pro
Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
10539128PRTHomo sapiens 39Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Ile 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 Gly Ile Ser Gly Ser Gly
Gly Ala Ser Asp Asn Gly Ala Ser Arg 50 55 60Tyr Tyr Ala Asp Ser Val
Lys Gly Arg Phe Ser Ile Ser Arg Asp Asn65 70 75 80Ser Lys Asn Thr
Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 85 90 95Thr Ala Val
Tyr Tyr Cys Ala Lys Asp Arg Leu Ser Gly Gly Phe Gly 100 105 110Glu
Leu Phe Gln Lys Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
12540107PRTHomo sapiens 40Asp Ile Gln Met Thr Gln Ser Pro Ser Thr
Leu Ala Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Asn Ile Asn Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Phe Leu Ile 35 40 45Tyr Lys Ala Ser Thr Leu Glu
Ser Gly Ala Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala
Thr Tyr Tyr Cys Gln His Tyr Tyr Ser Tyr Pro Tyr 85 90 95Thr Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 100 10541130PRTHomo sapiens 41Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Ser Val Ser Gly Tyr Phe Ile Ser Ser Gly
20 25 30His Tyr Trp Gly Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
Trp 35 40 45Ile Ala Ser Ile Tyr Gln Ser Gly Ser Lys Phe Gln Thr Gly
Asn Thr 50 55 60Tyr Tyr Asn Pro Ser Leu Glu Ser Arg Val Thr Ile Ser
Met Asp Thr65 70 75 80Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser
Val Thr Ala Ala Asp 85 90 95Thr Ala Val Tyr Phe Cys Ala Arg Asp Ala
Arg Ser Arg Ser Trp Asp 100 105 110Arg Thr Gly Phe Phe Gly Pro Trp
Gly Gln Gly Ile Leu Val Thr Val 115 120 125Ser Ser 13042108PRTHomo
sapiens 42Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Leu
Ser Ser Ser 20 25 30Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser
Pro Arg Leu Leu 35 40 45Ile Tyr Gly Thr Ser Ser Arg Asp Thr Gly Ile
Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ser Ala Val Tyr Tyr
Cys Gln Gln Tyr Gly Ser Ser Trp 85 90 95Gly Thr Phe Gly Gln Gly Thr
Lys Leu Glu Ile Lys 100 10543127PRTHomo sapiens 43Glu Val Gln Leu
Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg
Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30Ala Met
Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser
Thr Leu Gly Ala Thr Asp Asn Ser Gly Asp Ser Thr Tyr Tyr Val 50 55
60Glu Ser Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn65
70 75 80Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala
Val 85 90 95Tyr Phe Cys Ala Lys Asp Arg Thr Gly Asn Ile Gly Ala Gly
Thr Gly 100 105 110Tyr Phe Asp Lys Trp Gly Gln Gly Thr Leu Val Thr
Val Ser Ser 115 120 12544107PRTHomo sapiens 44Asp Ile Gln Met Thr
Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser His Arg Ile Ser Gly Trp 20 25 30Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Gln
Ala Ser Gly Leu Glu Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Tyr Gly Thr Glu Phe Thr Leu Thr
Ile Ser Ser Leu Gln Ala65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Tyr Asn Asn Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 100 10545122PRTHomo sapiens 45Glu 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 Tyr Ile Phe Asp Asn Tyr 20 25 30Ala Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Tyr
Ile Asn Gly Gly Gly Tyr Gly Thr Asp Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Arg Ile Leu Tyr65 70 75
80Leu Gln Met Asn Ser Leu Arg Val Gly Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Lys Ser Pro Tyr Val Gly Gly Tyr Gly Leu Pro Gly Asp Ser
Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
12046108PRTHomo sapiens 46Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln Thr Ile Phe Phe Asn 20 25 30Tyr Leu Ala Trp Tyr Gln Lys Lys
Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Val His Gly Ala Ser Thr Arg
Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Asn Ser Leu Asp65 70 75 80Pro Glu Asp Phe
Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asp Ser Pro 85 90 95Pro Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10547122PRTHomo sapiens
47Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1
5 10 15Ser Val Arg Leu Ser Cys Lys Ala Ser Gly Gly Ser Tyr Ser Thr
Tyr 20 25 30Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45Gly Arg Ile Ile Pro Ser Leu Gly Lys Thr His Leu Ala
Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Phe Thr Ala Asp Glu Ser Thr
Thr Thr Val Tyr65 70 75 80Met Ile Leu Ser Ser Leu Lys Ser Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95Ala Thr Pro Asp Trp Gln Tyr Ser Ser
Ala Tyr Ser Leu Asp His Trp 100 105 110Gly Gln Gly Thr Leu Val Thr
Val Ser Ser 115 12048112PRTHomo sapiens 48Asp Ile Val Met Thr Gln
Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile
Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Thr Gly Tyr Asn
Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu
Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro 50 55 60Asp Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75
80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile
Lys 100 105 11049114PRTHomo sapiens 49Gln Val Gln Leu Gln Glu Ser
Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Ser Cys
Thr Val Ser Ser Gly Ser Ile Ser Asn Tyr 20 25 30Tyr Trp Asn Trp Ile
Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Tyr Ile Tyr
Tyr Ser Gly Ser Ile Ser Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val
Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Leu Ser Leu65 70 75 80Lys
Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90
95Arg Gly Pro Asp Asn Arg Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110Ser Ser50109PRTHomo sapiens 50Glu Ile Val Met Thr Gln
Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu
Ser Cys Arg Ala Ser Gln Ser Val Ser Tyr Asn 20 25 30Leu Ala Trp His
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala
Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Asn Met Gln Ser65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Pro
85 90 95Val Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100
10551123PRTHomo sapiens 51Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Thr Ser
Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Tyr Met Asn Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Lys Pro Ser Asp
Gly Ser Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Met
Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75 80Met Glu Leu Arg
Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Gly Arg Asp
Ser Lys Gly Trp Leu Gln Leu Arg Gly Asp Ile Asp Tyr 100 105 110Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12052110PRTHomo sapiens
52Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln1
5 10 15Ser Ile Thr Ile Ser Cys Ala Gly Thr Ser Ser Asp Val Gly Asn
Tyr 20 25 30Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45Leu Ile Tyr Glu Val 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 Tyr Val Phe Gly Thr Gly Thr
Glu Val Thr Val Leu 100 105 11053122PRTHomo sapiens 53Glu Val Gln
Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu
Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30Ala
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45Ser Ser Phe Ser Gly Val Asp Asp Ser Thr Tyr Tyr Ala Glu Ser Val
50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val
Tyr65 70 75 80Leu Gln Met Thr Arg Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu
Phe Asp Ser Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 12054107PRTHomo sapiens 54Asp Ile Gln Met Thr Gln Ser Pro Ser
Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Met Thr Cys Arg
Ala Ser Gln Ser Ile Asn Arg Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Thr Thr Ser Thr Leu
Lys Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr
Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe
Ala Thr Tyr Tyr Cys Gln His Phe His Ser Val Pro Trp 85 90 95Thr Phe
Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10555122PRTHomo sapiens
55Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1
5 10 15Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Thr
Phe 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45Ser Ser Ile Ser Gly Ala Asp Asp Ser Thr Tyr Tyr Ala
Ala Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg
Ser Thr Leu Phe65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Gly Pro Arg Gly Val
Gly Glu Leu Phe Asp Ser Trp 100 105 110Gly Gln Gly Thr Leu Val Thr
Val Ser Ser 115 12056107PRTHomo sapiens 56Asp Ile Gln Met Thr Gln
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Lys Trp 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile 35 40 45Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75
80Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe Phe Ser Val Pro Trp
85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
10557122PRTHomo sapiens 57Glu 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 Ser Phe Ser Gly Ile Asp
Asp Ser Thr Trp Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Ser 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 Leu Val Arg Gly Phe Ala Glu Val Leu Asp Tyr Trp 100 105 110Gly
Arg Gly Thr Leu Val Thr Val Ser Ser 115 12058107PRTHomo sapiens
58Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Lys
Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Val Pro Asn Leu
Leu Ile 35 40 45Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr His Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys
Tyr Asn Ser Val Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 10559120PRTHomo sapiens 59Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys
Thr Ala Ser Gly Phe Thr Phe Arg Arg Tyr 20 25 30Ala Met Ala Trp Val
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile Tyr
Asp Gly Asp Asp Ser Thr Tyr Tyr Ala Lys Ser Val 50 55 60Lys Gly Arg
Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Ser65 70 75 80Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95Val Lys Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp Trp Gly Gln
100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12060106PRTHomo
sapiens 60Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser His Ser Ile
Ser Gly Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile Gly Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys
Gln Gln Tyr Ser Thr Phe Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 10561120PRTHomo sapiens 61Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser
Cys Thr Ala Ser Gly Phe Thr Phe Arg Arg Phe 20 25 30Ala Met Ala Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile
Trp Asn Gly Asp Asp Ser Thr Tyr Tyr Ala Glu Ser Val 50 55 60Arg Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser His Asn Thr Leu Ser65 70 75
80Leu Gln Met Arg Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95Val Lys Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp Trp Gly
Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12062106PRTHomo
sapiens 62Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile
Gly Asn Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Val Leu Glu Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys
Gln Gln Tyr Ser Thr Phe Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 10563120PRTHomo sapiens 63Glu Val Gln Leu Leu Glu
Ser Gly Gly Gly Leu Val Arg Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser
Cys Thr Ala Ser Gly Phe Thr Phe Arg Arg Tyr 20 25 30Ala Met Ala Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Leu Ile
Tyr Asn Gly Asp Asp Ser Thr Tyr Tyr Ala Glu Ser Val 50 55 60Lys Gly
Arg Phe Thr Val Ser Arg Asp Asn Ser Gln Asn Thr Leu Ser65 70 75
80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95Val Arg Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp Trp Gly
Gln 100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 12064106PRTHomo
sapiens 64Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg Thr Ile
Gly Ser Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Ile Leu Glu Gly Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Val Ser Gly Thr Glu Phe Thr Leu Thr
Ile Arg Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Phe Cys
Gln Gln Tyr Ser Thr Phe Trp Thr 85 90 95Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 10565122PRTHomo sapiens 65Glu 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 Arg Thr Tyr 20 25 30Ala Met Ser Trp
Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser Ile
Ser Ala Arg Glu Asp Ser Thr Tyr Phe Ala Ala Ser Val 50 55 60Arg Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75
80Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr
Ala Leu Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Leu Gln Leu Gly Val Gly
Glu Leu Tyr Glu Ser Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 12066107PRTHomo sapiens 66Asp Ile Gln Met Thr Gln Ser
Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Asn Ile Asn Ser Trp 20 25 30Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Met Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser
Gly Thr Glu Phe Thr Leu Thr Val Ser Ser Leu Gln Pro65 70 75 80Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Tyr Pro Trp 85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10567124PRTHomo
sapiens 67Glu 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 45Ser Gly Ile Gly Gly Arg Gly Ala Ile Ala Gly
Asp Gly Ser Ile Tyr 50 55 60Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser65 70 75 80Lys Asn Ile Val Tyr Leu Gln Met
Asn Gly Leu Arg Val Glu Asp Thr 85 90 95Ala Val Tyr Tyr Cys Ala Lys
Asp Arg Val Ala Phe Asp Gly Phe His 100 105 110Val Trp Gly Gln Gly
Thr Leu Val Thr Val Ser Ser 115 12068107PRTHomo sapiens 68Asp Ile
Gln Met Thr Gln Ser Pro Pro Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp 20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Ser Leu Thr Ile Ser Ser Leu
Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn
Ser Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 10569124PRTHomo sapiens 69Gln Val Gln Leu Val Gln Ser Gly Ala
Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala
Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30Tyr Val His Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Gly
Asn Asn Phe Val Ser Phe Ala Gln Asn Phe 50 55 60Tyr Asp Arg Ala Thr
Met Thr Arg Asp Thr Ser Thr Asn Thr Val Tyr65 70 75 80Met Glu Leu
Thr Asn Leu Gln Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg
Thr Leu Val Ala Pro Ser Ala Gln Ser Met Tyr Tyr Phe Asp 100 105
110Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
12070108PRTHomo sapiens 70Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Gly Thr Leu Ser Cys Arg Ala
Ser Gln Tyr Ile Thr Thr Gly 20 25 30His Phe Ala Trp Tyr Gln Gln Lys
Pro Gly Arg Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Val Arg
Ala Thr Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ala Glu Thr
Asp Phe Thr Leu Thr Ile Ser Arg Leu Asp65 70 75 80Pro Glu Asp Val
Gly Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95Val Thr Phe
Gly Pro Gly Thr Lys Val Asp Ile Lys 100 10571121PRTHomo sapiens
71Gln Val Gln Leu Val Gln Ser Gly Ala Gly Met Arg Lys Pro Gly Ala1
5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Asn Asp
Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45Gly Trp Ile Asn Pro Lys Ser Gly Phe Thr Asn Tyr Ala
Gln Arg Phe 50 55 60Gln Gly Arg Val Thr Met Thr Gly Asp Thr Ser Asn
Ser Val Ala Tyr65 70 75 80Met Glu Leu Thr Arg Leu Thr Ser Asp Asp
Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Arg Ile Asn Ala Pro
Leu Gly Phe Asp Pro Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val
Ser Ser 115 12072108PRTHomo sapiens 72Glu Ile Val Leu Thr Gln Ser
Pro Asp Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Thr Ala Thr Leu Ser
Cys Arg Ala Ser Gln Ser Ile Gly Ser Ile 20 25 30Ser Leu Gly Trp Tyr
Gln Gln Lys Phe Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala
Ser Thr Arg Ala Thr Gly Thr Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly
Ser Glu Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro
Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln Tyr Val Ser Ser Pro 85 90
95Leu Arg Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100
10573124PRTHomo sapiens 73Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Tyr Thr Phe Thr Thr Tyr 20 25 30Phe Ile His Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile Ile Asn Pro Asn Ser
Gly Ser Thr Asn Tyr Ala Gln Lys Ile 50 55 60Gln Gly Arg Val Thr Met
Thr Thr Asp Thr Ser Ala Ser Thr Val Tyr65 70 75 80Met Glu Leu Ser
Gly Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly
Gly Ser Tyr Pro Val Ala Ile Arg Gly Val Thr Phe Gly 100 105 110Ile
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 12074107PRTHomo
sapiens 74Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile
Ser Asn Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Asn Leu Leu Ile 35 40 45Phe Ala Thr Ser Ser Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Phe Ser Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys
Val Glu Ile Lys 100 10575130PRTHomo sapiens 75Gln Val Gln Leu Gln
Gln Trp Gly Ala Arg Pro Leu Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu
Thr Cys Gly Val Asn Gly Gly Ser Phe Ser Gly Tyr 20 25 30His Trp Ser
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Glu
Ile Asp His Asn Gly Arg Ile Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser
Arg Val Thr Ile Ser Ile Asp Thr Phe Lys Ser Gln Phe Ser Leu65 70 75
80Arg Leu Thr Ser Ile Ile Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95Arg Asp Val Val Thr Met Val Glu Gly Leu Arg Phe His Tyr Tyr
Tyr 100 105 110Asn Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
Val Thr Val 115 120 125Ser Ser 13076108PRTHomo sapiens 76Glu Ile
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Asp
Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln Ser Val Ser Ser Asn 20 25
30Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu
35 40 45Ile Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe
Ser 50 55 60Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Lys
Leu Glu65 70 75 80Ala Glu Asp Phe Ala Met Tyr Tyr Cys Gln Ile Tyr
Asp Ser Ser Val 85 90 95Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 100 10577122PRTHomo sapiens 77Glu Val Gln Leu Leu Glu Ser Gly
Gly Arg Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Thr Leu Ser Cys Ala
Ala Ser Gly Phe Pro Phe Ser Thr Tyr 20 25 30Ala Met Ser Trp Leu Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Gly Ile Thr Gly
Asp Ser Gly Ser Thr Tyr Tyr Ala Ala 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 Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala
Lys Asp Arg Leu His Ser Gly Leu Gly Glu Leu Phe Ser Tyr Trp 100 105
110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12078107PRTHomo
sapiens 78Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Asn Ile Thr Cys Arg Ala Ser Gln Ser Ile
Asn Gln Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Phe Leu Met 35 40 45Tyr Lys Ala Ser Thr Leu Glu Thr Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala Thr Tyr Tyr Cys
Gln His Tyr Phe Ser Tyr Pro Trp 85 90 95Thr Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 100 10579122PRTHomo sapiens 79Glu Val Gln Leu Leu
Glu Ser Gly Gly Gly Leu Ala Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu
Ser Cys Glu Thr Ser Gly Phe Thr Phe Arg Ser Tyr 20 25 30Gly Met Gly
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ser
Ile Tyr Ile Ser Gly Asp Ser Thr Tyr Tyr Ala Ala Ser Val 50 55 60Lys
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr65 70 75
80Leu Gln Met Asp Arg Leu Thr Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Val Arg Asp Arg Ile Gln Gly Gly Phe Gly Glu Leu Tyr Arg Tyr
Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
12080107PRTHomo sapiens 80Asp Ile Gln Met Thr Gln Ser Pro Ser Thr
Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Met Thr Cys Arg Ala
Ser Gln Ser Val Asn Lys Trp 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Glu Thr Ser Ile Leu Glu
Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp Phe Ala
Thr Tyr Tyr Cys Gln His Tyr His Gly Tyr Pro Trp 85 90 95Thr Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 100 10581122PRTHomo sapiens 81Glu
Val Gln Leu Leu Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Leu 35 40 45Ser Ser Ile Ser Ser Val Asp Asp Ser Lys Tyr Tyr Ala Ala
Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn
Thr Leu Tyr65 70 75 80Leu His Met Asn Ser Leu Arg Val Asp Asp Thr
Ala Val Tyr Tyr Cys 85 90 95Ala Lys Asp Arg Ile Pro His Gly Leu Gly
Glu Leu Tyr Ala Asn Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val
Ser Ser 115 12082107PRTHomo sapiens 82Asp Ile Gln Met Thr Gln Ser
Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Ser Ile Ser Gly Trp 20 25 30Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Met 35 40 45His Lys Ala Ser
Asn Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser
Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr His Ser Tyr Pro Tyr 85 90
95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 10583127PRTHomo
sapiens 83Glu 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 Thr 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 Arg 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 Gly
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ser Ser Gly Gly His
Asn Trp Asn Tyr Val Asp Tyr Tyr Tyr 100 105 110Gly Met Asp Val Trp
Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 12584107PRTHomo
sapiens 84Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile
Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Leu Asn Ser Tyr Pro Val 85 90 95Thr Phe Gly Pro Gly Thr Lys
Val Asp Ile Lys 100 10585125PRTHomo sapiens 85Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Thr 20 25 30Tyr Ile His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Ile
Ile Asn Pro Ser Ser Ser Asn Thr Asn Tyr Ala Gln Lys Phe 50 55 60Gln
Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr65 70 75
80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Asp Phe Gly Gly Tyr Ser Ser Ser Ser Val Ser Asp Ala
Phe 100 105 110Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120 12586110PRTHomo sapiens 86Gln 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 Phe 20 25 30Asn Leu Val Ser Trp Tyr
Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45Ile Ile Tyr Glu Val
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
Val His Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95Ser Arg Phe Val
Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 11087119PRTHomo
sapiens 87Glu Val Gln Leu Leu Glu Ser Gly Gly Ala Leu Val Gln Pro
Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Asn Tyr Tyr 20 25 30Ala Met Thr Trp Val Arg Gln Ala Pro Gly Arg Gly
Leu Glu Trp Val 35 40 45Ser Thr Ile Thr Asp Asn Gly Gly Thr Thr Tyr
Leu Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Gln Asn Thr Gln Ser65 70 75 80Leu Gln Met Asn Asn Leu Arg Ala
Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95Val Lys His Leu Arg Gly Trp
Tyr Thr Phe Glu Ile Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val
Ser Ser 11588109PRTHomo sapiens 88Glu Ile Val Leu Thr Gln Ser Pro
Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys
Arg Ala Ser Gln Ser Val Ser Gly Ser 20 25 30Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser
Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro 85 90 95Arg
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10589120PRTHomo
sapiens 89Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Lys Pro
Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe
Ser Thr 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 Pro Gly Ser Gly Asp Asn Ile
Tyr Tyr Gly Asp Ser 50 55 60Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu65 70 75 80Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr 85 90 95Cys Val Asn Gly Gly Phe Ser
Gly Tyr Tyr Ser Asp Tyr Trp Gly Gln 100 105 110Gly Thr Leu Val Thr
Val Ser Ser 115 12090106PRTHomo sapiens 90Glu Ile Val Leu Thr Gln
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Tyr 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala
Ser Asn Met Ala Pro Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Leu Thr
85 90 95Phe Gly Gly Gly Thr Lys Val Asp Ile Lys 100 10591129PRTHomo
sapiens 91Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Pro Gly Gly Thr Phe
Ser Arg Tyr 20 25 30Ser Ile Ala Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45Gly Gly Ile Asn Pro Thr Phe Thr Thr Pro Asn
Tyr Ala Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Ala Asp Glu
Ser Thr Asn Thr Ala Tyr65 70 75 80Leu Asp Leu Ser Ser Leu Arg Ser
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Phe Arg Tyr Tyr Tyr
Glu Ser Gly Gly Tyr Ser Asp Ala Ser 100 105 110Pro Tyr Tyr Leu Asp
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 115 120
125Ser92107PRTHomo sapiens 92Glu Ile Val Leu Thr Gln Ser Pro Ala
Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg
Ala Thr Gly Ile Pro Ala Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe
Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu 85 90 95Thr Phe
Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10593123PRTHomo sapiens
93Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Val Ser Ile Ser Ser
Gly 20 25 30Gly Tyr Tyr Tyr Ser Trp Phe Arg Gln Leu Pro Gly Lys Gly
Leu Glu 35 40 45Trp Ile Gly His Ile Tyr Tyr Thr Gly Asn Thr His Tyr
Asn Pro Ser 50 55 60Leu Arg Ser Arg Leu Thr Ile Ser Val Asp Thr Ser
Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr Ala Ala
Asp Thr Ala Arg Tyr Tyr 85 90 95Cys Ala Arg Ala Trp Cys Glu Tyr Ala
Ala Tyr Cys Trp Phe Asp Pro 100 105 110Trp Gly Arg Gly Thr Leu Val
Thr Val Ser Ser 115 12094108PRTHomo sapiens 94Glu Ile Val Leu Thr
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln Ser Val Thr Ser Ser 20 25 30Tyr Leu Ala
Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr
Gly Ala Ser Ser Arg Ala Pro Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75
80Pro Glu Asp Phe Ala Val Tyr Trp Cys Gln Gln Tyr Gly Arg Ser Pro
85 90 95Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100
10595124PRTHomo sapiens 95Gln Val Gln Leu Gln Glu Ser Gly Pro Gly
Leu Val Lys Pro Ser Gln1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser
Gly Gly Ser Ile Thr Gly Gly 20 25 30Val Tyr Tyr Trp Asn Trp Ile Arg
His His Pro Gly Lys Gly Leu Glu 35 40 45Trp Ile Gly Tyr Met Phe Tyr
Ser Gly Asp Thr Asp Tyr Asn Pro Ser 50 55 60Leu Arg Ser Arg Val Thr
Ile Ser Gly Asp Thr Ser Lys Asn Lys Phe65 70 75 80Ser Leu Asn Leu
Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg
Ala Gly Phe Asp Tyr Gly Ser Pro Val Ser Ala Phe Asp 100 105 110Ile
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 12096110PRTHomo
sapiens 96Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser
Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
Ser Ser Thr 20 25 30Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Phe
Cys Gln Gln Tyr Ala His Ser Pro 85 90 95Arg Gly Tyr Thr Phe Gly Gln
Gly Thr Lys Leu Glu Ile Lys 100 105 11097123PRTHomo sapiens 97Gln
Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu
Glu 35 40 45Phe Ile Gly Ser Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn
Pro Ser 50 55 60Leu Arg Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys
Asn Gln Phe65 70 75 80Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp
Thr Ala Val Tyr Tyr 85 90 95Cys Ala Arg His Gly Pro Gly Met Gly His
Asn Trp Tyr Phe Asp Leu 100 105 110Trp Gly Arg Gly Thr Leu Val Thr
Val Ser Ser 115 12098106PRTHomo sapiens 98Glu Ile Val Leu Thr Gln
Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Asp Ala
Ser Asn Arg Ala Pro Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro65 70 75
80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Trp Leu Thr
85 90 95Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 10599125PRTHomo
sapiens 99Gln Leu Gln Leu Gln Glu Ser Gly Pro Arg Leu Val Lys Pro
Ser Glu1 5 10 15Thr Leu Phe Leu Thr Cys Thr Val Ser Gly Asp Ser Ile
Ser Ser Ser 20 25 30Ser Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly
Lys Gly Leu Glu 35 40 45Trp Ile Gly Ser Ile Ser Tyr Ser Gly Ser Thr
Tyr Tyr Asn Pro Ser 50 55 60Leu Lys Ser Arg Val Thr Ile Ser Val Asp
Thr Ser Lys Asn Gln Phe65 70 75 80Ser Leu Lys Leu Ser Ser Val Thr
Ala Ala Asp Thr Val Val Tyr Tyr 85 90 95Cys Ala Lys His Leu Tyr Ser
Ser Ser Trp Asn Ile Gly Ser Ser Phe 100 105 110Asp Ser Trp Gly Pro
Gly Thr Leu Val Thr Val Ser Ser 115 120 125100108PRTHomo sapiens
100Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1
5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ile
Tyr 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
Leu Ile 35 40 45Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Ala Arg
Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
Arg Ser Asn Trp Pro Val 85 90 95Tyr Thr Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 105101124PRTHomo sapiens 101Glu Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Tyr Thr Phe Ser Gly Tyr 20 25 30Tyr Ile His Trp
Leu Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile
Asn Ser Asn Ser Gly Gly Ala Asp Ser Gly Pro Arg Phe 50 55 60His Gly
Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr65 70 75
80Leu Glu Leu Thr Asn Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Arg Thr Tyr Tyr Asp Thr Arg Phe Pro Tyr Trp Tyr Phe
Asp 100 105 110Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115
120102107PRTHomo sapiens 102Ala Ile Arg Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Asp Ile Gly Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Asn Val Leu Ile 35 40 45Ser Ala Ala Ser Thr Leu Gln
Ser Gly Val Pro Ser Arg Ile Ser Gly 50 55 60Ile Gly Ser Gly Thr Asp
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln Ser Leu Ser Ala Pro Tyr 85 90 95Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile Lys 100 105103121PRTHomo sapiens 103Glu
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10
15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asn Thr Phe Met Gly Tyr
20 25 30Tyr Phe His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45Gly Trp Ile Asn Pro Asn Ser Gly His Ala Asn Ile Ala Gln
Thr Phe 50 55 60Gln Gly Arg Val Thr Met Thr Arg Asp Pro Ser Ile Thr
Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr
Ala Val Phe Tyr Cys 85 90 95Ala Arg Gly Gly Met Leu Gly Gln Leu Trp
Ala Leu Asp Asn Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120104107PRTHomo sapiens 104Asp Ile Gln Met Thr Gln Ser Pro
Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys
Arg Ala Ser Gln Ser Ile Ser His Trp 20 25 30Leu Ala Trp Tyr Gln Gln
Arg Pro Gly Glu Ala Pro Lys Leu Leu Ile 35 40 45Tyr Gln Ala Ser Thr
Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly
Thr Glu Phe Thr Leu Ser Ile Ser Ser Leu Gln Pro65 70 75 80Asp Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Gln Ser Ser Pro Tyr 85 90 95Thr
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105105121PRTHomo
sapiens 105Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Arg Pro
Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
Ala Asp Tyr 20 25 30Tyr Ile His Trp Val Arg Gln Ala Pro Gly Leu Gly
Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Lys Thr Gly Phe Ser His
Tyr Glu Gln Thr Phe 50 55 60Gln Gly Arg Val Thr Met Ala Arg Asp Thr
Ser Ile Pro Ala Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Lys Ser
Asp Asp Thr Ala Ile Tyr Tyr Cys 85 90 95Ala Arg Gly Gly Arg Ile Asn
Val Ala Glu Ala Leu Arg Tyr Trp Gly 100 105 110Gln Gly Ser Leu Val
Thr Val Ser Ser 115 120106107PRTHomo sapiens 106Asp Ile Gln Met Thr
Gln Ser Pro Ser Thr Leu Ser Thr Phe Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Thr Ile Gly Asp Trp 20 25 30Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Ser Lys
Ala Thr Arg Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser
Gly Ser Glu Thr Glu Phe Ser Leu Thr Ile Asn Ser Leu Gln Pro65 70 75
80Asp Asp Val Ala Ala Tyr Tyr Cys Gln Gln Tyr Met Ser Tyr Pro Trp
85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100
105107122PRTHomo sapiens 107Glu Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ser Tyr 20 25 30Ala Ile Ile Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Ile Phe
Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55 60Arg Gly Arg Val Thr Ile
Ala Thr Asp Ala Ser Lys Ser Ala Ala Tyr65 70 75 80Met Asp Leu Ser
Ser Leu Lys Ser Glu Asp Thr Ala Ile Tyr Tyr Cys 85
90 95Ala Arg Ser Trp Gly Thr Ala Ala Thr Gly Gly Ser Phe Val Gln
Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120108109PRTHomo sapiens 108Glu Ile Val Met Thr Gln Ser Pro Ala Thr
Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser His Ser Val Thr Ser Asn 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Gly Ala Ser Thr Arg Ala
Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Ser Ala
Val Tyr Tyr Cys Gln Tyr Tyr Thr Asn Trp Pro Pro 85 90 95His Val Ala
Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105109120PRTHomo
sapiens 109Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Thr Pro
Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Thr Ser Gly Gly Thr Phe
Ser Asn Phe 20 25 30Ala Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45Gly Gly Ile Ile Pro Leu Phe Gly Ile Thr Asn
Tyr Thr Gln Lys Phe 50 55 60Gln Gly Arg Val Thr Ile Thr Thr Asp Glu
Ser Lys Thr Thr Ala Tyr65 70 75 80Met Asp Leu Ser Gly Leu Arg Ser
Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Ala Arg Gly Arg Asp Ser Ser
Gly Arg Leu Leu Asp His Trp Gly Gln 100 105 110Gly Thr Leu Val Thr
Val Ser Ser 115 120110108PRTHomo sapiens 110Glu Ile Val Met Thr Gln
Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln Thr Val Asn Arg Asn 20 25 30Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45Tyr Ala Ala
Ser Ala Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75
80Glu Asp Phe Val Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Pro
85 90 95Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100
105111124PRTHomo sapiens 111Gln Val Gln Leu Gln Glu Ser Gly Pro Gly
Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser
Gly Gly Ser Ile Ser Ser Tyr 20 25 30Tyr Trp Ser Trp Ile Arg Gln Pro
Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Phe Ile Tyr Tyr Ser Gly
Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60Ser Arg Val Thr Ile Ser
Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser
Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Gly Asp
Tyr Tyr Tyr Asp Ser Ser Gly Tyr Leu Tyr Tyr Phe Asp 100 105 110Tyr
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120112107PRTHomo
sapiens 112Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
Ser Ser Ser 20 25 30Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile
Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr
Cys Gln Gln Tyr Gly Thr Ser Val 85 90 95Thr Phe Gly Gly Gly Thr Lys
Val Glu Ile Lys 100 105113117PRTHomo sapiens 113Glu Val Gln Leu Val
Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Ser 20 25 30Thr Ile His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45Val Val
Ile Ser His Asp Gly Asn Thr Lys Tyr Tyr Ala Asp Ser Val 50 55 60Lys
Gly Arg Phe Ile Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Phe65 70 75
80Leu Gln Met Asn Ser Leu Arg Pro Val Asp Thr Ala Val Tyr Tyr Cys
85 90 95Ala Arg Gly Glu Val Gly Tyr Phe Asp Leu Trp Gly Arg Gly Thr
Leu 100 105 110Val Thr Val Ser Ser 115114108PRTHomo sapiens 114Glu
Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10
15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Phe
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Arg Leu Leu
Ile 35 40 45Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg
Ser Asn Trp Pro Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu
Ile Lys 100 105115120PRTHomo sapiens 115Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Ser Phe Ser Ser His 20 25 30Ala Met Tyr Trp Val
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Ile Val Ser
Tyr Asp Gly Ser Thr Lys Asn Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ile Tyr65 70 75 80Leu
His Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90
95Ala Arg Glu Val Asp Gly Ile Tyr Gly Tyr Leu His Tyr Trp Gly Gln
100 105 110Gly Thr Leu Val Thr Val Ser Ser 115 120116106PRTHomo
sapiens 116Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser
Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Arg Gln Asn Val
Arg Asn Phe 20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
Arg Leu Leu Ile 35 40 45Tyr Asp Ala Ser Asn Arg Ala Thr Asp Ile Pro
Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Glu Pro65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys
Gln Gln Arg Ser Tyr Ser Ile Thr 85 90 95Phe Gly Gln Gly Thr Arg Leu
Glu Ile Lys 100 105117101PRTZika virus 117Val Ser Tyr Ser Leu Cys
Thr Ala Ala Phe Thr Phe Thr Lys Ile Pro1 5 10 15Ala Glu Thr Leu His
Gly Thr Val Thr Val Glu Val Gln Tyr Ala Gly 20 25 30Thr Asp Gly Pro
Cys Lys Val Pro Ala Gln Met Ala Val Asp Met Gln 35 40 45Thr Leu Thr
Pro Val Gly Arg Leu Ile Thr Ala Asn Pro Val Ile Thr 50 55 60Glu Ser
Thr Glu Asn Ser Lys Met Met Leu Glu Leu Asp Pro Pro Phe65 70 75
80Gly Asp Ser Tyr Ile Val Ile Gly Val Gly Glu Lys Lys Ile Thr His
85 90 95His Trp His Arg Ser 10011898PRTDengue virus 1 118Met Ser
Tyr Val Met Cys Thr Gly Ser Phe Lys Leu Glu Lys Glu Val1 5 10 15Ala
Glu Thr Gln His Gly Thr Val Leu Val Gln Val Lys Tyr Glu Gly 20 25
30Thr Asp Ala Pro Cys Lys Ile Pro Phe Ser Ser Gln Asp Glu Lys Gly
35 40 45Val Thr Gln Asn Gly Arg Leu Ile Thr Ala Asn Pro Ile Val Thr
Asp 50 55 60Lys Glu Lys Pro Val Asn Ile Glu Ala Glu Pro Pro Phe Gly
Glu Ser65 70 75 80Tyr Ile Val Val Gly Ala Gly Glu Lys Ala Leu Lys
Leu Ser Trp Phe 85 90 95Lys Lys11924PRTHomo sapiens 119Met Pro Met
Gly Ser Leu Gln Pro Leu Ala Thr Leu Tyr Leu Leu Gly1 5 10 15Met Leu
Val Ala Ser Cys Leu Gly 2012021PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptide 120His His His His His His
Gly Leu Asn Asp Ile Phe Glu Ala Gln Lys1 5 10 15Ile Glu Trp His Glu
20121303DNAZika virus 121gtgtcatact ccttgtgtac cgcagcgttc
acattcacca agatcccggc tgaaacactg 60cacgggacag tcacagtgga ggtacagtac
gcagggacag atggaccttg caaggttcca 120gctcagatgg cggtggacat
gcaaactctg accccagttg ggaggttgat aaccgctaac 180cccgtaatca
ctgaaagcac tgagaactct aagatgatgc tggaacttga tccaccattt
240ggggactctt acattgtcat aggagtcggg gagaagaaga tcacccacca
ctggcacagg 300agt 303122294DNAArtificial SequenceDescription of
Artificial Sequence Synthetic polynucleotide 122atgtcatatg
tgatgtgtac ggggtccttt aaacttgaaa aggaggtggc agaaacacag 60cacggaacag
tacttgtgca ggttaaatat gagggaaccg atgctccttg taaaataccg
120ttttcaagcc aggacgaaaa gggtgtaaca caaaatggtc gcctgattac
agccaaccca 180atagtcactg ataaggagaa acctgtgaat atcgaggcag
agccaccatt cggcgaaagt 240tatatcgtag ttggtgctgg agaaaaggcc
ctgaaactct cttggtttaa gaag 294123294DNADengue virus 2 123atgtcatact
ctatgtgcac aggaaagttt aaagttgtga aggaaatagc agaaacacaa 60catggaacaa
tagttatcag agtgcaatat gaaggggacg gctctccatg caagatccct
120tttgagataa tggatttgga aaaaagacat gtcttaggtc gcctgattac
agtcaaccca 180attgtgacag aaaaagatag cccagtcaac atagaagcag
aacctccatt cggagacagc 240tacatcatca taggagtaga gccgggacaa
ctgaagctca actggtttaa gaaa 294124294DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
124atgtcatacg caatgtgtac gaacacattc gttcttaaaa aagaggtaag
tgaaacccaa 60catggtacta tccttataaa agttgagtac aagggcgagg acgctccctg
caaaataccg 120ttttccacag aggacgggca aggtaaggca cacaatggga
gacttataac cgccaatcca 180gtagtgacca agaaagagga accagtcaac
attgaagcgg agcccccttt cggagaatcc 240aacatagtga taggcattgg
ggacaacgct ctgaagatca actggtataa gaag 294125294DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
125atgtcatata caatgtgtag cggtaaattc agcattgata aagaaatggc
cgagacacag 60cacggcacca ccgtggtaaa agtgaaatac gaaggagcgg gagccccgtg
caaggtcccc 120atcgaaatca gggatgtaaa caaagagaag gtcgttggta
gaataatttc ttctacacca 180ctggccgaga acactaattc agttacgaat
atagaacttg agcccccctt tggtgacagc 240tatatagtta ttggcgtggg
aaattctgca ctgactctgc attggttccg aaaa 294126294DNAYellow fever
virus 126acatcctaca aaatgtgcac tgacaaaatg tcttttgtca agaacccaac
tgacactggc 60catggcactg ttgtgatgca ggtgaaagtg ccaaaaggag ccccctgcaa
gattccagtg 120atagtagctg atgatcttac agcggcaatc aataaaggca
ttttggttac agttaacccc 180atcgcctcaa ccaatgatga tgaagtgctg
attgaggtga acccaccttt tggagacagc 240tacattatcg ttgggacagg
agattcacgt ctcacttacc agtggcacaa agag 294127294DNAYellow fever
virus 127acatcctaca aaatatgcac tgacaaaatg ttttttgtca agaacccaac
tgacactggc 60catggcactg ttgtgatgca ggtgaaagtg tcaaaaggag ccccctgcag
gattccagtg 120atagtagctg atgatcttac agcggcaatc aataaaggca
ttttggttac agttaacccc 180atcgcctcaa ccaatgatga tgaagtgctg
attgaggtga acccaccttt tggagacagc 240tacattatcg ttgggagagg
agattcacgt ctcacttacc agtggcacaa agag 294128303DNAWest Nile virus
128acaacctatg gcgtctgttc aaaggctttc aagtttcttg ggactcccgc
agacacaggt 60cacggcactg tggtgttgga attgcagtac actggcacgg atggaccttg
caaagttcct 120atctcgtcag tggcttcatt gaacgaccta acgccagtgg
gcagattggt cactgtcaac 180ccttttgttt cagtggccac ggccaacgct
aaggtcctga ttgaattgga accacccttt 240ggagactcat acatagtggt
gggcagagga gaacaacaga tcaatcacca ctggcacaag 300tct
303129367DNAArtificial SequenceDescription of Artificial Sequence
Synthetic polynucleotide 129gaggtgcagc tgttggagtc tgggggaggt
cttgttcagc cgggtggatc attgagactt 60tcttgtgctg caagtggatt tactttctct
tcctacgcca tgtcttgggt tcgacaagct 120ccagggaaag gactcgaatg
ggttagtgcg atatctgggt ctggaggatc tacttactac 180gcagattcag
taaaagggcg cttcacaata tcacgcgata attccaagaa tacgctctac
240cttcagatga acagtcttcg ggcagaggac acagcggttt attattgtgc
gaaagatcgc 300ggtcccagag gcgtgggcga actgttcgac tattggggac
aaggcaccct ggtcaccgtc 360tcctcag 367130322DNAArtificial
SequenceDescription of Artificial Sequence Synthetic polynucleotide
130gacatccaga tgacccagtc accgtctacc ttgtcagcgt cagttggtga
ccgggtaacc 60attacttgcc gcgctagtca gagtatttcc tcctggctcg cctggtatca
acaaaaacca 120ggtaaagccc ccaaattgct gatctataag gcaagtagct
tggaatcagg agttcccagc 180cgcttctctg gctcagggtc cggtactgaa
tttacattga ccatctcttc tctccagcca 240gatgacttcg ccacgtacta
ttgtcaacag tataactcat atccctggac ttttggacag 300gggaccaagg
tggaaatcaa ac 322131115PRTHomo sapiens 131Gly Gly Gly Leu Ile Gln
Pro Gly Gly Thr Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Ser
Phe Thr Asn Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Ala Ile Thr Gly Asp Gly 35 40 45Glu Ser Thr
Tyr Tyr Ser Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Thr65 70 75
80Ala Asp Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Arg Pro Arg Gln
85 90 95Gly Val Gly Glu Leu Tyr Asp Ser Trp Gly Gln Gly Thr Leu Val
Thr 100 105 110Val Ser Ser 115132115PRTHomo sapiens 132Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser
Gly Phe Thr Phe Ser Ala Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Val Gln Ser 35 40
45Asp Ser Thr Tyr Phe Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
Arg65 70 75 80Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Arg
Leu Glu Lys 85 90 95Gly Ile Gly Glu Leu Phe His Ser Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110Val Ser Ser 115133115PRTHomo sapiens
133Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Phe Thr Phe Ser Ala Tyr Ala Met Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Val
Gln Ser 35 40 45Asp Ser Thr Tyr Leu Ala Asp Ser Val Lys Gly Arg Phe
Thr Thr Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
Asn Ser Leu Arg65 70 75 80Val Glu Asp Thr Ala Leu Tyr Tyr Cys Ala
Lys Asp Arg Leu Arg Gln 85 90 95Gly Val Gly Glu Leu Phe His Ser Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115134115PRTHomo
sapiens 134Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Gly Ala Tyr Ala Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
Ser Val His Ser 35 40 45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Arg Gly
Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr Ala Leu Tyr Tyr
Cys Ala Lys Asp Arg Leu Arg Glu 85 90 95Gly Val Gly Glu Leu Tyr Gln
Tyr Trp Gly His Gly Thr Leu Val Thr 100 105 110Val Ser Ser
115135115PRTHomo sapiens 135Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ala Tyr
Ala Met Ser Trp Val Arg Gln
20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asn Gly His
Ser 35 40 45Asp Ser Thr Tyr Phe Ala Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
Ser Leu Arg65 70 75 80Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys
Asp Arg Leu Arg Glu 85 90 95Gly Ile Gly Glu Leu Phe His Ser Trp Gly
Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115136112PRTHomo
sapiens 136Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Gly Ser Gly Phe Thr Phe Ser Ser Phe Ala Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile
Thr Gly Ile Gly 35 40 45Gly Asp Thr Tyr Tyr Thr Asp Ser Val Lys Gly
Arg Phe Thr Val Ser 50 55 60Arg Asp Asn Ser Lys Lys Thr Val Phe Leu
His Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr Ala Val Tyr Tyr
Cys Ala Lys Asp Arg Asp His Phe 85 90 95Asp Gly His Asp Val Trp Gly
Gln Gly Thr Met Val Thr Val Ser Ser 100 105 110137114PRTHomo
sapiens 137Gly Ala Gly Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Tyr Ile Phe Ser Asp Tyr Tyr Met Gln Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Gln Trp Met Gly Trp Ile
Asn Pro Lys Ser 35 40 45Gly Phe Thr Asn Tyr Ala Gln Lys Phe Gln Gly
Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met
Glu Leu Thr Gly Leu Thr65 70 75 80Ser Asp Asp Thr Ala Ile Tyr Tyr
Cys Ala Arg Gly Gly Pro Val Asn 85 90 95Ala Pro Arg Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser138114PRTHomo
sapiens 138Gly Ala Gly Val Lys Ile Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Tyr Ile Phe Ser Asp Tyr Tyr Met Gln Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Lys Ser 35 40 45Gly Phe Ser Asp Tyr Ala Gln Lys Phe Gln Gly
Arg Val Ser Met Thr 50 55 60Arg Asp Thr Ala Ile Ser Thr Ala Tyr Met
Glu Leu Thr Arg Leu Thr65 70 75 80Ser Asp Asp Thr Ala Val Tyr Tyr
Cys Ala Arg Gly Gly Pro Val Asn 85 90 95Ser Pro Leu Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser139114PRTHomo
sapiens 139Gly Pro Gly Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Tyr Ile Phe Ser Asp Tyr Tyr Ile Leu Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Tyr Met Gly Trp Met
Asn Pro Ile Ser 35 40 45Gly Phe Thr His Tyr Ala Gln Asn Phe Gln Gly
Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met
Glu Leu Thr Arg Leu Ala65 70 75 80Ser Asp Asp Thr Ala Val Tyr Tyr
Cys Ala Arg Gly Gly Arg Ile Asn 85 90 95Ser Pro Leu Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser140114PRTHomo
sapiens 140Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Val Ser Gly Tyr Thr Phe Thr Gly Tyr Tyr Met Gln Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Lys Thr 35 40 45Gly His Thr Asn Phe Ala Gln Lys Phe Gln Gly
Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Ile Ser Thr Ala Tyr Met
Glu Leu Ala Arg Leu Thr65 70 75 80Ser Asp Asp Thr Ala Val Tyr Phe
Cys Ala Arg Gly Gly Gln Ile Ser 85 90 95Ala Pro His Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser141114PRTHomo
sapiens 141Gly Ala Gly Met Arg Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Tyr Ser Phe Asn Asp Tyr Tyr Ile His Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Lys Ser 35 40 45Gly Phe Thr Asn Tyr Ala Gln Arg Phe Gln Gly
Arg Val Thr Met Thr 50 55 60Gly Asp Thr Ser Asn Ser Val Ala Tyr Met
Glu Leu Thr Arg Leu Thr65 70 75 80Ser Asp Asp Thr Ala Val Tyr Tyr
Cys Ala Arg Gly Gly Arg Ile Asn 85 90 95Ala Pro Leu Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser142114PRTHomo
sapiens 142Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Val Ser Gly Tyr Thr Phe Ser Asp Tyr Tyr Met Gln Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Lys Thr 35 40 45Gly His Thr Asn Phe Ala Gln Lys Phe Gln Gly
Arg Val Thr Val Thr 50 55 60Arg Asp Thr Ser Ile Thr Thr Ala Tyr Met
Glu Leu Arg Thr Leu Thr65 70 75 80Ser Asp Asp Thr Ala Val Tyr Phe
Cys Ala Arg Gly Gly Pro Ile Ser 85 90 95Ala Pro Leu Gly Phe Asp Pro
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser143120PRTHomo
sapiens 143Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Ala Tyr Ser Phe Thr Asp Tyr Tyr Ile His Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Gln Trp Met Gly Trp Ile
Asn Pro Asp Ser 35 40 45Gly Glu Val Asn Tyr Val Gln Lys Phe Gln Asp
Arg Val Thr Met Thr 50 55 60Arg Gly Thr Ser Ile Ser Thr Ala Tyr Met
Glu Leu Arg Arg Leu Arg65 70 75 80Ser Asp Asp Thr Ala Val Tyr Tyr
Cys Ala Arg Ala Ala Met Asn Arg 85 90 95Ile Ser Gly Val Val Pro Pro
Gly Asp Ala Phe Asp Leu Trp Gly Gln 100 105 110Gly Thr Leu Val Thr
Val Ser Ser 115 120144117PRTHomo sapiens 144Gly Ala Glu Val Lys Lys
Pro Gly Ala Ser Val Lys Leu Ser Cys Lys1 5 10 15Ser Ser Gly Tyr Ser
Phe Thr Ser Tyr Tyr Met His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln
Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Gly 35 40 45Val Phe Thr
Ser Tyr Ala Gln Arg Phe Gln Gly Arg Val Thr Met Thr 50 55 60Ser Asp
Thr Ala Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75
80Ser Gly Asp Thr Ala Val Tyr Tyr Cys Thr Arg Ser Leu Val Thr Pro
85 90 95Ala Ala Gln Ser Val Gln Tyr Phe Asp Ser Trp Gly Gln Gly Thr
Leu 100 105 110Ile Thr Val Ser Ser 115145117PRTHomo sapiens 145Gly
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Leu Ser Cys Lys1 5 10
15Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Tyr Val His Trp Val Arg Gln
20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Gly
Asn 35 40 45Asn Phe Val Ser Phe Ala Gln Asn Phe Tyr Asp Arg Ala Thr
Met Thr 50 55 60Arg Asp Thr Ser Thr Asn Thr Val Tyr Met Glu Leu Thr
Asn Leu Gln65 70 75 80Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
Thr Leu Val Ala Pro 85 90 95Ser Ala Gln Ser Met Tyr Tyr Phe Asp Phe
Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser
115146117PRTHomo sapiens 146Gly Ser Glu Val Lys Lys Pro Gly Ala Ser
Val Lys Leu Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
Tyr Ile His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp
Val Gly Val Ile Asn Pro Gly Asn 35 40 45Val Phe Thr Ser Tyr Ala Gln
Arg Phe His Asp Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Thr Ser
Thr Val Tyr Met Glu Met Ser Ser Leu Arg65 70 75 80Ser Glu Asp Thr
Ala Val Tyr Tyr Cys Thr Arg Thr Gln Val Val Pro 85 90 95Ser Ala Gln
Ser Val Tyr Tyr Phe Asp Phe Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115147117PRTHomo sapiens 147Gly Ala Glu Val Lys Lys
Pro Gly Thr Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr
Phe Thr Ser Tyr Tyr Ile His Trp Val Arg Glu 20 25 30Ala Pro Gly Gln
Gly Leu Glu Trp Val Gly Ile Ile Asn Pro Gly Asn 35 40 45Thr Phe Thr
Ser Tyr Ala Pro Arg Phe His Gly Arg Val Ser Met Thr 50 55 60Arg Asp
Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75
80Ser Glu Asp Thr Ala Val Tyr Tyr Cys Thr Arg Thr Arg Val Val Pro
85 90 95Ser Ala Gln Ser Val Tyr Tyr Phe Asp Phe Trp Gly Gln Gly Thr
Leu 100 105 110Val Thr Val Ser Ser 115148117PRTHomo sapiens 148Gly
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys1 5 10
15Thr Ser Gly Phe Thr Phe Thr Ser Tyr Tyr Ile His Trp Val Arg Gln
20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Phe Ile Asn Pro Thr
Ser 35 40 45Gly Phe Thr Ser Tyr Thr Gln Asn Leu His Gly Arg Val Thr
Met Thr 50 55 60Arg Asp Thr Ser Thr Arg Thr Val Phe Met Glu Leu Arg
Ser Leu Ala65 70 75 80Ser Gly Asp Thr Ala Val Tyr Tyr Cys Thr Arg
Thr Gln Ile Ile Pro 85 90 95Ala Ala Gln Ser Val Tyr Phe Phe Asp Tyr
Trp Gly Pro Gly Thr Leu 100 105 110Val Thr Val Ser Ser
115149117PRTHomo sapiens 149Gly Ala Glu Val Ala Lys Pro Gly Thr Ser
Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
Tyr Ile His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp
Val Gly Ile Ile Asn Pro Gly Gly 35 40 45Ala Phe Thr Ser Tyr Ala Gln
Arg Phe His Gly Arg Val Arg Met Thr 50 55 60Arg Asp Thr Ser Ala Ser
Thr Val Tyr Val Glu Leu Ser Ser Leu Arg65 70 75 80Ser Asp Asp Thr
Ala Val Tyr Tyr Cys Thr Arg Thr Arg Ile Ile Ala 85 90 95Ala Ala Gln
Ser Val Tyr His Tyr Asp Leu Trp Gly Gln Gly Thr Leu 100 105 110Val
Thr Val Ser Ser 115150117PRTHomo sapiens 150Gly Ala Glu Val Lys Lys
Pro Gly Ala Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr
Phe Ser Ser Tyr Tyr Ile His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln
Gly Leu Glu Trp Met Gly Ile Ile Lys Pro Ser Ser 35 40 45Gly Ser Thr
Asn Tyr Ala His Lys Phe Gln Asp Arg Val Thr Met Thr 50 55 60Thr Asp
Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75
80Tyr Gln Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gln Asp Pro Ala
85 90 95Thr Ala Ile Arg Gly Leu Arg Trp Glu Tyr Trp Gly Gln Gly Ser
Leu 100 105 110Val Thr Val Ser Ser 115151117PRTHomo sapiens 151Gly
Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys1 5 10
15Ala Ser Gly Tyr Thr Phe Thr Thr Tyr Phe Ile His Trp Val Arg Gln
20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Asn
Ser 35 40 45Gly Ser Thr Asn Tyr Ala Gln Lys Ile Gln Gly Arg Val Thr
Met Thr 50 55 60Thr Asp Thr Ser Ala Ser Thr Val Tyr Met Glu Leu Ser
Gly Leu Arg65 70 75 80Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
Gly Gly Ser Tyr Pro 85 90 95Val Ala Ile Arg Gly Val Thr Phe Gly Ile
Trp Gly Gln Gly Thr Met 100 105 110Val Thr Val Ser Ser
115152117PRTHomo sapiens 152Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
Val Arg Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
Tyr Met His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp
Met Gly Ile Ile Asn Pro Ser Ser 35 40 45Gly Ser Thr Ser Tyr Ala Gln
Lys Leu His Asp Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Thr Ser
Thr Val Tyr Met Glu Met Ser Ser Leu Arg65 70 75 80Ser Glu Asp Thr
Ala Val Tyr Tyr Cys Ala Arg Gly Ala Ala Tyr Pro 85 90 95Thr Ala Ile
Arg Gly Val Ile Tyr Gly Phe Trp Gly Gln Gly Thr Met 100 105 110Val
Thr Val Ser Ser 115153118PRTHomo sapiens 153Gly Ala Glu Val Lys Lys
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys1 5 10 15Ala Ser Ala Asp Thr
Phe Thr Lys Asn Tyr Val His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln
Gly Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Ser 35 40 45Gly Trp Thr
Ser Asn Pro Gln Lys Phe Gln Gly Arg Val Thr Met Thr 50 55 60Arg Asp
Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75
80Ser Asp Asp Thr Ala Leu Tyr Tyr Cys Ala Thr Ser Pro Ala Ala Ala
85 90 95Gly Ser Gly His Pro Ser Gly Trp Phe Asp Pro Trp Gly Pro Gly
Thr 100 105 110Leu Val Thr Val Ser Ser 115154114PRTHomo sapiens
154Gly Ala Glu Met Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Gln1
5 10 15Ala Ser Gly Tyr Ser Phe Thr Asn His Phe Ile His Trp Val Arg
Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Thr Ile Asn Pro
Ser Gly 35 40 45Gly Ser Thr Thr Phe Ala Gln Lys Phe Gln Gly Arg Val
Thr Met Thr 50 55 60Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu
Ser Ser Leu Arg65 70 75 80Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
Arg Pro Pro Gly Arg Ser 85 90 95Phe Leu Asp Gly Met Asp Val Trp Gly
Gln Gly Thr Thr Val Thr Val 100 105 110Ser Ser155115PRTHomo sapiens
155Gly Ala Gly Leu Leu Lys Thr Ser Glu Thr Leu Tyr Leu Thr Cys Thr1
5 10 15Val Tyr Gly Asp Ser Phe Asn His Tyr Tyr Trp Gly Trp Ile Arg
Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Glu Ile Asn His
Arg Gly 35 40 45Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Ser
Ile Leu Val 50 55 60Asp Thr Ser Gln Lys Gln Phe Ser Leu Arg Val Thr
Ser Val Thr Ala65 70 75 80Ala Asp Thr Ser Val Tyr Tyr Cys Thr Arg
Val Arg Trp Asp Gly Ile 85 90 95Glu Phe Thr Met Phe Phe Asp Ser Trp
Gly Gln Gly Ser Leu Val Thr 100 105 110Val Ser Pro 115156115PRTHomo
sapiens 156Gly Ala Gly Leu Leu Lys Thr Ser Glu Thr Leu Tyr Leu Thr
Cys Thr1 5 10 15Val Tyr Gly Asp Ser Phe Asn His Tyr Tyr Trp Gly Trp
Ile Arg Gln 20
25 30Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Glu Ile Asn His Arg
Gly 35 40 45Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Ser Ile
Leu Val 50 55 60Asp Thr Ser His Lys Gln Phe Ser Leu Arg Val Thr Ser
Val Thr Ala65 70 75 80Ala Asp Thr Ser Val Tyr Tyr Cys Ala Arg Val
Arg Trp Asp Gly Ile 85 90 95Glu Ser Thr Met Phe Phe Asp Ser Trp Gly
Gln Gly Ser Leu Val Thr 100 105 110Val Ser Pro 115157115PRTHomo
sapiens 157Gly Ala Gly Leu Leu Lys Thr Ser Glu Thr Leu Tyr Leu Thr
Cys Thr1 5 10 15Val Tyr Gly Asp Ser Phe Asn His Tyr Tyr Trp Gly Trp
Ile Arg Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Glu Ile
Asn His Arg Gly 35 40 45Thr Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg
Val Ser Ile Leu Val 50 55 60Asp Thr Ser Gln Lys Gln Phe Ser Leu Arg
Val Thr Ser Val Thr Ala65 70 75 80Ala Asp Thr Ser Val Tyr Tyr Cys
Thr Arg Val Arg Trp Asp Gly Ile 85 90 95Glu Ser Thr Met Phe Phe Asp
Ser Trp Gly Gln Gly Ser Leu Val Thr 100 105 110Val Ser Pro
115158123PRTHomo sapiens 158Gly Ala Arg Pro Leu Lys Pro Ser Glu Thr
Leu Ser Leu Thr Cys Gly1 5 10 15Val Asn Gly Gly Ser Phe Ser Gly Tyr
His Trp Ser Trp Ile Arg Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp
Ile Gly Glu Ile Asp His Asn Gly 35 40 45Arg Ile Asn Tyr Asn Pro Ser
Leu Lys Ser Arg Val Thr Ile Ser Ile 50 55 60Asp Thr Phe Lys Ser Gln
Phe Ser Leu Arg Leu Thr Ser Ile Ile Ala65 70 75 80Ala Asp Thr Ala
Val Tyr Tyr Cys Ala Arg Asp Val Val Thr Met Val 85 90 95Glu Gly Leu
Arg Phe His Tyr Tyr Tyr Asn Tyr Tyr Gly Met Asp Val 100 105 110Trp
Gly Gln Gly Thr Pro Val Thr Val Ser Ser 115 120159123PRTHomo
sapiens 159Gly Ala Arg Pro Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr
Cys Gly1 5 10 15Val Asn Gly Gly Ser Phe Ser Gly Tyr His Trp Thr Trp
Ile Arg Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile
Asp His Asn Gly 35 40 45Arg Ile Asn Tyr Asn Pro Ser Leu Lys Ser Arg
Val Thr Ile Ser Ile 50 55 60Asp Thr Phe Lys Ser Gln Phe Ser Leu Arg
Leu Thr Ser Ile Thr Ala65 70 75 80Ala Asp Thr Ala Ile Tyr Tyr Cys
Ala Arg Asp Val Val Thr Met Val 85 90 95Glu Gly Leu Arg Phe His Tyr
Tyr Tyr Asn Tyr Tyr Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr
Pro Val Thr Val Ser Ser 115 120160123PRTHomo sapiens 160Gly Ala Arg
Pro Leu Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Gly1 5 10 15Val Asn
Gly Gly Ser Phe Ser Gly Tyr His Trp Ser Trp Ile Arg Gln 20 25 30Pro
Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile Asp His Asn Gly 35 40
45Arg Ile Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Met Ser Ile
50 55 60Asp Thr Phe Lys Ser Gln Phe Ser Leu Arg Leu Thr Ser Ile Thr
Ala65 70 75 80Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Val Val
Thr Met Val 85 90 95Glu Gly Leu Arg Phe His Tyr Tyr Tyr Asn Tyr Tyr
Gly Met Asp Val 100 105 110Trp Gly Gln Gly Thr Pro Val Thr Val Ser
Ser 115 120161111PRTHomo sapiens 161Gly Pro Gly Leu Val Lys Pro Ser
Glu Thr Leu Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Gly Ser Ile Ser
Thr Tyr Tyr Trp Ser Trp Ile Arg Gln 20 25 30Thr Pro Gly Lys Gly Leu
Glu Trp Ile Gly Cys Ile Tyr Tyr Ser Val 35 40 45Asp Thr His Phe Asn
Pro Ser Leu Glu Ser Arg Val Thr Ile Ser Val 50 55 60Asp Thr Ser Lys
Asn Gln Phe Ser Leu Lys Met Thr Ser Met Thr Ala65 70 75 80Ala Asp
Thr Ala Val Tyr Tyr Cys Ala Arg Asn Gln Pro Gly Gly Arg 85 90 95Ala
Phe Asp Tyr Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105
110162111PRTHomo sapiens 162Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
Leu Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Gly Ser Ile Asp Thr Tyr
Tyr Trp Ser Trp Ile Arg Gln 20 25 30Thr Pro Gly Lys Gly Leu Glu Trp
Ile Gly Cys Phe Tyr Tyr Ser Val 35 40 45Asp Asn His Phe Asn Pro Ser
Leu Glu Ser Arg Val Thr Ile Ser Val 50 55 60Asp Thr Ser Lys Asn Gln
Phe Ser Leu Lys Met Thr Ser Met Thr Ala65 70 75 80Ser Asp Thr Ala
Val Tyr Tyr Cys Ala Arg Asn Gln Pro Gly Gly Arg 85 90 95Ala Phe Asp
Tyr Trp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105
110163121PRTHomo sapiens 163Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
Leu Arg Ile Ser Cys Lys1 5 10 15Thr Ser Gly Tyr Thr Phe Thr Ser His
Trp Leu Ala Trp Val Arg Gln 20 25 30Met Pro Gly Lys Gly Leu Glu Trp
Met Gly Ile Ile Tyr Pro Gly Asp 35 40 45Ser Asp Thr Arg Tyr Ser Pro
Ser Phe Gln Gly Gln Ile Ser Ile Ser 50 55 60Ala Asp Lys Ser Ile Asn
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys65 70 75 80Ala Ser Asp Thr
Ala Ile Tyr Tyr Cys Ala Arg His Asp Gly Arg Gly 85 90 95Tyr Cys Ser
Pro Thr Arg Cys Phe Phe Ser Gly Met Asp Val Trp Gly 100 105 110Gln
Gly Thr Thr Val Ile Val Ser Pro 115 120164121PRTHomo sapiens 164Gly
Ala Glu Val Arg Lys Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys1 5 10
15Thr Ser Gly Tyr Thr Phe Thr Ser His Trp Val Ala Trp Val Arg Gln
20 25 30Met Pro Gly Lys Gly Leu Glu Trp Met Gly Ile Ile Tyr Pro Gly
Asp 35 40 45Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Ile Ser
Ile Ser 50 55 60Ala Asp Lys Ser Ile Asn Thr Ala Tyr Leu Gln Trp Ser
Ser Leu Lys65 70 75 80Ala Ser Asp Thr Gly Ile Tyr Tyr Cys Ala Arg
His Asp Gly Arg Gly 85 90 95Tyr Cys Ser Pro Thr Arg Cys Phe Phe Ser
Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Ile Val Ser
Pro 115 120165117PRTHomo sapiens 165Gly Ala Glu Val Lys Lys Pro Gly
Ala Ser Val Arg Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Ser
Asp Tyr Tyr Val His Trp Leu Arg Gln 20 25 30Ala Pro Gly Gln Arg Leu
Glu Trp Met Gly Trp Ile Asn Ala Asn Thr 35 40 45Gly Gly Ser Asp Ser
Gly Pro Lys Phe Tyr Gly Arg Val Thr Leu Thr 50 55 60Arg Asp Thr Ser
Val Asn Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg65 70 75 80Ser Asp
Asp Thr Ala Val Tyr Phe Cys Ala Arg Arg Thr Tyr Tyr Asp 85 90 95Asn
Arg Phe Pro Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105
110Val Thr Val Ser Ser 115166117PRTHomo sapiens 166Gly Ala Glu Val
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly
Tyr Thr Phe Ser Gly Tyr Tyr Ile His Trp Leu Arg Gln 20 25 30Ala Pro
Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Ser Asn Ser 35 40 45Gly
Gly Ala Asp Ser Gly Pro Arg Phe His Gly Arg Val Thr Met Thr 50 55
60Arg Asp Thr Ser Ile Asn Thr Ala Tyr Leu Glu Leu Thr Asn Leu Arg65
70 75 80Ser Asp Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Thr Tyr Tyr
Asp 85 90 95Thr Arg Phe Pro Tyr Trp Tyr Phe Asp Leu Trp Gly Arg Gly
Thr Leu 100 105 110Val Thr Val Ser Ser 115167115PRTHomo sapiens
167Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys1
5 10 15Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ile Trp Val Arg
Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Ile Pro
Ile Phe 35 40 45Gly Thr Thr Asn Tyr Ala Gln Lys Phe Arg Gly Arg Val
Thr Ile Ala 50 55 60Thr Asp Ala Ser Lys Ser Ala Ala Tyr Met Asp Leu
Ser Ser Leu Lys65 70 75 80Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
Arg Ser Trp Gly Thr Ala 85 90 95Ala Thr Gly Gly Ser Phe Val Gln Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115168113PRTHomo
sapiens 168Gly Ala Glu Val Lys Thr Pro Gly Ser Ser Val Lys Val Ser
Cys Lys1 5 10 15Thr Ser Gly Gly Thr Phe Ser Asn Phe Ala Ile Thr Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly Ile
Ile Pro Leu Phe 35 40 45Gly Ile Thr Asn Tyr Thr Gln Lys Phe Gln Gly
Arg Val Thr Ile Thr 50 55 60Thr Asp Glu Ser Lys Thr Thr Ala Tyr Met
Asp Leu Ser Gly Leu Arg65 70 75 80Ser Glu Asp Thr Ala Val Tyr Phe
Cys Ala Arg Gly Arg Asp Ser Ser 85 90 95Gly Arg Leu Leu Asp His Trp
Gly Gln Gly Thr Leu Val Thr Val Ser 100 105 110Ser169114PRTHomo
sapiens 169Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Asn Thr Phe Met Gly Tyr Tyr Phe His Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Asn Ser 35 40 45Gly His Ala Asn Ile Ala Gln Thr Phe Gln Gly
Arg Val Thr Met Thr 50 55 60Arg Asp Pro Ser Ile Thr Thr Ala Tyr Met
Glu Leu Ser Arg Leu Arg65 70 75 80Ser Asp Asp Thr Ala Val Phe Tyr
Cys Ala Arg Gly Gly Met Leu Gly 85 90 95Gln Leu Trp Ala Leu Asp Asn
Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110Ser Ser170114PRTHomo
sapiens 170Gly Ala Glu Val Lys Arg Pro Gly Ala Ser Val Lys Val Ser
Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Ala Asp Tyr Tyr Ile His Trp
Val Arg Gln 20 25 30Ala Pro Gly Leu Gly Leu Glu Trp Met Gly Trp Ile
Asn Pro Lys Thr 35 40 45Gly Phe Ser His Tyr Glu Gln Thr Phe Gln Gly
Arg Val Thr Met Ala 50 55 60Arg Asp Thr Ser Ile Pro Ala Ala Tyr Met
Glu Leu Ser Ser Leu Lys65 70 75 80Ser Asp Asp Thr Ala Ile Tyr Tyr
Cys Ala Arg Gly Gly Arg Ile Asn 85 90 95Val Ala Glu Ala Leu Arg Tyr
Trp Gly Gln Gly Ser Leu Val Ile Val 100 105 110Ser Ser17115PRTHomo
sapiens 171Ala Lys Asp Arg Pro Arg Gln Gly Val Gly Glu Leu Tyr Asp
Ser1 5 10 1517215PRTHomo sapiens 172Ala Lys Asp Arg Leu Glu Lys Gly
Ile Gly Glu Leu Phe His Ser1 5 10 1517315PRTHomo sapiens 173Ala Lys
Asp Arg Leu Arg Gln Gly Val Gly Glu Leu Phe His Ser1 5 10
1517415PRTHomo sapiens 174Ala Lys Asp Arg Leu Arg Glu Gly Val Gly
Glu Leu Tyr Gln Tyr1 5 10 1517515PRTHomo sapiens 175Ala Lys Asp Arg
Leu Arg Glu Gly Ile Gly Glu Leu Phe His Ser1 5 10 1517612PRTHomo
sapiens 176Ala Lys Asp Arg Asp His Phe Asp Gly His Asp Val1 5
1017714PRTHomo sapiens 177Ala Arg Gly Gly Pro Val Asn Ala Pro Arg
Gly Phe Asp Pro1 5 1017814PRTHomo sapiens 178Ala Arg Gly Gly Pro
Val Asn Ser Pro Leu Gly Phe Asp Pro1 5 1017914PRTHomo sapiens
179Ala Arg Gly Gly Arg Ile Asn Ser Pro Leu Gly Phe Asp Pro1 5
1018014PRTHomo sapiens 180Ala Arg Gly Gly Gln Ile Ser Ala Pro His
Gly Phe Asp Pro1 5 1018114PRTHomo sapiens 181Ala Arg Gly Gly Arg
Ile Asn Ala Pro Leu Gly Phe Asp Pro1 5 1018214PRTHomo sapiens
182Ala Arg Gly Gly Pro Ile Ser Ala Pro Leu Gly Phe Asp Pro1 5
1018320PRTHomo sapiens 183Ala Arg Ala Ala Met Asn Arg Ile Ser Gly
Val Val Pro Pro Gly Asp1 5 10 15Ala Phe Asp Leu 2018417PRTHomo
sapiens 184Thr Arg Ser Leu Val Thr Pro Ala Ala Gln Ser Val Gln Tyr
Phe Asp1 5 10 15Ser18517PRTHomo sapiens 185Ala Arg Thr Leu Val Ala
Pro Ser Ala Gln Ser Met Tyr Tyr Phe Asp1 5 10 15Phe18617PRTHomo
sapiens 186Thr Arg Thr Gln Val Val Pro Ser Ala Gln Ser Val Tyr Tyr
Phe Asp1 5 10 15Phe18717PRTHomo sapiens 187Thr Arg Thr Arg Val Val
Pro Ser Ala Gln Ser Val Tyr Tyr Phe Asp1 5 10 15Phe18817PRTHomo
sapiens 188Thr Arg Thr Gln Ile Ile Pro Ala Ala Gln Ser Val Tyr Phe
Phe Asp1 5 10 15Tyr18917PRTHomo sapiens 189Thr Arg Thr Arg Ile Ile
Ala Ala Ala Gln Ser Val Tyr His Tyr Asp1 5 10 15Leu19017PRTHomo
sapiens 190Ala Arg Ala Gln Asp Pro Ala Thr Ala Ile Arg Gly Leu Arg
Trp Glu1 5 10 15Tyr19117PRTHomo sapiens 191Ala Arg Gly Gly Ser Tyr
Pro Val Ala Ile Arg Gly Val Thr Phe Gly1 5 10 15Ile19217PRTHomo
sapiens 192Ala Arg Gly Ala Ala Tyr Pro Thr Ala Ile Arg Gly Val Ile
Tyr Gly1 5 10 15Phe19318PRTHomo sapiens 193Ala Thr Ser Pro Ala Ala
Ala Gly Ser Gly His Pro Ser Gly Trp Phe1 5 10 15Asp Pro19414PRTHomo
sapiens 194Ala Arg Pro Pro Gly Arg Ser Phe Leu Asp Gly Met Asp Val1
5 1019516PRTHomo sapiens 195Thr Arg Val Arg Trp Asp Gly Ile Glu Phe
Thr Met Phe Phe Asp Ser1 5 10 1519616PRTHomo sapiens 196Ala Arg Val
Arg Trp Asp Gly Ile Glu Ser Thr Met Phe Phe Asp Ser1 5 10
1519716PRTHomo sapiens 197Thr Arg Val Arg Trp Asp Gly Ile Glu Ser
Thr Met Phe Phe Asp Ser1 5 10 1519824PRTHomo sapiens 198Ala Arg Asp
Val Val Thr Met Val Glu Gly Leu Arg Phe His Tyr Tyr1 5 10 15Tyr Asn
Tyr Tyr Gly Met Asp Val 2019924PRTHomo sapiens 199Ala Arg Asp Val
Val Thr Met Val Glu Gly Leu Arg Phe His Tyr Tyr1 5 10 15Tyr Asn Tyr
Tyr Gly Met Asp Val 2020024PRTHomo sapiens 200Ala Arg Asp Val Val
Thr Met Val Glu Gly Leu Arg Phe His Tyr Tyr1 5 10 15Tyr Asn Tyr Tyr
Gly Met Asp Val 2020112PRTHomo sapiens 201Ala Arg Asn Gln Pro Gly
Gly Arg Ala Phe Asp Tyr1 5 1020212PRTHomo sapiens 202Ala Arg Asn
Gln Pro Gly Gly Arg Ala Phe Asp Tyr1 5 1020321PRTHomo sapiens
203Ala Arg His Asp Gly Arg Gly Tyr Cys Ser Pro Thr Arg Cys Phe Phe1
5 10 15Ser Gly Met Asp Val 2020421PRTHomo sapiens 204Ala Arg His
Asp Gly Arg Gly Tyr Cys Ser Pro Thr Arg Cys Phe Phe1 5 10 15Ser Gly
Met Asp Val 2020517PRTHomo sapiens 205Ala Arg Arg Thr Tyr Tyr Asp
Asn Arg Phe Pro Tyr Trp Tyr Phe Asp1 5 10 15Leu20617PRTHomo sapiens
206Ala Arg Arg Thr Tyr Tyr Asp Thr Arg Phe Pro Tyr Trp Tyr Phe Asp1
5 10 15Leu20715PRTHomo sapiens 207Ala Arg Ser Trp Gly Thr Ala Ala
Thr Gly Gly Ser Phe Val Gln1 5
10 1520813PRTHomo sapiens 208Ala Arg Gly Arg Asp Ser Ser Gly Arg
Leu Leu Asp His1 5 1020914PRTHomo sapiens 209Ala Arg Gly Gly Met
Leu Gly Gln Leu Trp Ala Leu Asp Asn1 5 1021014PRTHomo sapiens
210Ala Arg Gly Gly Arg Ile Asn Val Ala Glu Ala Leu Arg Tyr1 5
1021196PRTHomo sapiens 211Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Gly Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Phe65 70 75 80Asn Ser Val Pro
Trp Thr Phe Gly Pro Gly Thr Lys Val Glu Val Lys 85 90
9521296PRTHomo sapiens 212Ser Ala Ser Leu Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Pro Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Gln Thr
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9521396PRTHomo sapiens 213Ser Ala Ser Ile Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Pro Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Gln Thr
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Leu Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9521496PRTHomo sapiens 214Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Ser Pro Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Gln Thr
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9521596PRTHomo sapiens 215Ser Ala Ser Ile Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Thr Pro Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Gln Thr
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9521696PRTHomo sapiens 216Ser Ala Ser Val Gly Gly Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Ser Lys Ala
Ser Asn Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Gly Gly
Ser Glu Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln Arg Tyr65 70 75 80Asp Ser Tyr Pro
Phe Thr Phe Gly Pro Gly Thr Lys Val Thr Ile Lys 85 90
9521797PRTHomo sapiens 217Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Glu Ile Gly Ser Phe Ser Leu Gly Trp
Tyr Gln Gln Lys Phe Gly Gln 20 25 30Pro Pro Arg Leu Leu Ile Tyr Gly
Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu Pro
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Val Ser Ser
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys21897PRTHomo sapiens 218Ser Leu Ser Pro Gly Asp Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Ile Gly Ser Phe Ser Leu Ala
Trp Tyr Gln Gln Lys Phe Gly His 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Asp Thr Asp Tyr Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Val Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys21997PRTHomo sapiens 219Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Thr Phe Ser Leu Ala
Trp Tyr Gln Gln Lys Phe Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Val Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Arg22097PRTHomo sapiens 220Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Ser Ile His Leu Gly
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys22197PRTHomo sapiens 221Ser Leu Ser Pro Gly Glu Thr Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Ile Gly Ser Ile Ser Leu Gly
Trp Tyr Gln Gln Lys Phe Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Thr Arg Ala Thr Gly Thr 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Glu Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Val Ser
Ser Pro Leu Arg Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys22297PRTHomo sapiens 222Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Ser Ile His Leu Ala
Trp Tyr Gln Gln Arg Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Asn
Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys22397PRTHomo sapiens 223Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Leu Ser Ser Asn Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Arg Gly Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 85 90
95Lys22497PRTHomo sapiens 224Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Leu Ser Phe Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Asn Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Gly Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 85 90
95Lys22597PRTHomo sapiens 225Ser Leu Ser Pro Gly Glu Arg Gly Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Tyr Ile Thr Thr Gly His Phe Ala
Trp Tyr Gln Gln Lys Pro Gly Arg 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Val Arg Ala Thr Gly Val 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ala Glu Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Asp
Pro Glu Asp Val Gly Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Val Thr Phe Gly Pro Gly Thr Lys Val Glu Ile 85 90
95Lys22697PRTHomo sapiens 226Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Asn Ile Gly Leu Asp Tyr Phe Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ile Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Val
Pro Glu Asp Ile Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Val Thr Phe Gly Pro Gly Thr Lys Val Glu Val 85 90
95Lys22797PRTHomo sapiens 227Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Thr Ser Gly Tyr Phe Ala
Trp Tyr Gln His Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ile Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Val Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 85 90
95Lys22897PRTHomo sapiens 228Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Phe Val Ile Ser Gly His Phe Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Thr Ser Asn Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Glu Ser Gly Ala Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Pro Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 85 90
95Lys22997PRTHomo sapiens 229Ser Leu Ser Pro Gly Asp Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15His Ile Thr Thr Gly His Phe Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Ser Ile Arg Ala Ser Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr 50 55 60Ile Ser Arg Leu Glu
Pro Glu Asp Cys Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser
Ser Pro Val Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 85 90
95Lys23096PRTHomo sapiens 230Ser Ala Ser Val Gly Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Asp Thr Tyr Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Val 20 25 30Pro Ala Ile Leu Ile Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser65 70 75 80Tyr Ile Thr
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 85 90
9523196PRTHomo sapiens 231Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Asn Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Asn Leu Leu Ile Phe Ala Thr
Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser65 70 75 80Phe Ser Thr Pro
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg 85 90
9523296PRTHomo sapiens 232Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Thr Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Phe Ala Ala
Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Thr Ser Leu Gln Pro Ala
Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Ser65 70 75 80Tyr Ile Ser Pro
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Asn 85 90
9523396PRTHomo sapiens 233Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ile Asn Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Ala
Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Ser Phe Thr Leu Thr Ile 50 55 60Ile Ser Leu Gln Pro Glu
Asp Phe Ala Ile Tyr Tyr Cys His Gln Ser65 70 75 80Phe Ser Ala Pro
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9523496PRTHomo sapiens 234Ser Ala Ser Val Gly His Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Phe Ala Ala
Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro Gly
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser65 70 75 80Tyr Ser Thr Pro
Leu Ser Phe Gly Gln Gly Thr Arg Val Glu Ile Lys 85 90
95235103PRTHomo sapiens 235Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
Ser Ile Thr Ile Tyr Cys1 5 10 15Ser Gly Ser Ser Ser Asp Val Gly Ser
Tyr Asn Leu Val Ser Trp Tyr 20 25 30Gln Gln His Pro Gly Lys Ala Pro
Lys Leu Ile Ile Tyr Gly Val Thr 35 40 45Arg Arg Pro Ser Gly Val Ser
Ser
Arg Phe Ser Gly Ser Lys Ser Gly 50 55 60Asn Thr Ala Ser Leu Thr Phe
Ser Gly Leu Gln Val Glu Asp Asp Ala65 70 75 80Asp Tyr Tyr Cys Cys
Ser Tyr Ala Asn Ser Gly Thr Phe Val Phe Gly 85 90 95Thr Gly Thr Lys
Val Thr Val 100236103PRTHomo sapiens 236Pro Ala Ser Val Ser Gly Ser
Pro Gly Gln Ser Ile Thr Ile Tyr Cys1 5 10 15Ser Gly Ser Ser Ser Asp
Val Gly Ser Tyr Asn Leu Val Ser Trp Tyr 20 25 30Gln Gln His Pro Gly
Lys Ala Pro Lys Leu Ile Ile Tyr Gly Val Thr 35 40 45Arg Arg Pro Ser
Gly Val Ser Ser Arg Phe Ser Gly Ser Lys Ser Gly 50 55 60Asn Thr Ala
Ser Leu Thr Phe Ser Gly Leu Gln Val Glu Asp Asp Ala65 70 75 80Asp
Tyr Tyr Cys Cys Ser Tyr Ala Asn Ser Gly Thr Phe Val Phe Gly 85 90
95Thr Gly Thr Lys Val Thr Val 100237103PRTHomo sapiens 237Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Tyr Cys1 5 10 15Ser
Gly Ser Ser Ser Asp Val Gly Ser Tyr Asn Leu Val Ser Trp Tyr 20 25
30Gln Gln His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Gly Val Thr
35 40 45Arg Arg Pro Ser Gly Val Ser Ser Arg Phe Ser Gly Ser Lys Ser
Gly 50 55 60Asn Thr Ala Ser Leu Thr Phe Ser Gly Leu Gln Val Glu Asp
Asp Ala65 70 75 80Asp Tyr Tyr Cys Cys Ser Tyr Ala Asn Ser Gly Thr
Phe Val Phe Gly 85 90 95Thr Gly Thr Lys Val Thr Val 10023897PRTHomo
sapiens 238Ser Leu Ser Pro Gly Asp Arg Ala Thr Leu Ser Cys Gly Ala
Ser Gln1 5 10 15Ser Val Ser Ser Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
Leu Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr Ala Ala Ser Thr Arg
Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr
Asp Phe Thr Leu Thr 50 55 60Ile Asn Lys Leu Glu Ala Glu Asp Phe Ala
Met Tyr Tyr Cys Gln Ile65 70 75 80Tyr Asp Ser Ser Val Arg Thr Phe
Gly Gln Gly Thr Lys Val Glu Ile 85 90 95Lys23997PRTHomo sapiens
239Ser Leu Ser Pro Gly Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1
5 10 15Ser Val Ser Ser Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly
Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr
Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe
Thr Leu Thr 50 55 60Ile Asn Lys Leu Glu Ala Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Ile65 70 75 80Tyr Asp Ser Ser Val Arg Thr Phe Gly Gln
Gly Thr Lys Val Glu Ile 85 90 95Lys24097PRTHomo sapiens 240Ser Leu
Ser Pro Gly Asp Arg Ala Thr Leu Ser Cys Gly Ala Ser Gln1 5 10 15Ser
Val Ser Ser Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln 20 25
30Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile
35 40 45Pro Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu
Thr 50 55 60Ile Asn Lys Leu Glu Ala Glu Asp Phe Ala Met Tyr Tyr Cys
Gln Ile65 70 75 80Tyr Asp Ser Ser Leu Arg Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile 85 90 95Lys24198PRTHomo sapiens 241Ser Leu Ser Pro
Gly Gln Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser
Asn Tyr Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg
Leu Leu Ile Tyr Asp Thr Ser Lys Arg Ala Thr Gly Thr Pro 35 40 45Ala
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55
60Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Glu Arg65
70 75 80Asn Asn Trp Pro Leu Thr Trp Thr Phe Gly Leu Gly Thr Lys Val
Glu 85 90 95Ile Lys24298PRTHomo sapiens 242Ser Leu Ser Pro Gly Gln
Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Asn Tyr
Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu
Ile Tyr Asp Thr Ser Lys Arg Ala Thr Gly Thr Pro 35 40 45Ala Arg Phe
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Glu Arg65 70 75
80Asn Asn Trp Pro Leu Thr Trp Thr Phe Gly Leu Gly Thr Lys Val Glu
85 90 95Ile Lys24396PRTHomo sapiens 243Ser Ala Ser Val Gly Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Asn Tyr Leu
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Asn Leu Leu Ile
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu
Gln Pro Glu Asp Tyr Ala Ile Tyr Tyr Cys Gln Gln Thr65 70 75 80Asp
Arg Thr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9524496PRTHomo sapiens 244Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Asn Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Asn Leu Leu Ile Tyr Ala Ala
Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu
Asp Tyr Ala Ile Tyr Tyr Cys Gln Gln Thr65 70 75 80Asp Arg Thr Pro
Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9524596PRTHomo sapiens 245Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Gly Lys Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Leu Ala 20 25 30Pro Glu Val Leu Ile Ser Gly Ala
Thr Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Glu Thr Asp Phe Thr Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro Glu
Asp Leu Ala Thr Tyr Val Cys Gln Gln Ser65 70 75 80Ile Ser Ala Pro
Tyr Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 85 90
9524696PRTHomo sapiens 246Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asp Ile Gly Ser Tyr Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Asn Val Leu Ile Ser Ala Ala
Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Ile Ser Gly Ile Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser65 70 75 80Leu Ser Ala Pro
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9524798PRTHomo sapiens 247Ser Val Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser His1 5 10 15Ser Val Thr Ser Asn Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Gly Ala
Ser Thr Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Ser Glu
Asp Ser Ala Val Tyr Tyr Cys Gln Tyr Tyr65 70 75 80Thr Asn Trp Pro
Pro His Val Ala Phe Gly Gln Gly Thr Lys Leu Glu 85 90 95Ile
Lys24897PRTHomo sapiens 248Ser Val Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Thr Val Asn Arg Asn Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Ala Ala
Ser Ala Arg Ala Thr Gly Val Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Ser Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Asn Trp Pro
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys24996PRTHomo sapiens 249Ser Ala Ser Val Gly Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser His Trp Leu Ala Trp
Tyr Gln Gln Arg Pro Gly Glu Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln
Ala Ser Thr Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Glu Phe Thr Leu Ser Ile 50 55 60Ser Ser Leu Gln Pro
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr65 70 75 80Gln Ser Ser
Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9525096PRTHomo sapiens 250Ser Thr Phe Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Gly Asp Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Ser Lys Ala
Thr Arg Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Glu Thr Glu Phe Ser Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro Asp
Asp Val Ala Ala Tyr Tyr Cys Gln Gln Tyr65 70 75 80Met Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 952519PRTHomo
sapiens 251Gln Lys Phe Asn Ser Val Pro Trp Thr1 52529PRTHomo
sapiens 252Gln His Tyr His Ser Tyr Pro Trp Thr1 52539PRTHomo
sapiens 253Gln His Tyr His Ser Tyr Pro Trp Thr1 52549PRTHomo
sapiens 254Gln His Tyr His Ser Tyr Pro Trp Thr1 52559PRTHomo
sapiens 255Gln His Tyr His Ser Tyr Pro Trp Thr1 52569PRTHomo
sapiens 256Gln Arg Tyr Asp Ser Tyr Pro Phe Thr1 52579PRTHomo
sapiens 257Gln Gln Tyr Val Ser Ser Pro Leu Thr1 52589PRTHomo
sapiens 258Gln Gln Tyr Val Ser Ser Pro Leu Thr1 52599PRTHomo
sapiens 259Gln Gln Tyr Val Ser Ser Pro Leu Thr1 52609PRTHomo
sapiens 260Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 52619PRTHomo
sapiens 261Gln Gln Tyr Val Ser Ser Pro Leu Arg1 52629PRTHomo
sapiens 262Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 52639PRTHomo
sapiens 263Gln Gln Tyr Gly Ser Ser Arg Gly Thr1 52649PRTHomo
sapiens 264Gln Gln Tyr Gly Ser Ser Pro Leu Thr1 52659PRTHomo
sapiens 265Gln Gln Tyr Gly Ser Ser Pro Val Thr1 52669PRTHomo
sapiens 266Gln Gln Tyr Gly Ser Ser Pro Val Thr1 52679PRTHomo
sapiens 267Gln Gln Tyr Gly Ser Ser Pro Val Thr1 52689PRTHomo
sapiens 268Gln Gln Tyr Gly Ser Ser Pro Pro Thr1 52699PRTHomo
sapiens 269Gln Gln Tyr Gly Ser Ser Pro Val Thr1 52709PRTHomo
sapiens 270Gln Gln Ser Tyr Ile Thr Pro Leu Thr1 52719PRTHomo
sapiens 271Gln Gln Ser Phe Ser Thr Pro Leu Thr1 52729PRTHomo
sapiens 272Gln Gln Ser Tyr Ile Ser Pro Leu Thr1 52739PRTHomo
sapiens 273His Gln Ser Phe Ser Ala Pro Tyr Thr1 52749PRTHomo
sapiens 274Gln Gln Ser Tyr Ser Thr Pro Leu Ser1 527510PRTHomo
sapiens 275Cys Ser Tyr Ala Asn Ser Gly Thr Phe Val1 5
1027610PRTHomo sapiens 276Cys Ser Tyr Ala Asn Ser Gly Thr Phe Val1
5 1027710PRTHomo sapiens 277Cys Ser Tyr Ala Asn Ser Gly Thr Phe
Val1 5 102789PRTHomo sapiens 278Gln Ile Tyr Asp Ser Ser Val Arg
Thr1 52799PRTHomo sapiens 279Gln Ile Tyr Asp Ser Ser Val Arg Thr1
52809PRTHomo sapiens 280Gln Ile Tyr Asp Ser Ser Leu Arg Thr1
528111PRTHomo sapiens 281Gln Glu Arg Asn Asn Trp Pro Leu Thr Trp
Thr1 5 1028211PRTHomo sapiens 282Gln Glu Arg Asn Asn Trp Pro Leu
Thr Trp Thr1 5 102839PRTHomo sapiens 283Gln Gln Thr Asp Arg Thr Pro
Leu Thr1 52849PRTHomo sapiens 284Gln Gln Thr Asp Arg Thr Pro Leu
Thr1 52859PRTHomo sapiens 285Gln Gln Ser Ile Ser Ala Pro Tyr Thr1
52869PRTHomo sapiens 286Gln Gln Ser Leu Ser Ala Pro Tyr Thr1
528711PRTHomo sapiens 287Gln Tyr Tyr Thr Asn Trp Pro Pro His Val
Ala1 5 1028810PRTHomo sapiens 288Gln Gln Tyr Asn Asn Trp Pro Pro
Leu Thr1 5 102899PRTHomo sapiens 289Gln Gln Tyr Gln Ser Ser Pro Tyr
Thr1 52909PRTHomo sapiens 290Gln Gln Tyr Met Ser Tyr Pro Trp Thr1
5291117PRTHomo sapiens 291Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ser Tyr
Ala Met Asn Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Gly Ile Gly Gly Arg Gly 35 40 45Ala Ile Ala Gly Asp Gly Ser
Ile Tyr Tyr Ala Asp Ser Val Lys Gly 50 55 60Arg Phe Thr Ile Ser Arg
Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln65 70 75 80Met Asn Gly Leu
Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys 85 90 95Asp Arg Val
Ala Phe Asp Gly Phe His Val Trp Gly Gln Gly Thr Thr 100 105 110Val
Thr Val Ser Ser 115292115PRTHomo sapiens 292Gly Gly Gly Leu Ile Gln
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser1 5 10 15Ala Ser Gly Phe Thr
Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Gly Ile Ser Pro Leu Asp 35 40 45Gly Ser Thr
Tyr Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Asn Thr Leu Phe Leu Gln Met Asn Ser Leu Arg65 70 75
80Val Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Lys Asp Arg Leu Thr Met
85 90 95Gly Val Gly Glu Leu Phe Val Asp Trp Gly Pro Gly Thr Leu Val
Ser 100 105 110Val Ser Ser 115293115PRTHomo sapiens 293Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Arg Arg Leu Ser Cys Ala1 5 10 15Thr Ser
Gly Phe Ser Phe Asp Thr Tyr Ala Met Ser Trp Leu Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Phe Ser Gly Leu Asp 35 40
45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu
Arg65 70 75 80Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Lys Asp Arg
Gly Pro Arg 85 90 95Gly Ile Gly Glu Leu Phe Asp Phe Trp Gly Gln Gly
Thr Leu Val Ser 100 105 110Val Ser Ser 115294115PRTHomo sapiens
294Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Val1
5 10 15Thr Ser Gly Phe Ser Phe Asp Thr Tyr Ala Leu Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Phe Ser Gly
Ile Asp 35 40 45Asp Ser Thr Tyr Tyr Thr Glu Ser Val Lys Gly Arg Phe
Thr Met Ser 50 55 60Arg Asp Asn Ser Lys Ser Thr Leu Phe Leu Gln Met
Asn Gly Leu Arg65 70 75 80Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ser
Lys Asp Arg Gly Pro Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp
Gly Gln Gly Thr Leu Val Ile 100 105 110Phe Ser Ser 115295115PRTHomo
sapiens 295Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Thr Ser Gly
Phe Thr Phe Ser Thr Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro
Gly Lys Gly Leu Glu Trp Val Ser Ser Phe Ser Gly Val Asp 35 40 45Asp
Ser Thr Tyr Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55
60Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Thr Arg Leu Arg65
70 75 80Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Arg Gly Pro
Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu
Val Thr 100 105 110Val Ser Ser 115296115PRTHomo sapiens 296Gly Gly
Gly Leu Val Arg Pro Gly Gly Ser Leu Thr Leu Thr Cys Ala1 5 10 15Thr
Ser Gly Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Val Arg Gln 20 25
30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Tyr Ser Gly Ile Asp
35 40 45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile
Ser 50 55 60Arg Asp Asn Ser Lys Arg Thr Leu Ser Leu His Met Asn Ser
Leu Arg65 70 75 80Ala Gly Asp Ser Ala Leu Tyr Tyr Cys Ala Lys Asp
Arg Gly Pro Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp Gly Pro
Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115297115PRTHomo sapiens
297Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Phe Thr Phe Ser Asp Tyr Ala Met Gly Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Leu Ser Ser Met Thr Arg
Thr Gly 35 40 45Asp Asn Leu Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
Ser Ser Leu Arg65 70 75 80Val Glu Asp Thr Ala Ile Tyr Phe Cys Ala
Lys Asp Arg Leu Pro Glu 85 90 95Gly Phe Gly Lys Leu Phe Asp Tyr Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Thr 115298114PRTHomo
sapiens 298Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Ala Ser Gly Phe Ser Phe Ser Asp Phe Ala Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Asn Gln Gly Leu Asp Trp Val Ser Cys Val
Ser Gly Gly Gly 35 40 45Asp Thr Thr Tyr Tyr Ala Asp Ser Val Lys Gly
Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Val Phe Leu
Glu Met Asn Asn Leu Arg65 70 75 80Pro Glu Asp Thr Ala Val Tyr Tyr
Cys Ala Arg Asp Gln Glu Val Ile 85 90 95Gly His Tyr Pro Ser Asp His
Trp Gly Gln Gly Thr Leu Val Ile Val 100 105 110Ser Ser299112PRTHomo
sapiens 299Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Val1 5 10 15Ala Ser Gly Phe Thr Phe Ser Asn Tyr Gly Met Asn Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile
Thr Gly Ser Gly 35 40 45Asp Asp Thr Tyr Tyr Ala Asp Ser Val Lys Gly
Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Arg Asn Thr Leu Tyr Val
Gln Met Asn Asn Leu Arg65 70 75 80Ala Glu Asp Thr Ala Ile Tyr Tyr
Cys Thr Lys Asp Arg Ile Leu Phe 85 90 95Asp Ala Phe His Val Trp Gly
Gln Gly Thr Met Val Thr Val Ser Ser 100 105 110300115PRTHomo
sapiens 300Gly Gly Asp Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Val1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ala Tyr Gly Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Met
Thr Gly Ser Gly 35 40 45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
Gln Met Asn Ser Leu Arg65 70 75 80Val Glu Asp Thr Ala Ile Tyr Tyr
Cys Ala Lys Asp Arg Val Ser Gly 85 90 95Gly Phe Gly Glu Leu Gln Asp
Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser
115301115PRTHomo sapiens 301Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Thr Ser Gly Phe Thr Phe Thr Thr Phe
Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Ile Ser Gly Ala Asp 35 40 45Asp Ser Thr Tyr Tyr Ala Ala
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Arg Ser
Thr Leu Phe Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr
Ala Val Tyr Tyr Cys Ala Lys Asp Arg Gly Pro Arg 85 90 95Gly Val Gly
Glu Leu Phe Asp Ser Trp Gly Gln Gly Thr Val Val Ser 100 105 110Val
Ser Ser 115302115PRTHomo sapiens 302Gly Gly Gly Leu Val Gln Pro Gly
Gly Ser Leu Thr Leu Ser Cys Ala1 5 10 15Gly Ser Gly Phe Pro Phe Asn
Thr Tyr Ala Leu Ile Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu
Glu Trp Val Ser Ser Ile Ser Tyr Asp Ser 35 40 45Ala Ser Thr Tyr Tyr
Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser
Gln Asn Thr Leu Tyr Leu Glu Met Asn Phe Leu Arg65 70 75 80Ala Asp
Asp Thr Ala Val Tyr Phe Cys Ala Lys Asp Arg Val Thr Met 85 90 95Gly
Phe Gly Glu Leu Phe Ala His Trp Gly Gln Gly Thr Leu Val Ala 100 105
110Val Ser Ser 115303115PRTHomo sapiens 303Gly Gly Gly Leu Lys Gln
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr
Phe Arg Asn Tyr Gly Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Ser Ile Ser Ser Leu Asp 35 40 45Asp Ser Thr
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Ser Ala Ile Ser 50 55 60Arg Asp
Asp Ser Lys Asn Thr Leu Tyr Leu Gln Ile His Ser Leu Arg65 70 75
80Ala Glu Asp Thr Ala Leu Tyr Phe Cys Ala Lys Asp Arg Val Glu Lys
85 90 95Gly Phe Gly Glu Leu Trp Ala Ser Trp Gly Gln Gly Thr Leu Val
Thr 100 105 110Val Ser Ser 115304115PRTHomo sapiens 304Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Thr Cys Ala1 5 10 15Thr Ser
Gly Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Tyr Ser Gly Ile Asp 35 40
45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Ile Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Ser Leu His Met Asn Ser Leu
Arg65 70 75 80Ala Glu Asp Ser Ala Leu Tyr Phe Cys Ala Lys Asp Arg
Gly Pro Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110Val Ser Ser 115305115PRTHomo sapiens
305Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Thr Cys Ala1
5 10 15Thr Ser Gly Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Tyr Ser Gly
Ile Asp 35 40 45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe
Thr Ile Ser 50 55 60Arg Asp Asn Ser Arg Ser Thr Leu Ser Leu His Met
Asn Ser Leu Arg65 70 75 80Ala Glu Asp Ser Ala Leu Tyr Phe Cys Ala
Lys Asp Arg Gly Pro Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115306117PRTHomo
sapiens 306Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Thr Ser Tyr Ala Met Asn Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile
Gly Gly Arg Gly 35 40 45Ala Ile Ala Gly Asp Gly Ser Ile Tyr Tyr Ala
Asp Ser Val Lys Gly 50 55 60Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Ile Val Tyr Leu Gln65 70 75 80Met Asn Gly Leu Arg Val Glu Asp
Thr Ala Val Tyr Tyr Cys Ala Lys 85 90 95Asp Arg Val Ala Phe Asp Gly
Phe His Val Trp Gly Gln Gly Thr Thr 100 105 110Val Thr Val Ser Ser
115307115PRTHomo sapiens 307Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Thr Cys Ala1 5 10 15Thr Ser Gly Phe Thr Phe Ser Asp Tyr
Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Tyr Ser Gly Ile Asp 35 40 45Asp Ser Thr Tyr Tyr Ala Asp
Ser Val Lys Gly Arg Phe Ile Ile Ser 50 55 60Arg Asp Asn Ser Lys Ser
Thr Leu Ser Leu His Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Ser
Ala Leu Tyr Phe Cys Ala Lys Asp Arg Gly Pro Arg 85 90 95Gly Val Gly
Glu Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val
Ser Ser 115308115PRTHomo sapiens 308Gly Gly Gly Leu Val Gln Pro Gly
Gly Ser Leu Arg Leu Thr Cys Ala1 5 10 15Thr Ser Gly Phe Thr Phe Arg
Asp Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu
Glu Trp Val Ser Ser Tyr Ser Gly Ile Asp 35 40 45Asp Ser Thr Tyr Tyr
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser
Lys Ser Thr Leu Ser Leu His Met Asn Ser Leu Arg65 70 75 80Ala Glu
Asp Ser Ala Leu Tyr Phe Cys Ala Lys Asp Arg Gly Pro Arg 85 90 95Gly
Val Gly Glu Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105
110Val Ser Ser 115309115PRTHomo sapiens 309Gly Gly Gly Leu Val Gln
Pro Gly Gly Ser Leu Arg Leu Thr Cys Ala1 5 10 15Thr Ser Gly Phe Thr
Phe Ser Asp Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Ser Tyr Ser Gly Ile Asp 35 40 45Asp Ser Thr
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Ser Thr Leu Ser Leu Tyr Met Lys Ser Leu Arg65 70 75
80Ala Glu Asp Ser Ala Leu Tyr Tyr Cys Ala Lys Asp Arg Gly Pro Arg
85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val
Thr 100 105 110Val Ser Ser 115310115PRTHomo sapiens 310Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Thr Cys Ala1 5 10 15Thr Ser
Gly Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Tyr Ser Gly Ile Asp 35 40
45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Ser Thr Leu Ser Leu His Met Asn Ser Leu
Arg65 70 75 80Ala Glu Asp Ser Ala Leu Tyr Phe Cys Ala Lys Asp Arg
Gly Pro Arg 85 90 95Gly Val Gly Glu Leu Phe Asp Ser Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110Val Ser Ser 115311115PRTHomo sapiens
311Gly Gly Asp Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
Phe Asp 35 40 45Pro Ser Thr Tyr Tyr Ala Asp Ser Val Arg Gly Arg Phe
Thr Ile Ala 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
Lys Ser Leu Arg65 70 75 80Val Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
Lys Asp Arg Leu Val Arg 85 90 95Gly Phe Gly Glu Val Leu Ala Ser Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115312115PRTHomo
sapiens 312Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Phe
Ser Gly Ile Asp 35 40 45Asp Ser Thr Trp Tyr Ala Asp Ser Val Lys Gly
Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Ser Thr Leu Tyr Leu
Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr Ala Val Tyr Tyr
Cys Ala Lys Asp Arg Leu Val Arg 85 90 95Gly Phe Ala Glu Val Leu Asp
Tyr Trp Gly Arg Gly Thr Leu Val Thr 100 105 110Val Ser Ser
115313115PRTHomo sapiens 313Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ser Tyr
Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Phe Ser Gly Ile Asp 35 40 45Asp Ser Thr Trp Tyr Ala Asp
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Ser
Thr Leu Phe Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr
Ala Val Tyr Tyr Cys Ala Lys Asp Arg Leu Val Arg 85 90 95Gly Phe Ala
Glu Val Leu Glu His Trp Gly Arg Gly Thr Leu Val Thr 100 105 110Val
Ser Ser 115314115PRTHomo sapiens 314Gly Gly Asp Leu Val Gln Pro Gly
Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser
Ser Tyr Gly Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu
Glu Trp Val Ser Ser Ile Ser Gly Phe Asp 35 40 45Pro Ser Thr Tyr Tyr
Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ala 50 55 60Arg Asp Asn Ser
Lys Asn Thr Leu Tyr Leu Gln Met Lys Ser Leu Arg65 70 75 80Val Glu
Asp Thr Ala Ile Tyr Tyr Cys Ala Lys Asp Arg Leu Val Arg 85 90 95Gly
Phe Gly Glu Val Leu Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105
110Val Ser Ser 11531512PRTHomo sapiens 315Ala Lys Asp Arg Val Ala
Phe Asp Gly Phe His Val1 5 1031615PRTHomo sapiens 316Ala Lys Asp
Arg Leu Thr Met Gly Val Gly Glu Leu Phe Val Asp1 5 10
1531715PRTHomo sapiens 317Ala Lys Asp Arg Gly Pro Arg Gly Ile Gly
Glu Leu Phe Asp Phe1 5 10 1531815PRTHomo sapiens 318Ser Lys Asp Arg
Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser1 5 10 1531915PRTHomo
sapiens 319Ala Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp
Ser1 5 10 1532015PRTHomo sapiens 320Ala Lys Asp Arg Gly Pro Arg Gly
Val Gly Glu Leu Phe Asp Ser1 5 10 1532115PRTHomo sapiens 321Ala Lys
Asp Arg Leu Pro Glu Gly Phe Gly Lys Leu Phe Asp Tyr1 5 10
1532214PRTHomo
sapiens 322Ala Arg Asp Gln Glu Val Ile Gly His Tyr Pro Ser Asp His1
5 1032312PRTHomo sapiens 323Thr Lys Asp Arg Ile Leu Phe Asp Ala Phe
His Val1 5 1032415PRTHomo sapiens 324Ala Lys Asp Arg Val Ser Gly
Gly Phe Gly Glu Leu Gln Asp Tyr1 5 10 1532515PRTHomo sapiens 325Ala
Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser1 5 10
1532615PRTHomo sapiens 326Ala Lys Asp Arg Val Thr Met Gly Phe Gly
Glu Leu Phe Ala His1 5 10 1532715PRTHomo sapiens 327Ala Lys Asp Arg
Val Glu Lys Gly Phe Gly Glu Leu Trp Ala Ser1 5 10 1532815PRTHomo
sapiens 328Ala Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp
Ser1 5 10 1532915PRTHomo sapiens 329Ala Lys Asp Arg Gly Pro Arg Gly
Val Gly Glu Leu Phe Asp Ser1 5 10 1533012PRTHomo sapiens 330Ala Lys
Asp Arg Val Ala Phe Asp Gly Phe His Val1 5 1033115PRTHomo sapiens
331Ala Lys Asp Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser1 5
10 1533215PRTHomo sapiens 332Ala Lys Asp Arg Gly Pro Arg Gly Val
Gly Glu Leu Phe Asp Ser1 5 10 1533315PRTHomo sapiens 333Ala Lys Asp
Arg Gly Pro Arg Gly Val Gly Glu Leu Phe Asp Ser1 5 10
1533415PRTHomo sapiens 334Ala Lys Asp Arg Gly Pro Arg Gly Val Gly
Glu Leu Phe Asp Ser1 5 10 1533515PRTHomo sapiens 335Ala Lys Asp Arg
Leu Val Arg Gly Phe Gly Glu Val Leu Ala Ser1 5 10 1533615PRTHomo
sapiens 336Ala Lys Asp Arg Leu Val Arg Gly Phe Ala Glu Val Leu Asp
Tyr1 5 10 1533715PRTHomo sapiens 337Ala Lys Asp Arg Leu Val Arg Gly
Phe Ala Glu Val Leu Glu His1 5 10 1533815PRTHomo sapiens 338Ala Lys
Asp Arg Leu Val Arg Gly Phe Gly Glu Val Leu Asp Ser1 5 10
1533996PRTHomo sapiens 339Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala
Ser Ser Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Ser Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534096PRTHomo sapiens 340Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Gln Ala
Ser Thr Leu Gln Asn Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Tyr Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534196PRTHomo sapiens 341Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Arg Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Thr
Ser Thr Leu Lys Ser Glu Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80His Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534296PRTHomo sapiens 342Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Tyr Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534396PRTHomo sapiens 343Ser Ala Ser Val Gly Asp Arg Val Thr Met
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Asn Arg Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80His Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534496PRTHomo sapiens 344Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Tyr Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534596PRTHomo sapiens 345Ser Ala Ala Ile Gly Asp Arg Val Thr Phe
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Asn Thr Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Met His Lys Ala
Ser Thr Leu His Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Tyr Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9534695PRTHomo sapiens 346Ser Val Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala
Ser Arg Leu Glu Arg Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Arg Gly
Ser Gly Thr Glu Phe Ala Leu Thr Ile 50 55 60Ser Gly Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr65 70 75 80Ser Ser Phe Phe
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 85 90 9534796PRTHomo
sapiens 347Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Asn Leu Leu Ile Tyr Lys Ala Ser Thr Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Asn Tyr Pro Trp Thr Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 85 90 9534896PRTHomo sapiens 348Ser
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10
15Asn Ile Asn Ser Trp Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala
20 25 30Pro Glu Leu Leu Ile Tyr Lys Thr Ser Thr Leu His Thr Gly Val
Pro 35 40 45Ser Arg Phe Arg Gly Arg Gly Ser Gly Thr Glu Phe Thr Leu
Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys
Gln His Tyr65 70 75 80Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys 85 90 9534996PRTHomo sapiens 349Ser Ala Ser Val
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser
Lys Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Arg
Leu Leu Ile Tyr Thr Thr Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55
60Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65
70 75 80Phe Ser Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 85 90 9535096PRTHomo sapiens 350Ser Ala Ser Ile Gly Asp Arg Val
Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Gly Trp Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile His
Lys Ala Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Thr Ser Leu Gln
Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Tyr Ser
Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Val Lys 85 90
9535196PRTHomo sapiens 351Pro Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Thr Pro Gly Arg Pro 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala
Ser Ala Ser Leu Asp Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Thr Ser Leu Gln Pro His
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535296PRTHomo sapiens 352Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80His Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535396PRTHomo sapiens 353Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80His Ser Val Pro
Trp Ala Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535496PRTHomo sapiens 354Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala
Ser Ser Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Ser Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535596PRTHomo sapiens 355Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Tyr Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535696PRTHomo sapiens 356Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Tyr Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535796PRTHomo sapiens 357Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Gly Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Phe Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ser Lys 85 90
9535896PRTHomo sapiens 358Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Lys Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Thr Thr
Ser Thr Leu Lys Thr Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Phe65 70 75 80Tyr Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9535996PRTHomo sapiens 359Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Gly Ile Ser Asn Tyr Leu Ala Trp Tyr
Gln Gln Lys Pro Arg Glu Val 20 25 30Pro Lys Leu Leu Ile Tyr Ala Ala
Ser Thr Leu His Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Gly Leu Gln Pro Glu
Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr65 70 75 80Asn Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Met Lys 85 90
9536096PRTHomo sapiens 360Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asp Ile Ser Lys Tyr Leu Ala Trp Tyr
Gln Gln Arg Pro Gly Lys Val 20 25 30Pro Asn Leu Leu Ile Tyr Thr Ala
Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr His Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu
Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr65 70 75 80Asn Ser Val Pro
Trp Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys 85 90 9536196PRTHomo sapiens 361Ser Ala Ser Val
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Asp Ile Ser
Lys Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Val 20 25 30Pro Asn
Leu Leu Ile Tyr Thr Ala Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser
Arg Phe Ser Gly Ser Gly Ser Gly Thr His Phe Thr Leu Thr Ile 50 55
60Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr65
70 75 80Asn Ser Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 85 90 9536296PRTHomo sapiens 362Ser Ala Ser Val Gly Asp Arg Val
Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Gly Ile Ser Asn Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Arg Glu Val 20 25 30Pro Lys Leu Leu Ile Tyr
Ala Ala Ser Thr Leu His Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Gly Leu Gln
Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr65 70 75 80Asn Ser
Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Met Lys 85 90
953639PRTHomo sapiens 363Gln Gln Tyr Asn Ser Tyr Pro Trp Thr1
53649PRTHomo sapiens 364Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
53659PRTHomo sapiens 365Gln His Phe His Ser Val Pro Trp Thr1
53669PRTHomo sapiens 366Gln His Phe Tyr Ser Val Pro Trp Thr1
53679PRTHomo sapiens 367Gln His Phe His Ser Val Pro Trp Thr1
53689PRTHomo sapiens 368Gln His Phe Tyr Ser Val Pro Trp Thr1
53699PRTHomo sapiens 369Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
53708PRTHomo sapiens 370Gln Gln Tyr Ser Ser Phe Phe Thr1
53719PRTHomo sapiens 371Gln Gln Tyr Asn Asn Tyr Pro Trp Thr1
53729PRTHomo sapiens 372Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
53739PRTHomo sapiens 373Gln His Phe Phe Ser Val Pro Trp Thr1
53749PRTHomo sapiens 374Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
53759PRTHomo sapiens 375Gln His Tyr His Ser Tyr Pro Trp Thr1
53769PRTHomo sapiens 376Gln His Phe His Ser Val Pro Trp Thr1
53779PRTHomo sapiens 377Gln His Phe His Ser Val Pro Trp Ala1
53789PRTHomo sapiens 378Gln Gln Tyr Asn Ser Tyr Pro Trp Thr1
53799PRTHomo sapiens 379Gln His Phe Tyr Ser Val Pro Trp Thr1
53809PRTHomo sapiens 380Gln His Phe Tyr Ser Val Pro Trp Thr1
53819PRTHomo sapiens 381Gln His Phe Phe Ser Val Pro Trp Thr1
53829PRTHomo sapiens 382Gln His Phe Tyr Ser Val Pro Trp Thr1
53839PRTHomo sapiens 383Gln Lys Tyr Asn Ser Val Pro Trp Thr1
53849PRTHomo sapiens 384Gln Lys Tyr Asn Ser Val Pro Trp Thr1
53859PRTHomo sapiens 385Gln Lys Tyr Asn Ser Val Pro Trp Thr1
53869PRTHomo sapiens 386Gln Lys Tyr Asn Ser Val Pro Trp Thr1
5387113PRTHomo sapiens 387Gly Gly Gly Leu Val Arg Pro Gly Gly Ser
Leu Arg Leu Ser Cys Lys1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg Tyr
Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala Lys
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asp Ser Gln Ser
Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr
Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser Ser
Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser388113PRTHomo sapiens 388Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ser
Lys Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Val Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser389113PRTHomo sapiens 389Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Phe Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser390113PRTHomo sapiens 390Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Leu Ala Trp Val Arg Gln 20 25 30Val Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser391113PRTHomo sapiens 391Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser392113PRTHomo sapiens 392Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asp Gly Glu 35 40 45Asp Ser Thr Tyr Tyr Ala
Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser393112PRTHomo sapiens 393Gly Gly Asp Leu Ala Gln Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala1 5 10 15Val Ser Gly Leu Ser Ile Gly Arg
Tyr Gly Met Asn Trp Ile Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Gly Ile Ser Asp Asp Gly 35 40 45Gly Ser Thr Tyr Tyr Ala
Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys
Asn Ser Val Tyr Leu Gln Met Ser Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Arg Tyr Tyr Cys Ala Lys Asp Arg Leu Met Phe 85 90 95Asp Gly
Phe His Met Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 100 105
110394115PRTHomo sapiens 394Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Arg Thr Tyr
Ala Met Ser Trp Val Arg Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Ile Ser Ala Arg Glu 35 40 45Asp Ser Thr Tyr Phe Ala Ala
Ser Val Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn
Thr Leu Tyr Leu Gln Met Asn Asn Leu Arg65 70 75 80Ala Glu Asp Thr
Ala Leu Tyr Tyr Cys Ala Lys Asp Arg Leu Gln Leu 85 90 95Gly Val Gly
Glu Leu Tyr Glu Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val
Ser Ser 115395113PRTHomo sapiens 395Gly Gly Gly Leu Val Arg Pro Gly
Gly Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg
Arg Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu
Glu Trp Val Ser Leu Ile Tyr Asn Ala Asp 35 40 45Asp Ser Thr Tyr Tyr
Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser
Gln Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu
Asp Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp
Ser Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser396113PRTHomo sapiens 396Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ser1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Leu Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Ile Ile Ser 50 55 60Arg Asp Asn Ser Leu
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser 100 105
110Ser397113PRTHomo sapiens 397Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asp Gly His 35 40 45Asp Thr Thr Tyr Tyr Ala
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Ala Val Ser 100 105
110Ser398113PRTHomo sapiens 398Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Asn Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Leu Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Lys Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser399113PRTHomo sapiens 399Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Trp Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Ser Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ala400113PRTHomo sapiens 400Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Leu Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Arg Ser
Ser Ile Val Glu Trp Gly Gln Gly Thr Trp Val Thr Val Ser 100 105
110Ser401115PRTHomo sapiens 401Gly Gly Gly Leu Val Gln Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Arg Thr
Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Ser Ile Ser Ala Ser Asp 35 40 45Asp Ser Thr Tyr Phe Ala
Ala Ser Val Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys
Asn Thr Leu Tyr Leu Gln Met Asn Asn Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Arg Leu Glu Leu 85 90 95Gly Val
Gly Glu Leu Tyr Glu Phe Trp Gly Gln Gly Thr Leu Val Thr 100 105
110Val Ser Ser 115402113PRTHomo sapiens 402Gly Gly Gly Leu Val Gln
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr
Phe Lys Asn Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Leu Leu Tyr Asn Ser Glu 35 40 45Glu Ser Thr
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Asn Thr Leu Phe Leu Gln Met Asn Arg Leu Arg65 70 75
80Val Glu Asp Thr Ala Val Tyr Phe Cys Val Arg Asp Arg Ser Asn Gly
85 90 95Trp Ser Ser Ile Asn Leu Trp Gly Arg Gly Thr Leu Val Thr Val
Ser 100 105 110Ser403113PRTHomo sapiens 403Gly Gly Gly Leu Val Arg
Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Asn
Phe Arg Arg Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Gln Ile Tyr Asn Gly Glu 35 40 45Asp Ser Thr
Tyr Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Gln Asn Thr Leu Ser Leu Gln Met Asn Gly Leu Arg65 70 75
80Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly
85 90 95Trp Ser Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val
Ser 100 105 110Ser404113PRTHomo sapiens 404Gly Gly Gly Leu Val Arg
Pro Gly Gly Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr
Phe Arg Arg Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Leu Ile Tyr Asp Gly Asp 35 40 45Asp Ser Thr
Tyr Tyr Ala Glu Ser
Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln Asn Thr
Val Ser Leu Gln Met Thr Ser Leu Arg65 70 75 80Ala Glu Asp Thr Ala
Leu Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser Ser Ile
Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser405113PRTHomo sapiens 405Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asp Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Lys Ser Val Lys Gly Arg Phe Ala Ile Ser 50 55 60Arg Asp Asn Ser Lys
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser406113PRTHomo sapiens 406Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Leu Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Lys Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Arg Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser407113PRTHomo sapiens 407Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Phe Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Gln Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Val Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser408113PRTHomo sapiens 408Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Phe Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Trp Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser His
Asn Thr Leu Ser Leu Gln Met Arg Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Val Lys Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser409113PRTHomo sapiens 409Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Val Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Val Arg Asp Arg Asp Asn Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser410113PRTHomo sapiens 410Gly Gly Gly Leu Ala Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Trp Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser411113PRTHomo sapiens 411Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Ala Tyr 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Ser Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Pro412113PRTHomo sapiens 412Gly Gly Gly Leu Val Arg Pro Gly Gly
Ser Leu Arg Leu Ser Cys Thr1 5 10 15Ala Ser Gly Phe Thr Phe Arg Arg
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Asn Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Glu Ser Val Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Val Lys Asp Arg Asp Thr Gly 85 90 95Trp Ser
Ser Ile Val Asp Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser413113PRTHomo sapiens 413Gly Gly Gly Leu Val Gln Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Asn
Tyr Ala Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ser Leu Ile Tyr Ser Gly Asp 35 40 45Asp Ser Thr Tyr Tyr Ala
Asp Phe Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg His Asn Ser Lys
Asn Thr Leu Ser Leu Gln Met Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Val Lys Asp Arg Gly Thr Gly 85 90 95Trp Ser
Ser Ile Val His Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser414121PRTHomo sapiens 414Gly Ala Glu Val Lys Arg Pro Gly Ala
Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe Thr Ser
Tyr Tyr Met His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu
Trp Met Gly Ile Ile Asn Pro Arg Gly 35 40 45Gly Ser Thr Thr Tyr Ala
Gln Lys Phe Gln Gly Arg Val Ala Leu Thr 50 55 60Gly Asp Thr Ser Thr
Ser Thr Val Tyr Met Glu Leu Thr Ser Leu Arg65 70 75 80Ser Asp Asp
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Lys Ala His Gln 85 90 95Thr Thr
Val Val Ile Leu Ser Trp Tyr Tyr Gly Met Asp Val Trp Gly 100 105
110Gln Gly Thr Thr Val Thr Val Ser Ser 115 120415121PRTHomo sapiens
415Gly Ala Glu Val Lys Lys Ser Gly Ala Ser Val Lys Val Ser Cys Lys1
5 10 15Ala Ser Gly Tyr Ser Phe Thr Thr Asn Tyr Ile His Trp Val Arg
Gln 20 25 30Ala Pro Gly Gln Gly Pro Glu Trp Met Gly Ile Ile Asn Pro
Arg Gly 35 40 45Gly Ser Thr Thr Tyr Ala Gln Lys Phe Gln Gly Arg Val
Leu Met Thr 50 55 60Ser Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu
Ser Ser Leu Arg65 70 75 80Ser Glu Asp Arg Ala Val Tyr Tyr Cys Ala
Arg Gly Lys Asn His Gln 85 90 95Thr Thr Val Ala Val Leu Ser Trp Tyr
Tyr Gly Met Asp Val Trp Gly 100 105 110Gln Gly Thr Thr Val Thr Val
Ser Ser 115 12041613PRTHomo sapiens 416Val Lys Asp Arg Asp Thr Gly
Trp Ser Ser Ile Val Asp1 5 1041713PRTHomo sapiens 417Val Lys Asp
Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5 1041813PRTHomo sapiens
418Val Lys Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5
1041913PRTHomo sapiens 419Val Lys Asp Arg Asp Asn Gly Trp Ser Ser
Ile Val Asp1 5 1042013PRTHomo sapiens 420Val Lys Asp Arg Asp Thr
Gly Trp Ser Ser Ile Val Asp1 5 1042113PRTHomo sapiens 421Val Lys
Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5 1042212PRTHomo
sapiens 422Ala Lys Asp Arg Leu Met Phe Asp Gly Phe His Met1 5
1042315PRTHomo sapiens 423Ala Lys Asp Arg Leu Gln Leu Gly Val Gly
Glu Leu Tyr Glu Ser1 5 10 1542413PRTHomo sapiens 424Val Lys Asp Arg
Asp Thr Gly Trp Ser Ser Ile Val Asp1 5 1042513PRTHomo sapiens
425Val Lys Asp Arg Asp Thr Gly Trp Ser Ser Ile Val Asp1 5
1042613PRTHomo sapiens 426Val Lys Asp Arg Asp Asn Gly Trp Ser Ser
Ile Val Asp1 5 1042713PRTHomo sapiens 427Val Lys Asp Arg Asp Asn
Gly Trp Ser Ser Ile Val Asp1 5 1042813PRTHomo sapiens 428Val Lys
Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5 1042913PRTHomo
sapiens 429Val Lys Asp Arg Asp Thr Gly Arg Ser Ser Ile Val Glu1 5
1043015PRTHomo sapiens 430Ala Lys Asp Arg Leu Glu Leu Gly Val Gly
Glu Leu Tyr Glu Phe1 5 10 1543113PRTHomo sapiens 431Val Arg Asp Arg
Ser Asn Gly Trp Ser Ser Ile Asn Leu1 5 1043213PRTHomo sapiens
432Val Lys Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5
1043313PRTHomo sapiens 433Val Lys Asp Arg Asp Asn Gly Trp Ser Ser
Ile Val Asp1 5 1043413PRTHomo sapiens 434Val Lys Asp Arg Asp Asn
Gly Trp Ser Ser Ile Val Asp1 5 1043513PRTHomo sapiens 435Val Arg
Asp Arg Asp Asn Gly Trp Ser Ser Ile Val Asp1 5 1043613PRTHomo
sapiens 436Val Lys Asp Arg Asp Thr Gly Trp Ser Ser Ile Val Asp1 5
1043713PRTHomo sapiens 437Val Lys Asp Arg Asp Asn Gly Trp Ser Ser
Ile Val Asp1 5 1043813PRTHomo sapiens 438Val Arg Asp Arg Asp Asn
Gly Trp Ser Ser Ile Val Asp1 5 1043913PRTHomo sapiens 439Val Lys
Asp Arg Asp Thr Gly Trp Ser Ser Ile Val Asp1 5 1044013PRTHomo
sapiens 440Val Lys Asp Arg Asp Thr Gly Trp Ser Ser Ile Val Asp1 5
1044113PRTHomo sapiens 441Val Lys Asp Arg Asp Thr Gly Trp Ser Ser
Ile Val Asp1 5 1044213PRTHomo sapiens 442Val Lys Asp Arg Gly Thr
Gly Trp Ser Ser Ile Val His1 5 1044321PRTHomo sapiens 443Ala Arg
Gly Lys Ala His Gln Thr Thr Val Val Ile Leu Ser Trp Tyr1 5 10 15Tyr
Gly Met Asp Val 2044421PRTHomo sapiens 444Ala Arg Gly Lys Asn His
Gln Thr Thr Val Ala Val Leu Ser Trp Tyr1 5 10 15Tyr Gly Met Asp Val
2044595PRTHomo sapiens 445Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Thr Ser Gln1 5 10 15Thr Ile Ala Asn Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Tyr Trp
Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85 90 9544695PRTHomo
sapiens 446Ser Ala Ser Val Gly Asp Thr Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Thr Leu Gly Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp Thr Phe Gly Gln
Gly Thr Lys Val Gly Ile Lys 85 90 9544795PRTHomo sapiens 447Ser Ala
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Thr
Ile Gly Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys His
Gln Tyr65 70 75 80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val
Gly Met Lys 85 90 9544895PRTHomo sapiens 448Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser His1 5 10 15Asn Ile Gly Gly Leu
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu
Ile Tyr Gln Ala Ser Arg Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Gly
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75
80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val Ala Ile Lys 85 90
9544995PRTHomo sapiens 449Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Thr Ser His1 5 10 15Thr Ile Gly Asn Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Arg Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp
Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85 90 9545095PRTHomo
sapiens 450Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Thr Ile Gly Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Lys Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Phe Cys His Gln Tyr65 70 75 80Ser Thr Tyr Trp Thr Phe Gly Gln
Gly Thr Lys Val Gly Ile Lys 85 90 9545196PRTHomo sapiens 451Ser Ala
Ser Val Gly Asp Ser Val Thr Ile Ser Cys Arg Ala Ser Arg1 5 10 15Ser
Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Leu Leu Ile Tyr Thr Ala Ser Thr Leu Glu Thr Gly Val Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Ala Glu Phe Thr Leu
Thr
Ile 50 55 60Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Tyr65 70 75 80Asn Asn Tyr Pro Trp Thr Phe Gly Gln Gly Thr Thr
Val Glu Ile Lys 85 90 9545296PRTHomo sapiens 452Ser Ala Ser Val Gly
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu
Leu Ile Tyr Met Ala Ser Ser Leu Gln Ser Gly Val Pro 35 40 45Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Val 50 55 60Ser
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75
80His Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
85 90 9545395PRTHomo sapiens 453Ser Ala Ser Val Gly Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln1 5 10 15Asn Val Asp Asn Trp Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln
Ala Ser Ile Leu Glu Asn Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro
Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe
Trp Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85 90
9545495PRTHomo sapiens 454Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Ser His Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Val Leu Glu Thr Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu
Asp Phe Gly Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 9545595PRTHomo
sapiens 455Ser Ala Ser Val Gly Asp Thr Val Thr Ile Thr Cys Arg Ala
Ser Arg1 5 10 15Thr Ile Gly Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Tyr Trp Thr Phe Gly Gln
Gly Thr Thr Val Gly Val Lys 85 90 9545695PRTHomo sapiens 456Ser Ala
Phe Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Thr
Ile Gly Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln
Gln Tyr65 70 75 80Ser Thr Phe Trp Thr Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 85 90 9545795PRTHomo sapiens 457Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Gly Asn Trp
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu
Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Gly
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75
80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85 90
9545895PRTHomo sapiens 458Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Gly Asn Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Tyr Trp
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 9545996PRTHomo
sapiens 459Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala Ser Ser Leu Gln
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Val 50 55 60Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr
Tyr Tyr Cys Gln His Tyr65 70 75 80Tyr Ser Tyr Pro Trp Thr Phe Gly
Gln Gly Thr Lys Val Glu Ile Lys 85 90 9546095PRTHomo sapiens 460Ser
Ala Ser Val Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln1 5 10
15Thr Ile Ser Gly Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Arg Leu Glu Ser Gly Ile
Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu
Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp Asp Val Ala Thr Tyr Tyr Cys
Gln Gln Tyr65 70 75 80Ser Thr Phe Trp Thr Phe Gly Leu Gly Thr Arg
Val Glu Ile Lys 85 90 9546195PRTHomo sapiens 461Ser Ala Ser Val Gly
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Gly Ser
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu
Leu Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75
80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85 90
9546296PRTHomo sapiens 462Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Thr Leu Asn Val Trp Leu Ala Trp Tyr
Gln Gln Gln Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Lys Ala
Ser Thr Leu Gln Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Asn Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9546395PRTHomo sapiens 463Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser His1 5 10 15Ser Ile Ser Gly Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Gly Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 9546495PRTHomo
sapiens 464Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Thr Ile Gly Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Arg Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp Thr Phe Gly Gln
Gly Thr Lys Val Gly Ile Lys 85 90 9546595PRTHomo sapiens 465Ser Ala
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Arg1 5 10 15Thr
Ile Gly Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Ile Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile 50 55 60Arg Gly Leu Gln Pro Glu Asp Phe Gly Thr Tyr Phe Cys Gln
Gln Tyr65 70 75 80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val
Gly Ile Lys 85 90 9546693PRTHomo sapiens 466Ser Val Gly Asp Arg Val
Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile1 5 10 15Gly Asn Trp Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys 20 25 30Leu Leu Ile Tyr
Gln Ala Ser Val Leu Glu Ser Gly Val Pro Ser Arg 35 40 45Phe Ser Gly
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser 50 55 60Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Ser Thr65 70 75
80Phe Trp Thr Phe Gly Gln Gly Thr Lys Val Gly Ile Lys 85
9046795PRTHomo sapiens 467Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Arg1 5 10 15Thr Ile Gly Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ile Leu Glu Gly Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Val
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 9546895PRTHomo
sapiens 468Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Thr Ile Ala Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Gln Pro 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu
Phe Thr Leu Thr Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Phe Cys Gln Gln Tyr65 70 75 80Ser Thr Phe Trp Thr Phe Gly Gln
Gly Thr Lys Val Gly Ile Lys 85 90 9546995PRTHomo sapiens 469Ser Ala
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser His1 5 10 15Thr
Ile Gly Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Leu Leu Ile Tyr Gln Ala Ser Ile Leu Glu Ser Gly Val Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile 50 55 60Arg Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln
Gln Tyr65 70 75 80Ser Thr Tyr Trp Thr Phe Gly Gln Gly Thr Lys Val
Gly Ile Lys 85 90 9547095PRTHomo sapiens 470Ser Ala Ser Val Gly Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser His1 5 10 15Thr Ile Ser Asn Trp
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu
Val Tyr Gln Ala Ser Ile Leu Glu Thr Gly Val Pro 35 40 45Ser Arg Phe
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Arg Ser
Leu Gln Pro Glu Asp Phe Gly Thr Tyr Phe Cys Gln Gln Tyr65 70 75
80Ser Thr Phe Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9547195PRTHomo sapiens 471Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Thr Ile Ser Asn Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Ser Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr65 70 75 80Ser Thr Tyr Trp
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90 9547296PRTHomo
sapiens 472Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln1 5 10 15Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys Ala 20 25 30Pro Lys Leu Leu Ile Ser Ala Ala Ser Ser Leu Gln
Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Tyr Cys Gln Gln Ala65 70 75 80Asn Ser Phe Pro Tyr Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile Lys 85 90 9547396PRTHomo sapiens 473Ser
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10
15Gly Ile Ser Ser Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala
20 25 30Pro Lys Leu Leu Ile Ser Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile 50 55 60Ser Asn Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys
Gln Gln Ala65 70 75 80Asn Ser Phe Pro Tyr Thr Phe Gly Gln Gly Thr
Lys Leu Glu Ile Lys 85 90 954748PRTHomo sapiens 474Gln Gln Tyr Ser
Thr Tyr Trp Thr1 54758PRTHomo sapiens 475Gln Gln Tyr Ser Thr Phe
Trp Thr1 54768PRTHomo sapiens 476His Gln Tyr Ser Thr Tyr Trp Thr1
54778PRTHomo sapiens 477Gln Gln Tyr Ser Thr Tyr Trp Thr1
54788PRTHomo sapiens 478Gln Gln Tyr Ser Thr Phe Trp Thr1
54798PRTHomo sapiens 479His Gln Tyr Ser Thr Tyr Trp Thr1
54809PRTHomo sapiens 480Gln Gln Tyr Asn Asn Tyr Pro Trp Thr1
54819PRTHomo sapiens 481Gln His Tyr His Ser Tyr Pro Trp Thr1
54828PRTHomo sapiens 482Gln Gln Tyr Ser Thr Phe Trp Thr1
54838PRTHomo sapiens 483Gln Gln Tyr Ser Thr Phe Trp Thr1
54848PRTHomo sapiens 484Gln Gln Tyr Ser Thr Tyr Trp Thr1
54858PRTHomo sapiens 485Gln Gln Tyr Ser Thr Phe Trp Thr1
54868PRTHomo sapiens 486Gln Gln Tyr Ser Thr Tyr Trp Thr1
54878PRTHomo sapiens 487Gln Gln Tyr Ser Thr Tyr Trp Thr1
54889PRTHomo sapiens 488Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
54898PRTHomo sapiens 489Gln Gln Tyr Ser Thr Phe Trp Thr1
54908PRTHomo sapiens 490Gln Gln Tyr Ser Thr Tyr Trp Thr1
54919PRTHomo sapiens 491Gln His Tyr His Ser Tyr Pro Trp Thr1
54928PRTHomo sapiens 492Gln Gln Tyr Ser Thr Phe Trp Thr1
54938PRTHomo sapiens 493Gln Gln Tyr Ser Thr Phe Trp Thr1
54948PRTHomo sapiens 494Gln Gln Tyr Ser Thr Tyr Trp Thr1
54958PRTHomo sapiens 495Gln Gln Tyr Ser Thr Phe Trp Thr1
54968PRTHomo sapiens 496Gln Gln Tyr Ser Thr Phe Trp Thr1
54978PRTHomo sapiens 497Gln Gln Tyr Ser Thr Phe Trp Thr1
54988PRTHomo sapiens 498Gln Gln Tyr Ser Thr Tyr Trp Thr1
54998PRTHomo sapiens 499Gln Gln Tyr Ser Thr Phe Trp Thr1
55008PRTHomo sapiens 500Gln Gln Tyr Ser Thr Tyr Trp Thr1
55019PRTHomo sapiens 501Gln Gln Ala Asn Ser Phe Pro Tyr Thr1
55029PRTHomo sapiens 502Gln Gln Ala Asn Ser Phe Pro Tyr Thr1
5503116PRTHomo sapiens 503Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Lys Leu Ser Cys Ser1 5 10 15Ala Ala Gly Phe Asn Phe Arg Ser Tyr
Ala Met Ser Trp Ile Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Leu Gly Thr Arg Gly 35 40 45Thr Glu Thr Thr Tyr Tyr Ala
Ala Ser Val Lys Gly Arg Phe Thr Ile 50 55 60Ser Arg Asp Asn Ser Lys
Asn Ile Leu Tyr Leu Gln Met Asn Ile Leu65 70 75 80Gly Ala Glu Asp
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Ile 85 90 95Glu Gly Leu
Gly Glu Leu Tyr Ser His Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 115504115PRTHomo sapiens 504Gly Gly Gly Leu Ala Gln Pro
Gly Gly Ser Leu Arg Leu Ser Cys Glu1 5 10 15Thr Ser Gly Phe Thr Phe
Arg Ser Tyr Gly Met Gly Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly
Leu Glu Trp Val Ser Ser Ile Tyr Ile Ser Gly 35 40 45Asp Ser Thr Tyr
Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn
Ser Lys Ser Thr Leu Tyr Leu Gln Met Asp Arg Leu Thr65 70 75 80Ala
Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg Asp Arg Ile Gln Gly 85 90
95Gly Phe Gly Glu Leu Tyr Arg Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110Val Ser Ser 115505112PRTHomo sapiens 505Gly Gly Gly Leu
Ala Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly
Phe Thr Phe Ser Ser Tyr Ala Met Thr Trp Val Arg Gln 20 25 30Ala Pro
Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Thr Gly Arg Asp 35 40 45Gly
Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55
60Arg Ala Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Gly Leu Arg65
70 75 80Ala Glu Asp Thr Ala Val Tyr Phe Cys Ala Lys Asp Arg Asp His
Phe 85 90 95Asp Gly His Asp Phe Trp Gly Gln Gly Ala Leu Val Thr Val
Ser Ser 100 105 110506115PRTHomo sapiens 506Gly Gly Arg Leu Val Gln
Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Pro
Phe Ser Thr Tyr Ala Met Ser Trp Leu Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Glu Trp Val Ser Gly Ile Thr Gly Asp Ser 35 40 45Gly Ser Thr
Tyr Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Thr65 70 75
80Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Arg Leu His Ser
85 90 95Gly Leu Gly Glu Leu Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val
Thr 100 105 110Val Ser Ser 115507115PRTHomo sapiens 507Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser
Gly Phe Ser Phe Arg Thr Tyr Gly Met Ser Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Ser Val Asp 35 40
45Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met His Asn Leu
Ser65 70 75 80Ala Lys Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Arg
Leu Ala Ser 85 90 95Gly Ile Gly Glu Leu Phe Ser Ser Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110Val Ala Ser 115508115PRTHomo sapiens
508Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Phe Thr Phe Arg Thr Tyr Gly Met Asn Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Gly Ile Ser Ser
Val Asp 35 40 45Pro Ser Thr Tyr Tyr Ala Gly Ser Val Lys Gly Arg Phe
Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Met Leu Tyr Leu Gln Met
Asn Ser Leu Thr65 70 75 80Ala Asp Asp Ser Ala Val Tyr Tyr Cys Ala
Lys Asp Arg Met Ser Gly 85 90 95Gly Phe Gly Glu Leu Asn Glu Ser Trp
Gly Gln Gly Thr Arg Val Thr 100 105 110Val Ser Ser 115509115PRTHomo
sapiens 509Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Val1 5 10 15Ala Ser Gly Phe Thr Phe Gly Ser Tyr Gly Met Ala Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Ile Ser Ser Ile
Ser Ser Ile Asp 35 40 45Pro Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
Arg Phe Thr Val Ser 50 55 60Arg Asp Asn Ser Glu Asn Thr Leu Tyr Leu
His Met Ser Ser Leu Lys65 70 75 80Val Glu Asp Thr Ala Val Tyr Phe
Cys Ala Lys Asp Arg Leu Asn Gly 85 90 95Gly Phe Gly Glu Leu Phe Ala
Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser
115510115PRTHomo sapiens 510Gly Gly Gly Leu Gly Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Pro Phe Ser Asp Phe
Gly Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Ser Ile Ser Gly Pro Gly 35 40 45Phe Asp Thr Tyr Tyr Ala Asp
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asp
Thr Leu Phe Leu Gln Met Ser Arg Leu Arg65 70 75 80Val Glu Asp Thr
Ala Val Tyr Tyr Cys Ala Arg Asp Arg Ile Lys Gly 85 90 95Gly Leu Gly
Glu Leu Phe His Leu Trp Gly Gln Gly Ala Leu Val Thr 100 105 110Val
Ser Ser 115511115PRTHomo sapiens 511Gly Gly Gly Leu Val Gln Pro Gly
Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Asn
Thr His Ala Met Ala Trp Leu Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu
Glu Trp Val Ser Ser Val Thr Ala Asn Gly 35 40 45Gly Asp Ser Trp Tyr
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser
Arg Asn Ile Leu Tyr Leu Gln Met Ser Ser Leu Arg65 70 75 80Val Glu
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Arg Leu Ala Ala 85 90 95Gly
Leu Gly Glu Leu Phe Ser His Trp Gly Gln Gly Thr Leu Val Ser 100 105
110Val Ser Ser 115512115PRTHomo sapiens 512Gly Gly Gly Leu Val Gln
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr
Phe Ser Thr Tyr Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Lys Trp Val Ser Gly Ile Thr Gly Asp Ser 35 40 45Gly Ser Thr
Tyr Tyr Ala Arg Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Asn Ser Lys Asn Thr Leu Tyr Leu Glu Ile Ser Ser Leu Arg65 70 75
80Ala Glu Asp Thr Ala Phe Tyr Phe Cys Thr Arg Asp Arg Leu Pro Asn
85 90 95Gly Ile Gly Glu Leu His Asp His Trp Gly Gln Gly Thr Leu Val
Thr 100 105 110Val Ser Ser 115513115PRTHomo sapiens 513Gly Gly Gly
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser
Gly Phe Thr Phe Arg Thr Tyr Gly Met Asn Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Gly Ile Asp 35 40
45Pro Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Ile Leu Phe Leu Gln Met Asn Ser Leu
Thr65 70 75 80Ala Asp Asp Thr Ala Val Tyr Tyr Cys Thr Lys Asp Arg
Leu Ser Gly 85 90 95Ala Phe Gly Glu Leu Asn Glu Ser Trp Gly Gln Gly
Thr Met Val Ile 100 105 110Val Ser Ser 115514115PRTHomo sapiens
514Gly Gly Ala Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Phe Thr Phe Arg Asn Tyr Gly Val Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Asn Thr
Asp Gly 35 40 45Gly Ser Thr Tyr Tyr Ala Ala Ser Val Lys Gly Arg Phe
Thr Ile Ser 50 55 60Arg Asp Asn Ser Arg Asn Thr Leu Tyr Leu Gln Met
Asp Gly Leu Thr65 70 75 80Val Ala Asp Thr Ala Met Tyr Phe Cys Thr
Lys Asp Arg Val Gln Gly 85 90 95Gly Phe Gly Glu Leu Phe His Ser Trp
Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Pro 115515121PRTHomo
sapiens 515Gly Gly Gly Leu Ile Gln Pro Gly Gly Ser Leu Arg Leu Ser
Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile
Ser Gly Ser Gly 35 40 45Gly Ala Ser Asp Asn Gly Ala Ser Arg Tyr Tyr
Ala Asp Ser Val Lys 50 55 60Gly Arg Phe Ser Ile Ser Arg Asp Asn Ser
Lys Asn Thr Val Tyr Leu65 70 75 80Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Lys Asp Arg Leu Ser Gly Gly
Phe Gly Glu Leu Phe Gln Lys Trp Gly 100 105 110Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120516115PRTHomo sapiens 516Gly Gly Asp Leu Val
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe
Thr Phe Ser Thr Tyr Gly Met Ala Trp Val Arg Gln 20 25 30Ala Pro Gly
Lys Gly Leu Glu Trp Leu Ser Ser Ile Ser Ser Val Asp 35 40 45Asp Ser
Lys Tyr Tyr Ala Ala Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg
Asp Asn Ser Arg Asn Thr Leu Tyr Leu His Met Asn Ser Leu Arg65 70 75
80Val Asp Asp Thr Ala Val Tyr Tyr Cys Ala Lys Asp Arg Ile Pro His
85 90 95Gly Leu Gly Glu Leu Tyr Ala Asn Trp Gly Gln Gly Thr Leu Val
Ala 100 105 110Val Ser Ser 115517115PRTHomo sapiens 517Gly Gly Asp
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser
Gly Phe Thr Phe Arg Thr Tyr Gly Met Thr Trp Val Arg Gln 20 25 30Ala
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Ser Val Asp 35 40
45Asp Ser Thr Tyr Tyr Ala Lys Ser Val Lys Gly Arg Phe Thr Ile Ser
50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu His Ile Thr Asn Leu
Arg65 70 75 80Val Asp Asp Thr Ala Met Tyr Tyr Cys Ala Lys Asp Arg
Ser Pro His 85 90 95Gly Leu Gly Glu Leu Tyr Gly Asp Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110Val Ser Ser 115518113PRTHomo sapiens
518Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala1
5 10 15Ala Ser Gly Leu Thr Phe Ser Thr Tyr Ala Met Ser Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Pro
Gly Ser 35 40 45Gly Asp Asn Ile Tyr Tyr Gly Asp Ser Val Lys Gly Arg
Phe Thr Ile 50 55 60Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
Met Asn Ser Leu65 70 75 80Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
Val Asn Gly Gly Phe Ser 85 90 95Gly Tyr Tyr Ser Asp Tyr Trp Gly Gln
Gly Thr Leu Val Ala Val Ser 100 105 110Ser519117PRTHomo sapiens
519Gly Gly Gly Leu Gly Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Gly1
5 10 15Ala Ser Gly Phe Thr Phe Ser Thr Tyr Ala Met Thr Trp Val Arg
Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Asp Ile Ser Ala
Asp Ser 35 40 45Asp Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe
Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
Asn Ser Leu Arg65 70 75 80Ala Glu Asp Ser Ala Val Tyr Tyr Cys Ala
Lys Val Lys Asp Ser Ser 85 90 95Gly Tyr Met Tyr Tyr Tyr Tyr Met Asp
Val Trp Gly Lys Gly Thr Thr 100 105 110Val Thr Val Ser Ser
115520111PRTHomo sapiens 520Gly Gly Gly Leu Val Leu Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Thr His
Ala Met Thr Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Val Ile Ser His Ser Gly 35 40 45Thr Thr Thr Tyr Tyr Ala Asp
Ser Phe Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn
Thr Val Tyr Leu Gln Met Asn Arg Leu Arg65 70 75 80Val Glu Asp Thr
Ala Val Tyr Tyr Cys Ala Lys Asp Leu Tyr Asn Gly 85 90 95Tyr Phe Asp
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105
110521110PRTHomo sapiens 521Gly Gly Gly Val Val Gln Pro Gly Arg Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Ile Ser
Thr Ile His Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Tyr
Val Val Val Ile Ser His Asp Gly 35 40 45Asn Thr Lys Tyr Tyr Ala Asp
Ser Val Lys Gly Arg Phe Ile Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn
Thr Val Phe Leu Gln Met Asn Ser Leu Arg65 70 75 80Pro Val Asp Thr
Ala Val Tyr Tyr Cys Ala Arg Gly Glu Val Gly Tyr 85 90 95Phe Asp Leu
Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 100 105
110522113PRTHomo sapiens 522Gly Gly Gly Val Val Gln Pro Gly Arg Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Ser Phe Ser Ser His
Ala Met Tyr Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ala Ile Val Ser Tyr Asp Gly 35 40 45Ser Thr Lys Asn Tyr Ala Asp
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Asn
Thr Ile Tyr Leu His Leu Asn Ser Leu Arg65 70 75 80Ala Glu Asp Thr
Ala Val Tyr Phe Cys Ala Arg Glu Val Asp Gly Ile 85 90 95Tyr Gly Tyr
Leu His Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 100 105
110Ser523114PRTHomo sapiens 523Gly Gly Gly Val Val Gln Pro Gly Arg
Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Ser Asn
Tyr Gly Met His Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu
Trp Val Ala Ile Ile Ser Tyr Asp Gly 35 40 45Asn Thr Lys Tyr Tyr Ala
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys
Asn Thr Leu Tyr Leu Gln Leu Asn Ser Leu Arg65 70 75 80Ala Glu Asp
Thr Ala Ile Tyr Tyr Cys Ala Arg Asp Gly Thr Thr Val 85 90
95Thr Asn Phe Tyr Leu Asp Val Trp Gly Lys Gly Ser Thr Val Thr Val
100 105 110Ser Ser524110PRTHomo sapiens 524Gly Gly Gly Val Val Gln
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr
Phe Asn Thr Tyr Ala Val His Trp Val Arg Gln 20 25 30Ala Pro Gly Lys
Gly Leu Asp Trp Val Thr Val Leu Ser His Asp Gly 35 40 45Asn Ser Lys
Tyr Tyr Thr Asp Ser Val Arg Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp
Ser Ser Lys Lys Thr Val Phe Leu Gln Met Asp Asn Leu Arg65 70 75
80Thr Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe His Gly Tyr
85 90 95Leu Asp Ser Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100
105 110525116PRTHomo sapiens 525Gly Pro Gly Leu Val Lys Pro Ser Glu
Thr Leu Ser Leu Thr Cys Gly1 5 10 15Val Ser Gly Tyr Ser Leu Thr Ser
Gly Tyr Tyr Trp Ser Trp Ile Arg 20 25 30Gln Pro Pro Gly Lys Gly Leu
Glu Trp Ile Gly Ser Ile Tyr His Thr 35 40 45Gly Asn Thr Tyr Tyr Asn
Pro Ser Leu Lys Ser Arg Val Thr Ile Leu 50 55 60Val Asp Thr Ser Lys
Asn His Phe Ser Leu Lys Leu Thr Ser Val Thr65 70 75 80Ala Ala Asp
Thr Ala Met Tyr Tyr Cys Ala Arg Thr Glu Thr Ile Thr 85 90 95Ile Arg
Gly Ala Val Ser Phe Asp Ile Trp Gly Gln Gly Arg Met Val 100 105
110Thr Val Ser Ser 115526123PRTHomo sapiens 526Gly Pro Gly Leu Val
Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Ser1 5 10 15Val Ser Gly Tyr
Phe Ile Ser Ser Gly His Tyr Trp Gly Trp Ile Arg 20 25 30Gln Ser Pro
Gly Lys Gly Leu Glu Trp Ile Ala Ser Ile Tyr Gln Ser 35 40 45Gly Ser
Lys Phe Gln Thr Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Glu 50 55 60Ser
Arg Val Thr Ile Ser Met Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75
80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95Arg Asp Ala Arg Ser Arg Ser Trp Asp Arg Thr Gly Phe Phe Gly
Pro 100 105 110Trp Gly Gln Gly Ile Leu Val Thr Ile Ser Ser 115
12052715PRTHomo sapiens 527Ala Arg Asp Arg Gly Ile Glu Gly Leu Gly
Glu Leu Tyr Ser His1 5 10 1552815PRTHomo sapiens 528Val Arg Asp Arg
Ile Gln Gly Gly Phe Gly Glu Leu Tyr Arg Tyr1 5 10 1552912PRTHomo
sapiens 529Ala Lys Asp Arg Asp His Phe Asp Gly His Asp Phe1 5
1053015PRTHomo sapiens 530Ala Lys Asp Arg Leu His Ser Gly Leu Gly
Glu Leu Phe Ser Tyr1 5 10 1553115PRTHomo sapiens 531Ala Lys Asp Arg
Leu Ala Ser Gly Ile Gly Glu Leu Phe Ser Ser1 5 10 1553215PRTHomo
sapiens 532Ala Lys Asp Arg Met Ser Gly Gly Phe Gly Glu Leu Asn Glu
Ser1 5 10 1553315PRTHomo sapiens 533Ala Lys Asp Arg Leu Asn Gly Gly
Phe Gly Glu Leu Phe Ala Ser1 5 10 1553415PRTHomo sapiens 534Ala Arg
Asp Arg Ile Lys Gly Gly Leu Gly Glu Leu Phe His Leu1 5 10
1553515PRTHomo sapiens 535Ala Lys Asp Arg Leu Ala Ala Gly Leu Gly
Glu Leu Phe Ser His1 5 10 1553615PRTHomo sapiens 536Thr Arg Asp Arg
Leu Pro Asn Gly Ile Gly Glu Leu His Asp His1 5 10 1553715PRTHomo
sapiens 537Thr Lys Asp Arg Leu Ser Gly Ala Phe Gly Glu Leu Asn Glu
Ser1 5 10 1553815PRTHomo sapiens 538Thr Lys Asp Arg Val Gln Gly Gly
Phe Gly Glu Leu Phe His Ser1 5 10 1553915PRTHomo sapiens 539Ala Lys
Asp Arg Leu Ser Gly Gly Phe Gly Glu Leu Phe Gln Lys1 5 10
1554015PRTHomo sapiens 540Ala Lys Asp Arg Ile Pro His Gly Leu Gly
Glu Leu Tyr Ala Asn1 5 10 1554115PRTHomo sapiens 541Ala Lys Asp Arg
Ser Pro His Gly Leu Gly Glu Leu Tyr Gly Asp1 5 10 1554212PRTHomo
sapiens 542Val Asn Gly Gly Phe Ser Gly Tyr Tyr Ser Asp Tyr1 5
1054317PRTHomo sapiens 543Ala Lys Val Lys Asp Ser Ser Gly Tyr Met
Tyr Tyr Tyr Tyr Met Asp1 5 10 15Val54411PRTHomo sapiens 544Ala Lys
Asp Leu Tyr Asn Gly Tyr Phe Asp Tyr1 5 1054510PRTHomo sapiens
545Ala Arg Gly Glu Val Gly Tyr Phe Asp Leu1 5 1054613PRTHomo
sapiens 546Ala Arg Glu Val Asp Gly Ile Tyr Gly Tyr Leu His Tyr1 5
1054714PRTHomo sapiens 547Ala Arg Asp Gly Thr Thr Val Thr Asn Phe
Tyr Leu Asp Val1 5 1054810PRTHomo sapiens 548Ala Arg Asp Phe His
Gly Tyr Leu Asp Ser1 5 1054916PRTHomo sapiens 549Ala Arg Thr Glu
Thr Ile Thr Ile Arg Gly Ala Val Ser Phe Asp Ile1 5 10
1555017PRTHomo sapiens 550Ala Arg Asp Ala Arg Ser Arg Ser Trp Asp
Arg Thr Gly Phe Phe Gly1 5 10 15Pro55196PRTHomo sapiens 551Ser Ala
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser
Ile Asn Ser Trp Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25
30Pro Lys Phe Leu Ile Tyr Lys Ala Ser Thr Leu Glu Ser Gly Val Pro
35 40 45Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr
Ile 50 55 60Thr Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln
His Tyr65 70 75 80Tyr Ser Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys
Val Glu Ile Lys 85 90 9555296PRTHomo sapiens 552Ser Ala Ser Val Gly
Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln1 5 10 15Ser Val Asn Lys
Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu
Leu Ile Tyr Glu Thr Ser Ile Leu Glu Ser Gly Val Ser 35 40 45Ser Arg
Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75
80His Gly Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg
85 90 9555396PRTHomo sapiens 553Ser Ala Ala Val Gly Asp Ser Val Thr
Ile Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Arg Ala 20 25 30Pro Lys Leu Leu Ile Ser Lys
Ala Ser Asn Val Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Lys Tyr65 70 75 80Asn Ser Tyr
Pro Phe Thr Phe Gly Pro Gly Thr Lys Leu Asp Ile Lys 85 90
9555496PRTHomo sapiens 554Ser Ala Ser Val Gly Asp Arg Val Asn Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Asn Gln Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Met Tyr Lys Ala
Ser Thr Leu Glu Thr Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Phe Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9555596PRTHomo sapiens 555Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asp Met Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Arg Ala 20 25 30Pro Lys Phe Leu Ile His Lys Ala
Ser Thr Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys 85 90
9555696PRTHomo sapiens 556Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Gly Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Arg Ala 20 25 30Pro Asn Leu Leu Ile Tyr Gln Ala
Ser Ala Leu His Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Ser Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Phe Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9555796PRTHomo sapiens 557Ser Ala Ser Val Gly Asp Ser Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile His Lys Ala
Ser Ser Leu Glu Ser Gly Ile Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Asn Asn Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9555896PRTHomo sapiens 558Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Ile Cys Arg Ala Ser Arg1 5 10 15Ser Ile Asp Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Arg Leu Leu Ile His Lys Ala
Ser Thr Leu His Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Phe Cys Gln His Tyr65 70 75 80Phe Ser Ser Pro
Tyr Ser Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9555996PRTHomo sapiens 559Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Gly Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile His Lys Ala
Ser Thr Leu Glu Ser Gly Val Ser 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Asn Asn Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9556096PRTHomo sapiens 560Ser Ala Ser Val Gly Asp Arg Val Ser Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asp Met Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Lys Ala
Ser Asn Leu Lys Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9556196PRTHomo sapiens 561Ser Ala Ser Ile Gly Ala Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asp Ile Ser Gly Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Arg Ala 20 25 30Pro Lys Leu Leu Ile Tyr Gln Ala
Ser Thr Leu Tyr Asn Gly Val Pro 35 40 45Pro Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Gly Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9556296PRTHomo sapiens 562Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Lys Phe Leu Met His Lys Ala
Ser Ile Leu Glu Ser Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Ser Tyr Phe Cys Gln Gln Tyr65 70 75 80His Ser Tyr Pro
Trp Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys 85 90
9556396PRTHomo sapiens 563Ala Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Asn Ile Asn Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Phe Leu Ile Tyr Lys Ala
Ser Thr Leu Glu Ser Gly Ala Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Tyr Ser Tyr Pro
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9556496PRTHomo sapiens 564Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Gly Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Arg Leu Leu Met His Lys Ala
Ser Ile Leu Tyr Arg Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80His Ser Tyr Pro
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 85 90
9556596PRTHomo sapiens 565Ser Ala Ser Val Gly Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala 20 25 30Pro Lys Leu Leu Met His Lys Ala
Ser Asn Leu His Val Gly Val Pro 35 40 45Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Thr Ser Leu Gln Pro Asp
Asp Phe Ala Thr Tyr Tyr Cys Gln His Tyr65 70 75 80Phe Ser Tyr Pro
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 85 90
9556695PRTHomo sapiens 566Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Asn Tyr Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Asp Ala
Ser Asn Met Ala Pro Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Glu Pro Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75 80Ser Asn Trp Leu
Thr Phe Gly Gly Gly Thr Lys Ile Glu Ile Lys 85 90 9556796PRTHomo
sapiens 567Ser Leu Ser Pro Gly Glu Arg Thr Thr Leu Ser Cys Arg Ala
Ser Gln1 5 10 15Ser Ile Ser Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala
Ala Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly Ser Gly Ile Asp
Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Glu Pro Glu Asp Phe Gly Val
Tyr Tyr Cys Gln Gln Arg65 70 75 80Gly Lys Trp Pro Pro Ser Phe Gly
Gly Gly Thr
Lys Val Glu Ile Lys 85 90 9556897PRTHomo sapiens 568Ser Leu Ser Pro
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Arg
Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg
Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro 35 40 45Ala
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55
60Ser Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65
70 75 80Gly Asn Trp Pro Pro Ala Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile 85 90 95Lys56997PRTHomo sapiens 569Ser Leu Ser Pro Gly Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Ser Phe Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro 20 25 30Pro Arg Leu Leu Ile
Tyr Asp Ala Ser Thr Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75 80Ser
Asn Trp Pro Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile 85 90
95Lys57095PRTHomo sapiens 570Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Arg Gln1 5 10 15Asn Val Arg Asn Phe Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Asp
Ala Ser Asn Arg Ala Thr Asp Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Glu Pro
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75 80Ser Tyr Ser
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Met Lys 85 90
9557196PRTHomo sapiens 571Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Asn Tyr Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Asp Ala
Ser Ser Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Ser Leu Thr Ile 50 55 60Ser Ser Leu Glu Pro Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75 80Ser Asn Gly Pro
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 85 90
9557297PRTHomo sapiens 572Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Asn Phe Phe Ala Trp Tyr
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Asp Ala
Ser Lys Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu Glu Pro Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75 80Ser Asn Trp Pro
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 85 90
95Lys57399PRTHomo sapiens 573Ser Leu Ser Pro Gly Glu Arg Ala Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Ser Ser Tyr Leu Ala
Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr
Gly Ala Tyr Asn Arg Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Asn Arg Leu Glu
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Thr
Ser Pro Pro Glu Phe Thr Phe Gly Arg Gly Thr Lys Val 85 90 95Glu Ile
Lys57497PRTHomo sapiens 574Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Ser Leu Ser Ser Ser Phe Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ser Pro Arg Leu Leu Ile Tyr Gly
Thr Ser Ser Arg Asp Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu Pro
Glu Asp Ser Ala Val Tyr Tyr Cys Gln Gln65 70 75 80Tyr Gly Ser Ser
Trp Gly Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 85 90
95Lys5759PRTHomo sapiens 575Gln His Tyr Tyr Ser Tyr Pro Trp Thr1
55769PRTHomo sapiens 576Gln His Tyr His Gly Tyr Pro Trp Thr1
55779PRTHomo sapiens 577Gln Lys Tyr Asn Ser Tyr Pro Phe Thr1
55789PRTHomo sapiens 578Gln His Tyr Phe Ser Tyr Pro Trp Thr1
55799PRTHomo sapiens 579Gln His Tyr His Ser Tyr Pro Trp Thr1
55809PRTHomo sapiens 580Gln His Tyr Phe Ser Tyr Pro Trp Thr1
55819PRTHomo sapiens 581Gln His Tyr His Ser Tyr Pro Trp Thr1
55829PRTHomo sapiens 582Gln His Tyr Phe Ser Ser Pro Tyr Ser1
55839PRTHomo sapiens 583Gln His Tyr His Ser Tyr Pro Trp Thr1
55849PRTHomo sapiens 584Gln His Tyr His Ser Tyr Pro Trp Thr1
55859PRTHomo sapiens 585Gln His Tyr His Ser Tyr Pro Trp Thr1
55869PRTHomo sapiens 586Gln Gln Tyr His Ser Tyr Pro Trp Thr1
55879PRTHomo sapiens 587Gln His Tyr Tyr Ser Tyr Pro Tyr Thr1
55889PRTHomo sapiens 588Gln His Tyr His Ser Tyr Pro Tyr Thr1
55899PRTHomo sapiens 589Gln His Tyr Phe Ser Tyr Pro Tyr Thr1
55908PRTHomo sapiens 590Gln Gln Arg Ser Asn Trp Leu Thr1
55919PRTHomo sapiens 591Gln Gln Arg Gly Lys Trp Pro Pro Ser1
559210PRTHomo sapiens 592Gln Gln Arg Gly Asn Trp Pro Pro Ala Thr1 5
1059310PRTHomo sapiens 593Gln Gln Arg Ser Asn Trp Pro Pro Ile Thr1
5 105948PRTHomo sapiens 594Gln Gln Arg Ser Tyr Ser Ile Thr1
55959PRTHomo sapiens 595Gln Gln Arg Ser Asn Gly Pro Leu Thr1
559610PRTHomo sapiens 596Gln Gln Arg Ser Asn Trp Pro Pro Leu Thr1 5
1059711PRTHomo sapiens 597Gln Gln Tyr Gly Thr Ser Pro Pro Glu Phe
Thr1 5 105989PRTHomo sapiens 598Gln Gln Tyr Gly Ser Ser Trp Gly
Thr1 5599112PRTHomo sapiens 599Gly Gly Ala Leu Val Gln Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Phe Thr Phe Asn Tyr
Tyr Ala Met Thr Trp Val Arg Gln 20 25 30Ala Pro Gly Arg Gly Leu Glu
Trp Val Ser Thr Ile Thr Asp Asn Gly 35 40 45Gly Thr Thr Tyr Leu Ala
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Gln
Asn Thr Gln Ser Leu Gln Met Asn Asn Leu Arg65 70 75 80Ala Asp Asp
Thr Ala Val Tyr Phe Cys Val Lys His Leu Arg Gly Trp 85 90 95Tyr Thr
Phe Glu Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105
110600115PRTHomo sapiens 600Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala1 5 10 15Ala Ser Gly Tyr Ile Phe Asp Asn Tyr
Ala Met Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Lys Gly Leu Glu Trp
Val Ser Tyr Ile Asn Gly Gly Gly 35 40 45Tyr Gly Thr Asp Tyr Ala Asp
Ser Val Lys Gly Arg Phe Thr Ile Ser 50 55 60Arg Asp Asn Ser Lys Arg
Ile Leu Tyr Leu Gln Met Asn Ser Leu Arg65 70 75 80Val Gly Asp Thr
Ala Val Tyr Tyr Cys Ala Lys Ser Pro Tyr Val Gly 85 90 95Gly Tyr Gly
Leu Pro Gly Asp Ser Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val
Ser Ser 115601119PRTHomo sapiensMOD_RES(18)..(18)Any amino
acidMOD_RES(27)..(27)Any amino acidMOD_RES(73)..(73)Any amino
acidMOD_RES(80)..(80)Any amino acid 601Gly Pro Gly Leu Val Lys Pro
Ser Glu Thr Leu Ser Leu Thr Cys Thr1 5 10 15Val Xaa Gly Gly Ser Ile
Ser Arg Tyr Phe Xaa Ser Trp Ile Arg Gln 20 25 30Pro Pro Gly Lys Gly
Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Thr Gly 35 40 45Ser Thr Asn Tyr
Asn Pro Ser Leu Lys Ser Arg Val Ile Ile Leu Val 50 55 60Asp Thr Ser
Lys Asn Gln Phe Ser Xaa Lys Leu Ser Ser Val Thr Xaa65 70 75 80Ala
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Pro His Tyr Tyr Asp 85 90
95Ser Ser Ala Tyr Phe Thr Tyr Asn Gly Met Asp Val Trp Gly Gln Gly
100 105 110Thr Thr Val Thr Val Ser Ser 115602117PRTHomo sapiens
602Gly Pro Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr1
5 10 15Val Ser Gly Gly Ser Ile Ser Ser Tyr Tyr Trp Ser Trp Ile Arg
Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Phe Ile Tyr Tyr
Ser Gly 35 40 45Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr
Ile Ser Val 50 55 60Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser
Ser Val Thr Ala65 70 75 80Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg
Gly Asp Tyr Tyr Tyr Asp 85 90 95Ser Ser Gly Tyr Leu Tyr Tyr Phe Asp
Tyr Trp Gly Gln Gly Thr Leu 100 105 110Val Thr Val Ser Ser
11560312PRTHomo sapiens 603Val Lys His Leu Arg Gly Trp Tyr Thr Phe
Glu Ile1 5 1060415PRTHomo sapiens 604Ala Lys Ser Pro Tyr Val Gly
Gly Tyr Gly Leu Pro Gly Asp Ser1 5 10 1560520PRTHomo sapiens 605Ala
Arg Gly Pro His Tyr Tyr Asp Ser Ser Ala Tyr Phe Thr Tyr Asn1 5 10
15Gly Met Asp Val 2060618PRTHomo sapiens 606Ala Arg Gly Asp Tyr Tyr
Tyr Asp Ser Ser Gly Tyr Leu Tyr Tyr Phe1 5 10 15Asp Tyr60798PRTHomo
sapiens 607Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala
Ser Gln1 5 10 15Ser Val Ser Gly Ser Tyr Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln 20 25 30Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg
Ala Thr Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr 50 55 60Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
Val Tyr Tyr Cys Gln Gln65 70 75 80Phe Gly Ser Ser Pro Arg Tyr Thr
Phe Gly Gln Gly Thr Lys Leu Glu 85 90 95Ile Lys60897PRTHomo sapiens
608Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1
5 10 15Thr Ile Phe Phe Asn Tyr Leu Ala Trp Tyr Gln Lys Lys Pro Gly
Gln 20 25 30Ala Pro Arg Leu Leu Val His Gly Ala Ser Thr Arg Ala Thr
Gly Ile 35 40 45Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr 50 55 60Ile Asn Ser Leu Asp Pro Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln65 70 75 80Tyr Gly Asp Ser Pro Pro Thr Phe Gly Gly
Gly Thr Lys Val Asp Ile 85 90 95Lys60998PRTHomo sapiens 609Ser Leu
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Val Ser Gln1 5 10 15Ser
Val Ser Ser Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 20 25
30Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile
35 40 45Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr 50 55 60Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys
Gln Gln65 70 75 80Tyr Gly Ser Ser Pro Pro Val Thr Phe Gly Gln Gly
Thr Arg Leu Glu 85 90 95Ile Lys61096PRTHomo sapiens 610Ser Leu Ser
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val
Ser Ser Ser Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile 35 40
45Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
50 55 60Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
Gln65 70 75 80Tyr Gly Thr Ser Val Thr Phe Gly Gly Gly Thr Lys Val
Glu Ile Lys 85 90 9561110PRTHomo sapiens 611Gln Gln Phe Gly Ser Ser
Pro Arg Tyr Thr1 5 106129PRTHomo sapiens 612Gln Gln Tyr Gly Asp Ser
Pro Pro Thr1 561310PRTHomo sapiens 613Gln Gln Tyr Gly Ser Ser Pro
Pro Val Thr1 5 106148PRTHomo sapiens 614Gln Gln Tyr Gly Thr Ser Val
Thr1 5615117PRTHomo sapiens 615Gly Ala Glu Val Lys Lys Pro Gly Ser
Ser Val Arg Val Ser Cys Lys1 5 10 15Ala Ser Gly Asp Thr Phe Ser Asn
Tyr Ala Ile Ser Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu
Trp Met Gly Gly Ile Ile Pro Ile Phe 35 40 45Gly Thr Ala Ser Tyr Ala
Gln Arg Phe Gln Asp Arg Val Thr Ile Thr 50 55 60Ala Asp Lys Ser Thr
Gly Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75 80Ser Glu Asp
Thr Ala Val Phe Tyr Cys Ala Arg Gln Lys Cys Thr Gly 85 90 95Gly Ser
Cys Tyr Ser Gly Asn Phe Asp Pro Trp Gly Gln Gly Thr Leu 100 105
110Val Thr Val Ser Ser 115616122PRTHomo sapiens 616Gly Ala Glu Val
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Pro Gly
Gly Thr Phe Ser Arg Tyr Ser Ile Ala Trp Val Arg Gln 20 25 30Ala Pro
Gly Gln Gly Leu Glu Trp Met Gly Gly Ile Asn Pro Thr Phe 35 40 45Thr
Thr Pro Asn Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Ile Thr 50 55
60Ala Asp Glu Ser Thr Asn Thr Ala Tyr Leu Asp Leu Ser Ser Leu Arg65
70 75 80Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Arg Tyr Tyr
Tyr 85 90 95Glu Ser Gly Gly Tyr Ser Asp Ala Ser Pro Tyr Tyr Leu Asp
Tyr Trp 100 105 110Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115
120617116PRTHomo sapiens 617Gly Pro Gly Leu Val Lys Pro Ser Gln Thr
Leu Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Val Ser Ile Ser Ser Gly
Gly Tyr Tyr Tyr Ser Trp Phe 20 25 30Arg Gln Leu Pro Gly Lys Gly Leu
Glu Trp Ile Gly His Ile Tyr Tyr 35 40 45Thr Gly Asn Thr His Tyr Asn
Pro Ser Leu Arg Ser Arg Leu Thr Ile 50 55 60Ser Val Asp Thr Ser Lys
Asn Gln Phe Ser Leu Lys Leu Ser Ser Val65 70 75 80Thr Ala Ala Asp
Thr Ala Arg Tyr Tyr Cys Ala Arg Ala Trp Cys Glu 85 90 95Tyr Ala Ala
Tyr Cys Trp Phe Asp Pro Trp Gly Arg Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 115618117PRTHomo sapiens 618Gly Pro Gly Leu Val Lys Pro
Ser Gln Thr Leu Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Gly Ser Ile
Thr Gly Gly Val Tyr Tyr Trp Asn Trp Ile 20 25 30Arg His His Pro Gly
Lys Gly Leu Glu Trp Ile Gly Tyr Met Phe Tyr 35 40 45Ser Gly Asp Thr
Asp Tyr Asn Pro Ser Leu Arg Ser Arg Val Thr Ile 50 55 60Ser Gly Asp
Thr Ser Lys Asn Lys Phe Ser Leu Asn Leu Asn Ser Val65 70 75 80Thr
Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ala Gly Phe Asp 85 90
95Tyr Gly Ser Pro Val Ser Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110Val Thr Val Ser Ser 115619116PRTHomo sapiens 619Gly Pro
Gly Leu Val Lys Pro Ser Glu Thr Leu
Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Gly Ser Ile Ser Ser Tyr Asn
Tyr Tyr Trp Gly Trp Ile 20 25 30Arg Gln Pro Pro Gly Lys Gly Leu Glu
Phe Ile Gly Ser Ile Tyr Tyr 35 40 45Thr Gly Ser Thr Tyr Tyr Asn Pro
Ser Leu Arg Ser Arg Val Thr Ile 50 55 60Ser Val Asp Thr Ser Lys Asn
Gln Phe Ser Leu Lys Leu Thr Ser Val65 70 75 80Thr Ala Ala Asp Thr
Ala Val Tyr Tyr Cys Ala Arg His Gly Pro Gly 85 90 95Met Gly His Asn
Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val 100 105 110Thr Val
Ser Ser 115620118PRTHomo sapiens 620Gly Pro Arg Leu Val Lys Pro Ser
Glu Thr Leu Phe Leu Thr Cys Thr1 5 10 15Val Ser Gly Asp Ser Ile Ser
Ser Ser Ser Tyr Phe Trp Gly Trp Ile 20 25 30Arg Gln Pro Pro Gly Lys
Gly Leu Glu Trp Ile Gly Ser Ile Ser Tyr 35 40 45Ser Gly Ser Thr Tyr
Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile 50 55 60Ser Val Asp Thr
Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val65 70 75 80Thr Ala
Ala Asp Thr Val Val Tyr Tyr Cys Ala Lys His Leu Tyr Ser 85 90 95Ser
Ser Trp Asn Ile Gly Ser Ser Phe Asp Ser Trp Gly Pro Gly Thr 100 105
110Leu Val Thr Val Ser Ser 115621107PRTHomo sapiens 621Gly Pro Gly
Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Ser Cys Thr1 5 10 15Val Ser
Ser Gly Ser Ile Ser Asn Tyr Tyr Trp Asn Trp Ile Arg Gln 20 25 30Pro
Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly 35 40
45Ser Ile Ser Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val
50 55 60Asp Thr Ser Lys Asn Gln Leu Ser Leu Lys Leu Asn Ser Val Thr
Ala65 70 75 80Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Pro Asp
Asn Arg Tyr 85 90 95Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100
105622107PRTHomo sapiens 622Gly Pro Gly Leu Val Lys Pro Ser Glu Thr
Leu Ser Leu Thr Cys Thr1 5 10 15Val Ser Gly Gly Ser Ile Ser Asn Tyr
Tyr Trp Asn Trp Ile Arg Gln 20 25 30Pro Pro Gly Lys Gly Leu Glu Trp
Ile Gly Tyr Ile Tyr Tyr Ser Gly 35 40 45Ser Ile Ser Tyr Asn Pro Ser
Leu Lys Ser Arg Val Thr Ile Ser Val 50 55 60Asp Thr Ser Lys Asn Gln
Leu Ser Leu Lys Leu Asn Ser Val Thr Ala65 70 75 80Ala Asp Thr Ala
Val Tyr Tyr Cys Ala Arg Gly Pro Asp Asn Arg Tyr 85 90 95Trp Gly Gln
Gly Thr Leu Val Thr Val Ser Ser 100 105623115PRTHomo sapiens 623Gly
Ala Glu Val Lys Lys Pro Gly Ser Ser Val Arg Leu Ser Cys Lys1 5 10
15Ala Ser Gly Gly Ser Tyr Ser Thr Tyr Ala Ile Ser Trp Val Arg Gln
20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Ile Pro Ser
Leu 35 40 45Gly Lys Thr His Leu Ala Gln Lys Phe Gln Gly Arg Val Thr
Phe Thr 50 55 60Ala Asp Glu Ser Thr Thr Thr Val Tyr Met Val Leu Ser
Ser Leu Lys65 70 75 80Ser Asp Asp Thr Ala Leu Tyr Tyr Cys Ala Thr
Pro Asp Trp Gln Tyr 85 90 95Ser Ser Ala Tyr Ser Leu Asp His Trp Gly
Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 115624115PRTHomo
sapiens 624Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Arg Leu Ser
Cys Lys1 5 10 15Ala Ser Gly Gly Ser Tyr Ser Thr Tyr Ala Ile Ser Trp
Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile
Ile Pro Ser Leu 35 40 45Gly Lys Thr His Leu Ala Gln Lys Phe Gln Gly
Arg Val Thr Phe Thr 50 55 60Ala Asp Glu Ser Thr Thr Thr Val Tyr Met
Ile Leu Ser Ser Leu Lys65 70 75 80Ser Glu Asp Thr Ala Leu Tyr Tyr
Cys Ala Thr Pro Asp Trp Gln Tyr 85 90 95Ser Ser Ala Tyr Ser Leu Asp
His Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser
115625116PRTHomo sapiens 625Gly Ala Glu Val Lys Lys Pro Gly Ala Ser
Val Lys Val Ser Cys Lys1 5 10 15Thr Ser Gly Tyr Thr Phe Thr Ser Tyr
Tyr Met Asn Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly Leu Glu Trp
Met Gly Ile Ile Lys Pro Ser Asp 35 40 45Gly Ser Thr Asn Tyr Ala Gln
Lys Phe Gln Gly Arg Val Thr Met Thr 50 55 60Arg Asp Thr Ser Thr Ser
Thr Val Tyr Met Glu Leu Arg Ser Leu Arg65 70 75 80Ser Glu Asp Thr
Ala Val Tyr Tyr Cys Gly Arg Asp Ser Lys Gly Trp 85 90 95Leu Gln Leu
Arg Gly Asp Ile Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser 115626118PRTHomo sapiens 626Gly Ala Glu Val Lys Lys Pro
Gly Ala Ser Val Lys Val Ser Cys Lys1 5 10 15Ala Ser Gly Tyr Thr Phe
Thr Ser Thr Tyr Ile His Trp Val Arg Gln 20 25 30Ala Pro Gly Gln Gly
Leu Glu Trp Met Gly Ile Ile Asn Pro Ser Ser 35 40 45Ser Asn Thr Asn
Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr 50 55 60Arg Asp Thr
Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg65 70 75 80Ser
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Phe Gly Gly Tyr 85 90
95Ser Ser Ser Ser Val Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110Met Val Thr Val Ser Ser 11562717PRTHomo sapiens 627Ala
Arg Gln Lys Cys Thr Gly Gly Ser Cys Tyr Ser Gly Asn Phe Asp1 5 10
15Pro62822PRTHomo sapiens 628Ala Arg Phe Arg Tyr Tyr Tyr Glu Ser
Gly Gly Tyr Ser Asp Ala Ser1 5 10 15Pro Tyr Tyr Leu Asp Tyr
2062915PRTHomo sapiens 629Ala Arg Ala Trp Cys Glu Tyr Ala Ala Tyr
Cys Trp Phe Asp Pro1 5 10 1563016PRTHomo sapiens 630Ala Arg Ala Gly
Phe Asp Tyr Gly Ser Pro Val Ser Ala Phe Asp Ile1 5 10
1563115PRTHomo sapiens 631Ala Arg His Gly Pro Gly Met Gly His Asn
Trp Tyr Phe Asp Leu1 5 10 1563217PRTHomo sapiens 632Ala Lys His Leu
Tyr Ser Ser Ser Trp Asn Ile Gly Ser Ser Phe Asp1 5 10
15Ser6338PRTHomo sapiens 633Ala Arg Gly Pro Asp Asn Arg Tyr1
56348PRTHomo sapiens 634Ala Arg Gly Pro Asp Asn Arg Tyr1
563515PRTHomo sapiens 635Ala Thr Pro Asp Trp Gln Tyr Ser Ser Ala
Tyr Ser Leu Asp His1 5 10 1563615PRTHomo sapiens 636Ala Thr Pro Asp
Trp Gln Tyr Ser Ser Ala Tyr Ser Leu Asp His1 5 10 1563716PRTHomo
sapiens 637Gly Arg Asp Ser Lys Gly Trp Leu Gln Leu Arg Gly Asp Ile
Asp Tyr1 5 10 1563818PRTHomo sapiens 638Ala Arg Asp Phe Gly Gly Tyr
Ser Ser Ser Ser Val Ser Asp Ala Phe1 5 10 15Asp Ile63986PRTHomo
sapiensMOD_RES(11)..(11)Any amino acidMOD_RES(46)..(46)Any amino
acid 639Ser Gly Arg Ala Ile Glu Ser Val Ser Gly Xaa Leu Ala Trp Tyr
Gln1 5 10 15Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala
Ser Asn 20 25 30Arg Ala Thr Gly Ile Pro Pro Arg Phe Ser Gly Ser Gly
Xaa Gly Thr 35 40 45Glu Phe Thr Leu Thr Ile Ser Ser Ala Glu Pro Glu
Asp Phe Ala Val 50 55 60Tyr Tyr Cys His Gln Ser Ile Lys Trp Pro Pro
Thr Phe Gly Gly Gly65 70 75 80Ser Lys Val Glu Ile Lys
8564091PRTHomo sapiens 640Glu Arg Val Thr Leu Ser Cys Arg Ala Ser
Gln Ser Val Ser Ser Tyr1 5 10 15Leu Ala Trp Tyr Gln Gln Lys Pro Gly
Gln Ala Pro Arg Leu Leu Ile 20 25 30Tyr Asp Ala Ser Asn Arg Ala Thr
Gly Ile Pro Ala Arg Phe Thr Gly 35 40 45Ser Gly Ser Gly Thr Asp Phe
Thr Leu Thr Ile Ser Ser Leu Glu Pro 50 55 60Glu Asp Phe Ala Val Tyr
Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu65 70 75 80Thr Phe Gly Gly
Gly Thr Lys Val Glu Ile Lys 85 9064197PRTHomo sapiens 641Ser Leu
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser
Val Thr Ser Ser Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly Gln 20 25
30Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Pro Gly Ile
35 40 45Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr 50 55 60Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Trp Cys
Gln Gln65 70 75 80Tyr Gly Arg Ser Pro Phe Thr Phe Gly Gln Gly Thr
Asn Leu Glu Ile 85 90 95Lys64299PRTHomo sapiens 642Ser Leu Ser Pro
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser
Ser Thr Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln 20 25 30Ala Pro
Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile 35 40 45Pro
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 50 55
60Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln65
70 75 80Tyr Ala His Ser Pro Arg Gly Tyr Thr Phe Gly Gln Gly Thr Lys
Leu 85 90 95Glu Ile Lys64395PRTHomo sapiens 643Ser Leu Ser Pro Gly
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Ile Ser Ser
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu
Leu Ile Tyr Asp Ala Ser Asn Arg Ala Pro Gly Ile Pro 35 40 45Ala Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg65 70 75
80Ser Thr Trp Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 85 90
9564497PRTHomo sapiensMOD_RES(20)..(20)Any amino
acidMOD_RES(37)..(37)Any amino acid 644Ser Leu Ser Pro Gly Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Xaa Tyr Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Xaa
Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 50 55 60Ser Ser Leu
Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly65 70 75 80Ser
Lys Trp Pro Val Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 85 90
95Lys64598PRTHomo sapiens 645Ser Val Ser Pro Gly Glu Arg Val Thr
Leu Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Tyr Asn Leu Ala Trp
His Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Gly
Ala Ser Thr Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Asn Met Gln Ser
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Asn Trp
Pro Pro Val Phe Thr Phe Gly Pro Gly Thr Lys Val Asp 85 90 95Ile
Lys64698PRTHomo sapiens 646Ser Val Ser Pro Gly Glu Arg Val Thr Leu
Ser Cys Arg Ala Ser Gln1 5 10 15Ser Val Ser Tyr Asn Leu Ala Trp His
Gln Gln Lys Pro Gly Gln Ala 20 25 30Pro Arg Leu Leu Ile Tyr Ser Ala
Ser Thr Arg Ala Thr Gly Ile Pro 35 40 45Ala Arg Phe Ser Gly Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile 50 55 60Ser Asn Met Gln Ser Glu
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr65 70 75 80Asn Asn Trp Pro
Pro Val Phe Thr Phe Gly Pro Gly Thr Lys Val Asp 85 90 95Ile
Lys647101PRTHomo sapiens 647Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
Ser Cys Arg Ser Ser Gln1 5 10 15Ser Leu Leu His Ser Thr Gly Tyr Asn
Tyr Leu Asp Trp Tyr Leu Gln 20 25 30Lys Pro Gly Gln Ser Pro Gln Leu
Leu Ile Tyr Leu Gly Ser Asn Arg 35 40 45Ala Ser Gly Val Pro Asp Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp 50 55 60Phe Thr Leu Lys Ile Ser
Arg Val Glu Ala Glu Asp Val Gly Val Tyr65 70 75 80Tyr Cys Met Gln
Ala Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr 85 90 95Lys Val Asp
Ile Lys 100648101PRTHomo sapiens 648Pro Val Thr Pro Gly Glu Pro Ala
Ser Ile Ser Cys Arg Ser Ser Gln1 5 10 15Ser Leu Leu His Ser Thr Gly
Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln 20 25 30Lys Pro Gly Gln Ser Pro
Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg 35 40 45Ala Ser Gly Val Pro
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 50 55 60Phe Thr Leu Lys
Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr65 70 75 80Tyr Cys
Met Gln Ala Leu Gln Thr Pro Phe Thr Phe Gly Pro Gly Thr 85 90 95Lys
Val Asp Ile Lys 100649103PRTHomo sapiens 649Pro Ala Ser Val Ser Gly
Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys1 5 10 15Ala Gly Thr Ser Ser
Asp Val Gly Asn Tyr Asn Leu Val Ser Trp Tyr 20 25 30Gln Gln His Pro
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Glu Val Ser 35 40 45Lys Arg Pro
Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly 50 55 60Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala65 70 75
80Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Ser Thr Tyr Val Phe Gly
85 90 95Thr Gly Thr Glu Val Thr Val 100650103PRTHomo sapiens 650Pro
Ala Ser Val Ser Gly Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys1 5 10
15Thr Gly Thr Ser Ser Asp Val Gly Ser Phe Asn Leu Val Ser Trp Tyr
20 25 30Gln Gln His Pro Gly Lys Ala Pro Lys Leu Ile Ile Tyr Glu Val
Ser 35 40 45Lys Arg Pro Ser Gly Val Ser Asn Arg Phe Ser Gly Ser Lys
Ser Gly 50 55 60Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala Glu
Asp Glu Val65 70 75 80His Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser Ser
Arg Phe Val Phe Gly 85 90 95Thr Gly Thr Lys Val Thr Val
1006519PRTHomo sapiens 651His Gln Ser Ile Lys Trp Pro Pro Thr1
56529PRTHomo sapiens 652Gln Gln Arg Ser Asn Trp Pro Leu Thr1
56539PRTHomo sapiens 653Gln Gln Tyr Gly Arg Ser Pro Phe Thr1
565411PRTHomo sapiens 654Gln Gln Tyr Ala His Ser Pro Arg Gly Tyr
Thr1 5 106558PRTHomo sapiens 655Gln Gln Arg Ser Thr Trp Leu Thr1
565610PRTHomo sapiens 656Gln Gln Gly Ser Lys Trp Pro Val Tyr Thr1 5
1065711PRTHomo sapiens 657Gln Gln Tyr Asn Asn Trp Pro Pro Val Phe
Thr1 5 1065811PRTHomo sapiens 658Gln Gln Tyr Asn Asn Trp Pro Pro
Val Phe Thr1 5 106599PRTHomo sapiens 659Met Gln Ala Leu Gln Thr Pro
Phe Thr1 56609PRTHomo sapiens 660Met Gln Ala Leu Gln Thr Pro Phe
Thr1
566110PRTHomo sapiens 661Cys Ser Tyr Ala Gly Ser Ser Thr Tyr Val1 5
1066210PRTHomo sapiens 662Cys Ser Tyr Ala Gly Ser Ser Arg Phe Val1
5 1066311PRTHomo sapiens 663Ala Arg Thr Ala Gly Asp Tyr Gly Met Asp
Val1 5 1066412PRTHomo sapiens 664Tyr Arg Val Val Ala Phe Asp Asp
Pro Val Asn Ile1 5 1066521PRTHomo sapiens 665Ala Arg Leu Pro Ala
Tyr Tyr Asp Ile Leu Thr Gly His Ile Lys Gly1 5 10 15Gly Tyr Phe Asp
Tyr 2066618PRTHomo sapiens 666Ala Arg Leu Gly Gly Phe Ser Arg Thr
Leu Tyr Ser Tyr Tyr Ser Met1 5 10 15Asn Val66718PRTHomo sapiens
667Ala Arg Gly Asp Tyr Arg Ser Ser Tyr Gly Tyr Arg Tyr Tyr Gly Phe1
5 10 15Asp Val66815PRTHomo sapiens 668Ala Lys Asp Leu Tyr Ser Ser
Gly Trp Tyr Met Gly Pro Asp Tyr1 5 10 1566917PRTHomo sapiens 669Ala
Arg Asp Leu Trp Asp Lys Tyr Ser Ser Ser Leu Gly Ala Phe His1 5 10
15Ile67012PRTHomo sapiens 670Ala Arg Asn Gln Pro Gly Gly Arg Ala
Phe Asp Phe1 5 1067117PRTHomo sapiens 671Ala Arg Lys Lys Gly Gly
Tyr Gly Ser His Tyr Tyr Tyr Gly Met Asp1 5 10 15Val67212PRTHomo
sapiens 672Gly Arg Thr Phe Thr Ser Ala Pro Phe Val Asp Gln1 5
1067312PRTHomo sapiens 673Ala Arg His Leu Pro Tyr Tyr Tyr Gly Met
Asp Val1 5 1067418PRTHomo sapiens 674Ala Arg Gly Arg Arg Arg Ile
Gln Gly Val Gly Glu Tyr Ser Gly Met1 5 10 15Asp Val67511PRTHomo
sapiens 675Ala Ser His Asp Tyr Gly Gly Asn Phe Arg Val1 5
1067612PRTHomo sapiens 676Ala Arg Val Gly Gly Arg Val Trp Trp Phe
Asp Pro1 5 1067715PRTHomo sapiens 677Ala Lys Tyr Arg Asp Leu Trp
Ser Gly Tyr Asp Ala Phe Asp Ile1 5 10 156789PRTHomo sapiens 678Ala
Thr Val Ile Arg His Phe Asp Asn1 567912PRTHomo sapiens 679Ala Lys
Val Gln Thr Phe Val Gly Ala Phe Asp Leu1 5 1068013PRTHomo sapiens
680Ala Arg Asp Tyr Gly Asn Met Arg Tyr Gly Met Asp Gly1 5
1068112PRTHomo sapiens 681Ala Arg Gly Leu Arg Phe Leu Tyr Gly Met
Asp Val1 5 1068224PRTHomo sapiens 682Ala Ser Glu Asn Leu Ile Ser
Gln Gly His Cys Thr Gly Ala Ile Cys1 5 10 15Tyr Ser Thr Tyr Gly Met
Asp Val 2068326PRTHomo sapiens 683Ala Arg Asp Ser Pro Tyr Tyr Tyr
Asp Ala Thr Gly Ser Pro Leu Leu1 5 10 15Gly Pro Gly Thr Leu Val Thr
Val Ser Ser 20 2568416PRTHomo sapiens 684Ala Asn His Trp Gly Ser
Ala Val Met Val Thr Gly Tyr Phe Asp Tyr1 5 10 1568516PRTHomo
sapiens 685Thr Arg Val Arg Trp Asp Gly Ile Glu Ser Thr Met Phe Phe
Asp Ser1 5 10 1568616PRTHomo sapiens 686Ala Arg Val Lys Met Ala Asn
Gly Ala Ile Pro Pro Tyr Phe Asp His1 5 10 1568716PRTHomo sapiens
687Val Arg Val Asn Arg Leu His Ser Gly Ser Tyr Phe Ser Phe Asp Tyr1
5 10 1568818PRTHomo sapiens 688Ala Arg Leu Gly Leu Ile Gln Ser Leu
Arg Asn Tyr Tyr Tyr Gly Leu1 5 10 15Asp Val68911PRTHomo sapiens
689Thr Thr Ala Ile Arg Val Thr Gly Met Asp Val1 5 1069011PRTHomo
sapiens 690Ala Arg Gly Trp Ser Asp Asn Ser Met Asp Val1 5
1069114PRTHomo sapiens 691Val Thr Leu Leu His Asp Tyr Gly Asp Tyr
Ser Phe Asp Tyr1 5 1069215PRTHomo sapiens 692Ala Arg Gly Asn Ile
Thr His Tyr Asp Leu Leu Pro Cys Asp Ser1 5 10 1569311PRTHomo
sapiens 693Ser Leu Gly Arg Ile Asn Tyr Phe Phe Asp Tyr1 5
1069410PRTHomo sapiens 694Ala Arg Ala Ser Gln Leu Val Pro Asp Tyr1
5 1069514PRTHomo sapiens 695Ala Arg Gly Gly Pro Ile Asn Val Pro Leu
Gly Phe Asp Pro1 5 1069622PRTHomo sapiens 696Ala Arg Asp Glu Gly
Gly Pro Asn Cys Ser Gly Gly Asn Cys Tyr Tyr1 5 10 15Tyr Tyr Gly Met
Asp Val 2069713PRTHomo sapiens 697Ala Asn Gly Gly Trp Gln Val Pro
His Trp Phe Asp Pro1 5 1069815PRTHomo sapiens 698Ala Arg Ala Arg
Ser Gly Tyr Ser Leu Gly Tyr Tyr Phe Asp Tyr1 5 10 1569915PRTHomo
sapiens 699Ala Lys Val Ser Arg Pro Lys Gly Ala Gln Ala Ser Phe Asp
Pro1 5 10 1570015PRTHomo sapiens 700Ala Thr Pro Lys Gly Gly Tyr Ser
Gly Tyr Asp Gln Leu Asp Tyr1 5 10 1570118PRTHomo sapiens 701Ala Arg
Pro Gly Tyr Thr Phe Gly Tyr His Ser Tyr Tyr Tyr Ala Met1 5 10 15Asp
Val7026PRTHomo sapiens 702Ala Arg Gly Ile Asp Tyr1 570322PRTHomo
sapiens 703Ala Arg Gly Ser Leu Arg Gly Thr Asn Gly Trp His Ser His
Leu Gly1 5 10 15Tyr Tyr Gly Met Asp Val 2070415PRTHomo sapiens
704Ala Arg Ser Arg Leu Arg Tyr Ser Ser Ser Trp Tyr Phe Asp Tyr1 5
10 1570516PRTHomo sapiens 705Ala Arg Asp Ile Leu Pro His Gly Thr
His Gly Trp Tyr Phe Asp Val1 5 10 1570612PRTHomo sapiens 706Ala Arg
Ala Lys Gly Met Ile Ala Glu Leu Asp Tyr1 5 1070710PRTHomo sapiens
707Gln Ala Trp Asp Ser Ser Thr Ala Val Val1 5 1070811PRTHomo
sapiens 708Gln Ser Ala Asp Thr Asn Gly Ser Ser Trp Ile1 5
107099PRTHomo sapiens 709Gln Gln Tyr Tyr Thr Thr Pro Gln Thr1
57109PRTHomo sapiens 710Gln Gln Ser Gly Ser Leu Pro Trp Thr1
571111PRTHomo sapiens 711Gln Ser Ala Asp Thr Asn Gly Ser Ser Trp
Ile1 5 1071211PRTHomo sapiens 712Gln Ser Tyr Asp Ser Ser Leu Ser
Gly Tyr Val1 5 107139PRTHomo sapiens 713Gln Gln Tyr Asn Asn Trp Pro
Leu His1 571411PRTHomo sapiens 714Gln Glu Arg Asp Asn Trp Pro Leu
Thr Trp Pro1 5 107159PRTHomo sapiens 715Gln Gln Asp Tyr Ser Leu Pro
Thr Thr1 57169PRTHomo sapiens 716Gln Gln Tyr Tyr Ser Thr Pro Tyr
Thr1 57179PRTHomo sapiens 717Gln Gln Tyr Asn Asn Trp Pro Pro Thr1
571811PRTHomo sapiens 718Met Gln Ser Leu Gln Thr Pro Arg Ala Leu
Thr1 5 107199PRTHomo sapiens 719Gln Gln Tyr Gly Ser Ser Pro Arg
Thr1 57209PRTHomo sapiens 720Gln Gln Thr Tyr Ser Thr Pro Trp Thr1
57218PRTHomo sapiens 721Gln Gln Tyr Gly Ser Ser Leu Thr1
572210PRTHomo sapiens 722Gln Gln Tyr Asp Asn Leu Pro Gly Phe Thr1 5
1072311PRTHomo sapiens 723Gln His Tyr Asp Ser Leu Pro Leu Leu Ile
Ser1 5 1072410PRTHomo sapiens 724Gln Gln Asn Asp Asp Ala Arg Ala
Leu Thr1 5 107258PRTHomo sapiens 725Gln His Tyr Asp Ser Ser Ile
Thr1 57269PRTHomo sapiens 726Gln Gln Ser Tyr Thr Val Pro Arg Thr1
57279PRTHomo sapiens 727Gln Gln Tyr Asn Ser Tyr Pro Arg Thr1
57289PRTHomo sapiens 728Gln Gln Tyr Tyr Ser Tyr Pro Arg Thr1
572912PRTHomo sapiens 729Ser Ser Tyr Ala Gly Ser Asn Asn Phe Glu
Val Val1 5 107309PRTHomo sapiens 730Gln Gln Leu Ile Ser Tyr Pro Pro
Thr1 573110PRTHomo sapiens 731Cys Ser Tyr Ala Ala Gly Ser Thr Phe
Val1 5 107329PRTHomo sapiens 732Gln Ala Trp Asp Ser Arg Ser Val
Val1 57339PRTHomo sapiens 733Gln Ser Tyr Asp Ser Ser His Tyr Val1
57349PRTHomo sapiens 734Gln Gln Tyr Gly Ser Ser Pro Ile Thr1
57359PRTHomo sapiens 735Gln Gln Ser Ser Ser Ile Pro Tyr Thr1
57369PRTHomo sapiens 736Gln Gln Tyr Tyr Ser Thr Pro His Thr1
57379PRTHomo sapiens 737Gln Gln Leu Asn Ser Tyr Pro Leu Thr1
57388PRTHomo sapiens 738Gln Gln Arg Ser Asn Trp Leu Thr1
57399PRTHomo sapiens 739His Gln Tyr Val Ser Ser Pro Leu Thr1
57409PRTHomo sapiens 740Asn Asn Met Ile Leu Ser Leu Gln Leu1
57419PRTHomo sapiens 741Gln Gln Ser Tyr Ser Ile Pro Leu Thr1
57428PRTHomo sapiens 742Gln Gln Tyr Asp Asp Leu Leu Thr1
57439PRTHomo sapiens 743Leu Gln Asp Tyr Asp Tyr Pro Leu Ser1
57449PRTHomo sapiens 744Gln Gln Ser Tyr Asn Phe Pro Arg Thr1
57456PRTHomo sapiens 745Gln Gln Arg Ala Gly Thr1 57469PRTHomo
sapiens 746Thr Gln Ala Thr Gln Phe Pro Trp Thr1 57479PRTHomo
sapiens 747His Gln Ser Phe Ser Ser Pro Asp Thr1 574810PRTHomo
sapiens 748Gln Gln Tyr Tyr Ser Thr Pro Arg Ile Thr1 5
1074910PRTHomo sapiens 749Gln His Arg Arg Asp Trp Pro Arg Tyr Thr1
5 1075010PRTHomo sapiens 750Gln Gln Tyr Arg Asp Thr Pro Ser Tyr
Thr1 5 1075123PRTHomo sapiens 751Thr Thr Glu Ile Gly Leu Gly Gly
Pro Asn Thr Pro Ser Ala Gln Leu1 5 10 15Tyr Tyr Tyr Gly Ile Asp Val
2075210PRTHomo sapiens 752Ala Ser Phe Arg Ser Gly Ala Phe Glu Ile1
5 1075320PRTHomo sapiens 753Ala Arg Val Arg Tyr Glu Tyr Asp Ser Gly
Gly Tyr Tyr Tyr Val Tyr1 5 10 15Asp Phe Glu Tyr 2075419PRTHomo
sapiens 754Ala Arg Val Ala Leu Ser Ser Ser Ser Phe Gly Glu His Tyr
Tyr Gly1 5 10 15Val Asp Val75515PRTHomo sapiens 755Ala Arg Ala Gly
Thr Val Phe Ala Gly His Tyr Gly Met Asp Val1 5 10 1575624PRTHomo
sapiens 756Ala Lys Asp Pro Arg Arg Asp Tyr Tyr Asp Ser Ser Gly Tyr
Tyr Tyr1 5 10 15Pro Ser Arg Gly His Phe Asp Tyr 2075713PRTHomo
sapiens 757Ala Arg Ile Ile Thr Arg Asn Gly Asp Ala Phe Asp Ile1 5
1075813PRTHomo sapiens 758Ala Lys Phe Gln Ser Ser Asn Trp Ser Pro
Phe Asp Ser1 5 1075913PRTHomo sapiens 759Ala Arg Gly Val Trp Phe
Gly Glu Phe Ala Val Gly Tyr1 5 1076013PRTHomo sapiens 760Ile Thr
Gly Ile Phe Lys Ser Thr Trp Lys Thr Asp Tyr1 5 1076113PRTHomo
sapiens 761Ala Arg Glu Ser Asp Phe Asn Tyr Gly Ala Val Asp His1 5
1076214PRTHomo sapiens 762Ala Lys Thr Gln Gly Tyr Asn Pro Asn Trp
Pro His Asp Phe1 5 1076310PRTHomo sapiens 763Ala Lys Asp Gly Arg
Gly Ser Ile Asp Tyr1 5 1076413PRTHomo sapiens 764Glu Arg Asp Ile
Val Trp Gly Val Ala Gly Thr Asp Tyr1 5 1076511PRTHomo sapiens
765Ala Arg Glu Asn Ile Ala Val Phe Phe Asp Ile1 5 1076615PRTHomo
sapiens 766Ala Arg Asp Lys Arg Tyr Ser Ser Gly Trp Tyr Tyr Phe Glu
Ser1 5 10 1576712PRTHomo sapiens 767Val Lys Pro Ser Val Thr Thr His
Tyr Phe Asp Tyr1 5 1076819PRTHomo sapiens 768Ala Arg Asp His Ser
Pro Gly Thr Thr Trp Gly Asn Tyr Asn Tyr Gly1 5 10 15Met Asp
Val76920PRTHomo sapiens 769Ala Arg Asp Ser Arg Tyr Tyr Asp Ser Arg
Ser Ser Tyr Tyr Tyr Tyr1 5 10 15Gly Met Asp Val 2077015PRTHomo
sapiens 770Ala Arg Val Ala Arg Pro Gly Gly Tyr Gly Arg Thr Phe Asp
Glu1 5 10 1577115PRTHomo sapiens 771Ala Arg Val Arg Glu Arg Tyr Tyr
Tyr Phe Tyr Gly Leu Asp Val1 5 10 1577212PRTHomo sapiens 772Ala Lys
Gly Val Ala Ala Pro Gly Tyr Phe Glu Tyr1 5 1077311PRTHomo sapiens
773Val Ala Trp Asp Asp Ser Leu Ser Gly Arg Val1 5 107749PRTHomo
sapiens 774Gln Gln Tyr Gly Ser Ser Ala Val Ser1 57758PRTHomo
sapiens 775Cys Ser Tyr Ala Gly Ser Tyr Val1 577610PRTHomo sapiens
776Gln Gln Tyr Gly Gly Ser Pro Leu Phe Thr1 5 107779PRTHomo sapiens
777Gln Gln Tyr Lys Ser Tyr Pro Leu Thr1 577810PRTHomo sapiens
778Ser Ser Tyr Ala Gly Ser Arg Thr Trp Val1 5 107798PRTHomo sapiens
779Cys Ser Tyr Ala Gly Ser Tyr Thr1 57809PRTHomo sapiens 780Gln Gln
Tyr Gly Asn Leu Pro Arg Thr1 578112PRTHomo sapiens 781Gln Gln Tyr
Asn Asn Trp Pro Pro Arg Gly Ala Thr1 5 107828PRTHomo sapiens 782Gln
Gln Arg Ser Asn Gly Trp Thr1 57839PRTHomo sapiens 783Gln Gln Tyr
Asn Asn Trp Pro Tyr Thr1 57849PRTHomo sapiens 784Gln Gln Leu Asn
Gly His Pro Arg Thr1 578510PRTHomo sapiens 785Met Gln Ser Ile Gln
Leu Pro Pro Ile Thr1 5 107869PRTHomo sapiens 786Gln Tyr Tyr Gly Asp
Ser Pro Arg Pro1 57879PRTHomo sapiens 787Gln Gln His Asp Asn Leu
Gln Val Ile1 57888PRTHomo sapiens 788Gln His Arg Ala Asn Trp Pro
Thr1 578910PRTHomo sapiens 789Gln Gln Arg Ser Asn Trp Pro Pro Phe
Thr1 5 107909PRTHomo sapiens 790Gln Gln Ser Tyr Ser Thr Pro Gln
Thr1 57919PRTHomo sapiens 791Met Gln Ala Leu Gln Thr Pro Lys Thr1
57928PRTHomo sapiens 792Gln Gln Ser Tyr Ser Asp Phe Ser1
57938PRTHomo sapiens 793Met Gln Ala Leu Gln Thr Phe Thr1
579410PRTHomo sapiens 794Gln Gln Arg Ser Asn Trp Pro Pro Ile Thr1 5
1079517PRTHomo sapiens 795Ala Arg Gly Asn Ser Tyr Gly Ser Gly Asn
Leu Gly Tyr Tyr Leu Asp1 5 10 15Phe79616PRTHomo sapiens 796Ala Arg
Gly Pro Asp Tyr Asn Asp Thr Pro Gly Tyr Tyr Gly Asn Tyr1 5 10
1579720PRTHomo sapiens 797Ala Arg Gly Ala His Tyr Tyr Asp Ser Ser
Gly Tyr Arg Gln Leu Tyr1 5 10 15Gly Leu Asp Val 2079812PRTHomo
sapiens 798Ala Arg Ala Asn Val Ala Thr Arg Tyr Phe Asp Tyr1 5
1079914PRTHomo sapiens 799Ala Arg Leu Arg Val Arg Gly Ala Gly Trp
Ala Phe Asp Leu1 5 1080020PRTHomo sapiens 800Ala Lys Ser Asp Tyr
Tyr Gly Ser Gly His Tyr Thr Thr Ile Pro Ser1 5 10 15Ser Phe Glu Asp
2080115PRTHomo sapiens 801Ala Arg His Pro Thr Gln Asn Tyr Ala Ser
Gly Asp Tyr Tyr Thr1 5 10 1580214PRTHomo sapiens 802Ala Lys Gly Ala
Arg Ile Thr Val Phe Gly Gly Leu Asp Val1 5 1080318PRTHomo sapiens
803Ala Arg Pro Tyr Phe Asp Gly Arg Ser Asn Ser Asn Leu Ile Phe Phe1
5 10 15Asp Tyr80420PRTHomo sapiens 804Ala Arg Val Ile Val Val Val
Val Ala Ala Thr Ser Asp Leu Pro Val1 5 10 15Gly Phe Asp Pro
2080514PRTHomo sapiens 805Ala Arg Trp Leu Asp Asn Gly Ile Gln Gly
Lys Tyr Asp Tyr1 5 1080616PRTHomo sapiens 806Ala Arg Gly Pro Val
Trp Phe Gly Glu Tyr Gly Gly Ala Phe Asp Pro1 5 10 1580714PRTHomo
sapiens 807Ala Arg Ala Lys Gly Arg Gly Leu Gln Asn Trp Phe Asp Pro1
5 1080825PRTHomo sapiens 808Ala Arg Val Ser Pro Leu Trp Asp Tyr Tyr
Asp Ser Gly Pro Tyr Tyr1 5 10 15Asn Asp Phe Tyr Tyr Gly Met Asp Val
20 2580911PRTHomo sapiens 809Ser Thr Trp Asp Asp Ser Leu Asn Gly
Pro Val1 5 108106PRTHomo sapiens 810His His Tyr Gly Arg Thr1
581110PRTHomo sapiens 811Gln Gln Arg Ala Asn Trp Pro Ala Leu Thr1 5
108129PRTHomo sapiens 812Gln His Leu Ser Thr Tyr Pro Ile Thr1
581311PRTHomo sapiens 813Gln Gln Arg Ser Asn Trp Pro Pro Ala Ile
Thr1 5 108149PRTHomo sapiens 814Gln Gln Tyr Asn Asn Trp Pro Leu
Thr1 58159PRTHomo sapiens 815Gln Gln Leu Thr Thr Tyr Pro Gly Thr1
58169PRTHomo sapiens 816Gln Gln Tyr Met Ser Leu Pro Tyr Ser1
581711PRTHomo sapiens 817Gln Gln Tyr Asn Thr Trp Pro Pro Ala Leu
Thr1 5 108189PRTHomo sapiens 818Gln His Tyr His Ser Tyr Pro Trp
Thr1 58198PRTHomo sapiens 819Gln Gln Arg His Glu Trp Pro Val1
58209PRTHomo sapiens 820Ser Asn Met Leu Gly His Arg Ser Pro1
582110PRTHomo sapiens 821Gln Gln Tyr Gly Ser Ser Pro Pro Ile Thr1 5
108226PRTHomo sapiens 822Gln Gln His Met Tyr Thr1 582316PRTHomo
sapiens 823Ala Arg Gly Gly Asp Gly Tyr Thr Thr Arg Trp Phe Tyr Phe
Asn His1 5 10 1582419PRTHomo sapiens 824Ala Arg Leu Gly Ala Glu Tyr
Tyr Val Asp Ser Ser Gly Tyr Arg Gly1 5 10 15Ile Asp His82521PRTHomo
sapiens 825Ala Arg Val Glu Arg Gly His Thr Tyr Gly Leu Asn Tyr Tyr
Tyr Tyr1 5 10 15Tyr Gly Met Asp Val 2082618PRTHomo sapiens
826Ala
Arg Asp Ser Ser Asn Thr Phe His His Asp Ser Ser Gly Tyr Phe1 5 10
15Asp Asn82716PRTHomo sapiens 827Ala Arg Leu Ile Pro Gly Ser Gly
Trp Arg Lys Gly Gly Phe Asp Tyr1 5 10 1582819PRTHomo sapiens 828Ala
Arg Asp Ser Gly Trp Ser Gly Ile Thr Thr Val Arg Gly Val Pro1 5 10
15Pro Asp Phe82916PRTHomo sapiens 829Ala Arg Gly Tyr Phe Tyr Thr
Ser Ser Asn Tyr Tyr Asn Thr Asp His1 5 10 1583020PRTHomo sapiens
830Ala Arg Asp Arg Phe Ser Arg His Tyr Gly Ser Gly Ser Leu His Tyr1
5 10 15Ala Met Asp Val 2083112PRTHomo sapiens 831Ala Thr Gly Tyr
Gly Gly Asn Phe Ala Phe Asp Met1 5 1083212PRTHomo sapiens 832Ala
Ser Gly Gly Tyr Gly Val Tyr Gly Phe Asp Tyr1 5 1083314PRTHomo
sapiens 833Ala Arg Ala His Ser Tyr Tyr Val Tyr Tyr Tyr Met Asp Val1
5 1083421PRTHomo sapiens 834Val Arg His Gly Pro His Pro Gly Val Leu
Val Trp Phe Gly Glu Gln1 5 10 15Ser Lys Ile Asp Tyr 2083522PRTHomo
sapiens 835Ala Lys Asp Ile Gly Asn Ile Ala Gly Val Ala Gln Gly Ile
Tyr Phe1 5 10 15Tyr Phe Gly Met Asp Val 2083612PRTHomo sapiens
836Ala Arg Lys Ser Tyr Gly Asp Pro Phe Phe Asp Tyr1 5
1083712PRTHomo sapiens 837Ala Ser Ser Val Met Val Val Ala Gln Phe
Asp Ser1 5 1083814PRTHomo sapiens 838Ala Thr Gly Ala Gly Tyr Ser
Tyr Pro Val Ala Met Asp Val1 5 1083913PRTHomo sapiens 839Ala Arg
Ile Ile Ile Asn Arg Gly Gln Ser Phe Asp Tyr1 5 1084020PRTHomo
sapiens 840Ala Arg Asn Ala Pro Lys Val Phe Gly Ser Gly Ser Tyr Tyr
Ser Asn1 5 10 15Trp Phe Asp Pro 2084112PRTHomo sapiens 841Ala Arg
Ser Tyr Ser Glu Val Leu Val Gly Tyr Asp1 5 108429PRTHomo sapiens
842Gln Gln Tyr Tyr Ser Ala Pro Leu Thr1 584310PRTHomo sapiens
843Met Gln Ala Leu Gln Thr Leu Ser Leu Thr1 5 1084412PRTHomo
sapiens 844Ala Ala Trp Asp Asp Ser Leu Arg Gly His Trp Val1 5
108459PRTHomo sapiens 845Gln Thr Trp Gly Thr Gly Ile Arg Val1
58469PRTHomo sapiens 846Gln His Tyr Lys Asn Trp Pro Gly Thr1
584711PRTHomo sapiens 847Leu His Tyr Asn Asn Trp Pro Pro Arg Tyr
Thr1 5 108489PRTHomo sapiens 848Gln Gln Tyr Lys Ser Tyr Pro Phe
Thr1 584910PRTHomo sapiens 849Gly Ser Tyr Thr Ser Thr Ser Thr Cys
Val1 5 108509PRTHomo sapiens 850Met Gln Ala Leu Gln Thr Pro Pro
Thr1 58519PRTHomo sapiens 851His Gln Tyr Asn Ala Tyr Pro Trp Thr1
585210PRTHomo sapiens 852Gln Gln Tyr Asn Asn Trp Leu Pro Ile Thr1 5
108539PRTHomo sapiens 853Gln Gln Tyr Tyr Thr Thr Pro Leu Thr1
585410PRTHomo sapiens 854Gln Arg Leu Asn Ser Tyr Pro Arg Val Thr1 5
1085510PRTHomo sapiens 855Ser Ser Tyr Thr Ser Arg Ser Thr Trp Val1
5 108569PRTHomo sapiens 856Gln Gln Tyr Gly Asn Ser Pro Trp Thr1
58579PRTHomo sapiens 857Met Gln Ala Leu Gln Thr Pro Tyr Thr1
58588PRTHomo sapiens 858Cys Ser Tyr Ala Gly Lys Tyr Val1
58599PRTHomo sapiens 859Gln Gln Arg Leu Tyr Trp Pro Val Thr1
58608PRTHomo sapiens 860Gln Gln Arg Ser Asn Trp Leu Thr1
586117PRTHomo sapiens 861Ala Lys Asp Arg Thr Gly Asn Ile Gly Ala
Gly Thr Gly Tyr Phe Asp1 5 10 15Lys86214PRTHomo sapiens 862Ala Arg
Thr Pro Arg Glu Tyr Ile Ala Glu Tyr Phe Gln His1 5 1086317PRTHomo
sapiens 863Ala Arg Val Lys Leu Arg Asp Gly Ser Ser Trp Tyr His Ala
Phe Asp1 5 10 15Ile86417PRTHomo sapiens 864Ala Arg Trp Gly Leu Ser
Ser Ala Trp Val Ala Pro Leu Gly Phe Asp1 5 10 15Tyr86521PRTHomo
sapiens 865Ala Arg Glu Leu Leu Tyr Ser Gly Arg Gln Thr Tyr Tyr Tyr
Ser Tyr1 5 10 15Tyr Gly Met Asp Val 2086619PRTHomo sapiens 866Ala
Arg Arg Gln Gly Ala His Gly Arg Asp Leu Gly Phe His Tyr Ala1 5 10
15Met Asp Val86710PRTHomo sapiens 867Ala Arg Asp Gly Ala Ala Ala
Gly Asp Tyr1 5 1086820PRTHomo sapiens 868Gly Asn Leu Ala Thr Val
Gly Ala Thr Ala Pro Tyr Tyr Asn Tyr Tyr1 5 10 15Gly Met Tyr Val
2086911PRTHomo sapiens 869Ala Arg Gly Met Ala Thr Pro Ala Leu Leu
Asn1 5 1087017PRTHomo sapiens 870Ala Arg Gly His Asn Lys Trp Leu
Gln Leu Asn Phe Tyr Ala Met Asp1 5 10 15Val87118PRTHomo sapiens
871Leu Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu1
5 10 15Thr Leu87217PRTHomo sapiens 872Val Lys Gly Gly Tyr Asn Ser
Val Trp Ser Asn Ser Tyr Gly Met Asp1 5 10 15Val87319PRTHomo sapiens
873Ala Arg Ala Leu Tyr Val Arg Gly Tyr Asn Tyr Gly Phe Leu Tyr Gly1
5 10 15Met Asp Val87419PRTHomo sapiens 874Ala Lys Gly Gly Pro Thr
Ala Arg Val Leu Ser Gly Gln Leu Tyr Tyr1 5 10 15Phe Asp
Tyr87528PRTHomo sapiens 875Ala Arg Gly Pro Ser Gly Leu Ala Val Ala
Gly Thr Val Gly Glu Arg1 5 10 15Asp Arg Asn Tyr His Tyr Tyr Tyr Gly
Met Asp Val 20 2587617PRTHomo sapiens 876Ala Arg Leu Gly Asp Ile
Leu Thr Gly Tyr Val Asp Tyr Gly Met Asp1 5 10 15Val87713PRTHomo
sapiens 877Ala Arg Ser Pro Ile Tyr Gly Asp Tyr Gly Phe Asp Pro1 5
1087817PRTHomo sapiens 878Ala Arg Thr His Cys Thr Gly Gly Ser Cys
Phe Ser Ser Ser Phe Asp1 5 10 15Tyr87921PRTHomo sapiens 879Ala Arg
Asp Arg Asp Tyr Gly Ser Gly Ser Gln Pro Leu Tyr Tyr Tyr1 5 10 15Tyr
Ala Met Asp Val 2088011PRTHomo sapiens 880Ala Arg Val Leu Gly Asn
Trp Gly Phe Asp Tyr1 5 1088120PRTHomo sapiens 881Ala Arg Gly Gly
Lys Arg Leu Gly Glu Leu Ser Leu Phe His Tyr Tyr1 5 10 15Gly Met Asp
Val 2088217PRTHomo sapiens 882Ala Arg His Arg Arg Gly Tyr Tyr Asp
Ser Ser Gly Tyr Tyr Tyr Asp1 5 10 15Tyr88312PRTHomo sapiens 883Thr
Arg Tyr Ser Tyr Gly Phe Ser Tyr Phe Asp Tyr1 5 1088414PRTHomo
sapiens 884Ala Arg Ala Pro Thr Arg Ser Ile Gly His Gly Met Asp Leu1
5 1088518PRTHomo sapiens 885Ala Arg Glu Asn Asn Asn Ile Ala Leu Pro
Tyr Tyr Tyr Tyr Gly Met1 5 10 15Asp Val88620PRTHomo sapiens 886Ala
Arg Asp Ile Arg Tyr Thr Tyr Gly Pro Met Trp Gly Gly Asp Tyr1 5 10
15Gly Met Asp Val 2088719PRTHomo sapiens 887Ala Arg Arg Pro Pro Leu
Leu Arg Ser His Asn Tyr Asn Tyr Leu Gly1 5 10 15Met Asp
Val88820PRTHomo sapiens 888Ala Lys Ser Ser Gly Gly His Asn Trp Asn
Tyr Val Asp Tyr Tyr Tyr1 5 10 15Gly Met Asp Val 2088910PRTHomo
sapiens 889Ala Ser Thr His Leu Gly Gly Leu Asp Val1 5
1089011PRTHomo sapiens 890Ser Arg Ala Thr Asn Tyr Tyr Ala Leu Gly
Tyr1 5 108919PRTHomo sapiens 891Ala Arg Asp Trp Pro Val Met Asp
Val1 589213PRTHomo sapiens 892Ala Arg Val Val Gly Thr Thr Leu Tyr
Ser Met Gly Tyr1 5 1089313PRTHomo sapiens 893Ala Arg Val Ala Ala
Trp Tyr Ala Gly Ser Phe Asp Ser1 5 1089417PRTHomo sapiens 894Ala
Lys Ala Gly Ala Tyr Cys Gly Gly Asp Cys Tyr Ser Tyr Leu Gln1 5 10
15Tyr8959PRTHomo sapiens 895Gln Gln Tyr Asn Asn Tyr Pro Trp Thr1
58969PRTHomo sapiens 896Gln Gln Tyr Asn Asn Trp Leu Ile Thr1
589710PRTHomo sapiens 897Gln Gln Tyr Tyr Thr Thr Pro Pro Trp Thr1 5
108989PRTHomo sapiens 898Gln Gln Tyr Tyr Thr Thr Pro Phe Thr1
589910PRTHomo sapiens 899Ser Ser Tyr Thr Ser Asp Asn Thr Arg Val1 5
1090010PRTHomo sapiens 900Cys Ser Tyr Ala Gly Ser Tyr Ser Trp Val1
5 109019PRTHomo sapiens 901Gln Gln Tyr Tyr Asp Tyr Pro Leu Thr1
590211PRTHomo sapiens 902Ala Ala Trp Asp Asp Ser Leu Asn Gly Arg
Val1 5 109039PRTHomo sapiens 903His Gln Tyr Asn Asn Trp Pro Leu
Thr1 59049PRTHomo sapiens 904Gln Gln Arg Ile Asn Trp Pro Ile Thr1
59059PRTHomo sapiens 905Gln Gln Ser Tyr Ser Arg Pro Tyr Ser1
59069PRTHomo sapiens 906Gln Gln Tyr Asp Asn Val Pro Tyr Thr1
59079PRTHomo sapiens 907Gln Gln Tyr Asp Asn Ser Arg Phe Thr1
59088PRTHomo sapiens 908Met Gln Gly Ile His Leu Trp Thr1
59099PRTHomo sapiens 909Ser Ser Tyr Ala Gly Thr Ser Tyr Val1
591012PRTHomo sapiens 910Ala Ala Trp Asp Asp Ser Leu Asn Gly Leu
Tyr Val1 5 109119PRTHomo sapiens 911Met Gln Ala Leu Gln Ile Pro Pro
Thr1 59129PRTHomo sapiens 912Gln Gln Tyr Asn Ser Tyr Pro Pro Thr1
59139PRTHomo sapiens 913Gln Gln Ser Tyr Ser Thr Pro Tyr Ser1
59149PRTHomo sapiens 914Gln Gln Leu Asn Ser Tyr Pro Phe Thr1
59159PRTHomo sapiens 915Met Gln Ala Leu His Thr Pro Trp Thr1
591610PRTHomo sapiens 916Ser Ser Tyr Thr Arg Ser Ser Thr Val Val1 5
109179PRTHomo sapiens 917Gln Gln Arg Ser Asn Trp Pro Leu Thr1
591810PRTHomo sapiens 918Val Leu Tyr Val Gly Ala Ala Ile Ser Leu1 5
109199PRTHomo sapiens 919Gln Gln Ser Ser Asn Trp Pro Ile Thr1
59209PRTHomo sapiens 920Gln Gln Tyr Gly Gly Ser Pro Tyr Thr1
592110PRTHomo sapiens 921Gln Gln Tyr Gly Ser Ser Pro Leu Ile Thr1 5
109229PRTHomo sapiens 922Gln Gln Leu Asn Ser Tyr Pro Val Thr1
59239PRTHomo sapiens 923Met Gln Gly Thr His Trp Pro Leu Thr1
592410PRTHomo sapiens 924Ser Ser Tyr Thr Ser Ser Ala Thr Trp Val1 5
1092510PRTHomo sapiens 925Met Gln Gly Thr His Trp Pro Pro Trp Thr1
5 109268PRTHomo sapiens 926Gln Gln Tyr Tyr Asn Thr Trp Thr1
59279PRTHomo sapiens 927Ser Ser Tyr Thr Ser Thr Ser Ala Phe1
59289PRTHomo sapiens 928Gln Gln Tyr Gln Ser Asp Leu Phe Thr1
592919PRTHomo sapiens 929Ala Arg Leu Leu Ile Asp Tyr Thr Asn Tyr
Lys Ser Val Ala Ser Ala1 5 10 15Phe Asp Ile93021PRTHomo sapiens
930Ala Ser Ser Pro Gly Tyr Asp Thr Arg Gly Tyr Tyr Ile Ala Gly Gln1
5 10 15Tyr Tyr Phe Val Asn 2093112PRTHomo sapiens 931Ala Arg Asp
Gly Thr Ile Pro Gly Tyr Gly Asp Tyr1 5 1093216PRTHomo sapiens
932Ala Arg Met Pro Val Ala Ala His Tyr Phe Tyr Asp Gly Met Asp Val1
5 10 1593315PRTHomo sapiens 933Ala Lys Phe Pro His Arg Ser Thr Ser
Trp Tyr Tyr Phe Asp Ser1 5 10 1593413PRTHomo sapiens 934Ala Arg Gly
Leu Arg Val Glu Ile Pro Ile Phe Ala Tyr1 5 1093514PRTHomo sapiens
935Thr Arg Asp Thr Ile Val Gly Ala Thr Tyr Ala Phe Asp Ile1 5
1093619PRTHomo sapiens 936Ala Arg Glu Pro Asp Ser Ser Ser Trp Tyr
Gln Asp Tyr Tyr Cys Ala1 5 10 15Met Asp Val93713PRTHomo sapiens
937Thr Arg Asp Leu Gly Asn Phe Ile Ala Tyr Met Asp Val1 5
1093824PRTHomo sapiens 938Ser Arg Gly Ser Tyr Tyr Tyr Asp Ser Arg
Gly Tyr Tyr Phe Arg Pro1 5 10 15Pro Ser Ala Gly Pro Phe Asp Tyr
2093916PRTHomo sapiens 939Val Lys Ile Ala Val Gly Gly Ser Trp Ser
Ser Glu Ala Leu Asp Tyr1 5 10 1594017PRTHomo sapiens 940Ala Arg Gly
His Leu Val Gly Ala Thr Ser Tyr Tyr Tyr Gly Met Asp1 5 10
15Val94120PRTHomo sapiens 941Ala Arg Val Ser Leu Leu Trp Phe Gly
Glu Leu Gly Ala Val Pro Tyr1 5 10 15Tyr Phe Asp Tyr 2094216PRTHomo
sapiens 942Ala Arg Asp Arg His Arg Ala Gly Ala Leu Arg Tyr Gly Met
Asp Val1 5 10 1594316PRTHomo sapiens 943Ala Lys Gly Gly Thr Ser Val
Ala Ile Gly Trp Asn Trp Phe Asp Pro1 5 10 1594418PRTHomo sapiens
944Ala Arg Gly Tyr Arg Gly Asn Ile Leu Thr Gly Arg Leu Gly Tyr Phe1
5 10 15Asp Tyr94523PRTHomo sapiens 945Thr Thr Ala Gly Asn Tyr Tyr
Asp Ser Arg Gly Tyr Tyr Phe Ser Arg1 5 10 15Pro Arg His Ser Phe Asp
Tyr 2094619PRTHomo sapiens 946Ala Arg Ala Pro Gln Asn Tyr Tyr Gly
Ser Gly Arg Tyr Tyr Ser Gly1 5 10 15Cys Asp Tyr94723PRTHomo sapiens
947Ala Arg Thr Ala Val Asp Arg Tyr Ser Ser Gly Trp Tyr Gly Glu Tyr1
5 10 15Tyr Tyr Tyr Ser Met Asp Val 2094821PRTHomo sapiens 948Ala
Arg Arg Pro Leu Thr Ser Tyr Tyr Asp Ser Gly Ala Tyr Tyr Pro1 5 10
15Tyr Tyr Phe Asp Tyr 2094925PRTHomo sapiens 949Thr Arg Asp Thr Thr
Tyr Phe Tyr Asp Asn Ser Gly Tyr Tyr Gly Trp1 5 10 15Ala Ser Lys Gly
Gly Tyr Phe Asp Tyr 20 2595023PRTHomo sapiens 950Ala Arg Gln Pro
Val Arg Gly Arg His Ser Ser Ser Gly Tyr Arg His1 5 10 15Tyr Tyr Tyr
Gly Met Asp Val 2095123PRTHomo sapiens 951Ala Arg Val Glu Thr Tyr
Asp His Val Trp Gly Ala Phe Arg Phe Gly1 5 10 15Glu Gly Gly Tyr Phe
Asp His 2095221PRTHomo sapiens 952Ala Arg Gly Gly His Tyr Tyr Asp
Ser Arg Gly Tyr Phe Thr Leu Ala1 5 10 15Gly Pro Ile Asp Tyr
2095311PRTHomo sapiens 953Gln Gln Tyr His Asn Trp Pro Pro Arg Leu
Thr1 5 109548PRTHomo sapiens 954Gln Gln Tyr Asn Arg Tyr Val Ser1
595510PRTHomo sapiens 955Gln Gln Arg Ser Asn Trp Pro Pro Trp Thr1 5
109569PRTHomo sapiens 956Gln Gln Tyr Gly Ser Ser Pro Ile Thr1
595713PRTHomo sapiens 957Gln Ser Tyr Asp Ser Ser Leu Ser Gly Ser
Phe Tyr Val1 5 1095811PRTHomo sapiens 958Gln Gln Tyr Gly Gly Ser
Pro Pro Arg Phe Thr1 5 109599PRTHomo sapiens 959Gln Gln His Tyr Ser
Thr Pro Phe Thr1 596010PRTHomo sapiens 960Cys Ser Tyr Ala Gly Ser
Arg Thr Arg Val1 5 1096111PRTHomo sapiens 961Ala Ser Trp Asp Asp
Asn Leu Asn Ser Arg Val1 5 1096210PRTHomo sapiens 962Met Gln Gly
Ile Ile Phe Pro Pro Ile Thr1 5 1096310PRTHomo sapiens 963Ser Ser
Tyr Thr Ser Ser Ser Thr Leu Val1 5 109649PRTHomo sapiens 964Gln Gln
Leu Asn Ser Tyr Pro Glu Thr1 59659PRTHomo sapiens 965Leu Gln Val
Asn Ser Tyr Pro Leu Thr1 596610PRTHomo sapiens 966Ser Ser Tyr Thr
Thr Ser Thr Thr Val Ile1 5 1096711PRTHomo sapiens 967Cys Ser Tyr
Gly Gly Thr Tyr Ser Pro Tyr Val1 5 109689PRTHomo sapiens 968Gln Gln
Tyr Ala Lys Tyr Pro Leu Thr1 59699PRTHomo sapiens 969Gln Gln Tyr
Ala Thr Ser Ser Leu Thr1 597011PRTHomo sapiens 970Gly Thr Trp Asp
Ser Ser Leu Ser Ala Tyr Val1 5 1097111PRTHomo sapiens 971Gly Thr
Trp Asp Ser Ser Leu Ser Ala Gly Val1 5 1097210PRTHomo sapiens
972Gln Ser Phe Asp Ser Ser Asn Gln Glu Val1 5 1097312PRTHomo
sapiens 973Gln Ser Tyr Asp Arg Ser Leu Ser Gly Ser Arg Val1 5
109749PRTHomo sapiens 974Gln Gln Phe Asn Ser Tyr Pro Gln Thr1
59757PRTHomo sapiens 975His His Tyr Asn Asn Trp Thr1 597610PRTHomo
sapiens 976Gln Gln Tyr His Asp Trp Pro Leu Trp Thr1 5
1097748DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 977ctagtagcaa ctgcaaccgg tgtacattcc caggtgcagc
tggtgcag 4897848DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 978ctagtagcaa ctgcaaccgg tgtacattcc
gaggtgcagc tggtgcag 4897948DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 979ctagtagcaa ctgcaaccgg
tgtacattcc caggttcagc tggtgcag 4898048DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
980ctagtagcaa ctgcaaccgg tgtacattcc caggtccagc tggtacag
4898148DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
981ctagtagcaa ctgcaaccgg tgtacattct gaggtgcagc tggtggag
4898248DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 982ctagtagcaa ctgcaaccgg tgtacattct caggtgcagc
tggtggag 4898348DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 983ctagtagcaa ctgcaaccgg tgtacattct
gaggtgcagc tgttggag 4898448DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 984ctagtagcaa ctgcaaccgg
tgtacattct caggtgcagc tggtggag 4898548DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
985ctagtagcaa ctgcaaccgg tgtacattct gaagtgcagc tggtggag
4898648DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 986ctagtagcaa ctgcaaccgg tgtacattcc caggtgcagc
tgcaggag 4898750DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 987ctagtagcaa ctgcaaccgg tgtacattcc
caggtgcagc tacagcagtg 5098848DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 988ctagtagcaa ctgcaaccgg
tgtacattcc cagctgcagc tgcaggag 4898948DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
989ctagtagcaa ctgcaaccgg tgtacattcc caggtacagc tgcagcag
4899040DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 990ccgatgggcc cttggtcgac gctgaggaga cggtgaccag
4099142DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 991ccgatgggcc cttggtcgac gctgaagaga cggtgaccat tg
4299240DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 992ccgatgggcc cttggtcgac gctgaggaga cggtgaccag
4099341DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 993ccgatgggcc cttggtcgac gctgaggaga cggtgaccgt g
4199447DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 994gtagcaactg caaccggtgt acattctgac atccagatga
cccagtc 4799548DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 995gtagcaactg caaccggtgt acattcagac
atccagttga cccagtct 4899647DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 996gtagcaactg caaccggtgt
acattgtgcc atccggatga cccagtc 4799747DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
997gtagcaactg caaccggtgt acatggggat attgtgatga cccagac
4799847DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 998gtagcaactg caaccggtgt acatggggat attgtgatga
ctcagtc 4799947DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 999gtagcaactg caaccggtgt acatggggat
gttgtgatga ctcagtc 47100047DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1000gtagcaactg caaccggtgt
acattcagaa attgtgttga cacagtc 47100147DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1001gtagcaactg caaccggtgt acattcagaa atagtgatga cgcagtc
47100248DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1002gtagcaactg caaccggtgt acattcagaa attgtgttga
cgcagtct 48100347DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1003gtagcaactg caaccggtgt acattcggac
atcgtgatga cccagtc 47100446DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1004gaagacagat ggtgcagcca
ccgtacgttt gatytccacc ttggtc 46100546DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1005gaagacagat ggtgcagcca ccgtacgttt gatctccagc ttggtc
46100646DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1006gaagacagat ggtgcagcca ccgtacgttt gatatccact
ttggtc 46100746DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1007gaagacagat ggtgcagcca ccgtacgttt
aatctccagt cgtgtc 46100848DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1008ctagtagcaa ctgcaaccgg
ttcctgggcc cagtctgtgc tgackcag 48100948DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1009ctagtagcaa ctgcaaccgg ttcctgggcc cagtctgccc tgactcag
48101048DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1010ctagtagcaa ctgcaaccgg ttctgtgacc tcctatgagc
tgacwcag 48101147DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1011ctagtagcaa ctgcaaccgg ttctctctcs
cagcytgtgc tgactca 47101248DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1012ctagtagcaa ctgcaaccgg
ttcttgggcc aattttatgc tgactcag 48101348DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1013ctagtagcaa ctgcaaccgg ttccaattcy cagrctgtgg tgacycag
48101437DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1014ggcttgaagc tcctcactcg agggygggaa cagagtg
37101528DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1015gttaagggat tttggacatg agattatc
28101628DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1016gataatctca tgtccaaaat cccttaac
28101723DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1017cttggttgag tactcaccag tca
23101820DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1018gaagactaca gcgtcgccag 20101923DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1019gttattgtct catgcgcgga tac 23102023DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1020gtatccgcgc atgagacaat aac 23102124DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1021cttcatgcaa ttgtcggtca agcc 24102223DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1022tgactggtga gtactcaacc aag 23102324DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1023aggagtcggg gcgaagaaga tcac 24102424DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1024gtgatcttct tcgccccgac tcct 24102524DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1025aggagtcggg gaggcgaaga tcac 24102624DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1026gtgatcttcg cctccccgac tcct 24102755DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1027acttggtcat gatactgctg attgccccgg catacagcat caggtgcata ggagt
55102853DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1028ttcgaaccgc ggctgggtcc tattaagcag agacagctgt
ggataagaag atc 53102922DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1029cttgaccgac aattgcatga ag
22103044DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1030gtctttttcc gttggttgtt catagcctgc ttttttgtac
aaac 44103144DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1031gtttgtacaa aaaagcaggc tatgaacaac
caacggaaaa agac 44103250DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1032ttcgaaccgc ggctgggtcc
tattacgcct gaaccatgac tcctaggtac 50103328DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1033caaagagtgg ttccatgaca tcccattg 28103428DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1034caatgggatg tcatggaacc actctttg 28103555DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1035acttggtcat gatactgctg attgccccgg catacagcat caggtgcata ggagt
55103653DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1036ttcgaaccgc ggctgggtcc tattaagcag agacagctgt
ggataagaag atc 53103725DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1037tgaactcctg aggggaccgt
cagtc 25103818DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1038ggtgctgggc acggtggg
18103921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1039aacaaagccc gcccagcccc c 21104025DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1040ggagaccttg cacttgtact ccttg 25104121DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1041atgctccgtg ctgcatgagg c 21104218DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1042gagaagacgt tcccctgc 18104321DNAArtificial SequenceDescription
of Artificial Sequence Synthetic primer 1043gctctgcaca gccactacac g
21104420DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1044ctcatgcagc acggagcatg 20104555DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1045acttggtcat gatactgctg attgccccgg catacagcat caggtgcata ggagt
55104653DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1046ttcgaaccgc ggctgggtcc tattaagcag agacagctgt
ggataagaag atc 53104728DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 1047aggagtcggg gcggcgaaga
tcacccac 28104828DNAArtificial SequenceDescription of Artificial
Sequence Synthetic primer 1048gtgggtgatc ttcgccgccc cgactcct
28104940DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1049ttgtcatagg agtcggggcg gcgaagatca cccaccactg
40105031DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1050cataggagtc ggggacaaga agatcaccca c
31105139DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1051gtcataggag tcggggagcg taagatcacc caccactgg
39105221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1052acaaggagtg gttccatgac a 21105320DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1053ttttccgatg gtgctgccac 20105421DNAArtificial SequenceDescription
of Artificial Sequence Synthetic primer 1054gtatgcaggg acagatggac c
21105521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1055accgcatctc gtttccttct t 21105621DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1056ggatgatcgt taatgacaca g 21105718DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1057accatcttcc caggcttg 18105821DNAArtificial SequenceDescription
of Artificial Sequence Synthetic primer 1058ggatcctgat ttgaaagctg c
21105920DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1059ttccacgaca ttccattacc 20106022DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
1060atctacgggg ggagtcagga tg 22106114PRTZika virus 1061Ile Val Ile
Gly Val Gly Glu Lys Lys Ile Thr His His Trp1 5 10106214PRTZika
virus 1062Ile Val Ile Gly Val Gly Asp Lys Lys Ile Thr His His Trp1
5 10106314PRTDengue virus 1 1063Ile Val Val Gly Ala Gly Glu Lys Ala
Leu Lys Leu Ser Trp1 5 10106414PRTDengue virus 2 1064Ile Ile Ile
Gly Val Glu Pro Gly Gln Leu Lys Leu Asn Trp1 5 10106514PRTDengue
virus 3 1065Ile Val Ile Gly Ile Gly Asp Asn Ala Leu Lys Ile Asn
Trp1 5 10106614PRTDengue virus 4 1066Ile Val Ile Gly Val Gly Asn
Ser Ala Leu Thr Leu His Trp1 5 10106714PRTYellow fever virus
1067Ile Ile Val Gly Arg Gly Asp Ser Arg Leu Thr Tyr Gln Trp1 5
10106814PRTYellow fever virus 1068Ile Ile Val Gly Arg Gly Asp Ser
Arg Leu Thr Tyr Gln Trp1 5 10106914PRTWest Nile virus 1069Ile Val
Val Gly Arg Gly Glu Gln Gln Lys Asn His His Trp1 5 10107014PRTZika
virus 1070Ile Val Ile Gly Val Gly Glu Arg Lys Ile Thr His His Trp1
5 10
* * * * *