U.S. patent application number 16/626163 was filed with the patent office on 2020-06-04 for broadly neutralizing antibodies against hiv.
The applicant listed for this patent is Dongkyoon Cavet Kim. Invention is credited to Guy Cavet, Amir Dashti, Anthony DeVico, Dongkyoon Kim, George K. Lewis, Marzena E. Pazgier, Mohammad Sajadi, William David Tolbert.
Application Number | 20200172601 16/626163 |
Document ID | / |
Family ID | 64736132 |
Filed Date | 2020-06-04 |
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United States Patent
Application |
20200172601 |
Kind Code |
A1 |
Sajadi; Mohammad ; et
al. |
June 4, 2020 |
BROADLY NEUTRALIZING ANTIBODIES AGAINST HIV
Abstract
The present invention provides broadly neutralizing antibodies
against HIV, compositions comprising the same and methods of use
thereof. Specifically, the invention provides isolated anti-HIV
antibodies that are capable of neutralizing at least 95% of the HIV
pseudoviruses listed in Table 1 and neutralizing 100% of the HIV
clade B, G and D viruses listed in Table 1 with an IC50 value of
less than 50 ug/mL. Further provides are the sequences especially
complementarity-determining region (CDR) sequences of antibodies
disclosed.
Inventors: |
Sajadi; Mohammad;
(Cockeysville, MD) ; Lewis; George K.; (Baltimore,
MD) ; DeVico; Anthony; (Alexandria, VA) ;
Dashti; Amir; (Baltimore, MD) ; Pazgier; Marzena
E.; (Mt. Airy, MD) ; Tolbert; William David;
(Baltimore, MD) ; Kim; Dongkyoon; (Palo Alto,
CA) ; Cavet; Guy; (Hillsborough, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Kim; Dongkyoon
Cavet; Guy
University of Maryland, Baltimore
The United States Government as Represented by the Department of
Veterans Affairs |
Palo Alto
Hillsborough
Baltimore
Washington |
CA
CA
MD
DC |
US
US
US
US |
|
|
Family ID: |
64736132 |
Appl. No.: |
16/626163 |
Filed: |
June 22, 2018 |
PCT Filed: |
June 22, 2018 |
PCT NO: |
PCT/US2018/039162 |
371 Date: |
December 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62673607 |
May 18, 2018 |
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62591244 |
Nov 28, 2017 |
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62589614 |
Nov 22, 2017 |
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62573764 |
Oct 18, 2017 |
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62523437 |
Jun 22, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12N 15/00 20130101;
C07K 14/005 20130101; C07K 2317/565 20130101; A61P 31/18 20180101;
A61K 39/00 20130101; C12N 2740/16122 20130101; C07K 2317/21
20130101; C07K 2317/33 20130101; C07K 2317/76 20130101; C07K
2317/92 20130101; C07K 16/1063 20130101; C12N 2740/16134 20130101;
A61K 39/42 20130101; C07K 2317/55 20130101; C07K 2317/34
20130101 |
International
Class: |
C07K 16/10 20060101
C07K016/10; A61K 39/42 20060101 A61K039/42; A61P 31/18 20060101
A61P031/18 |
Goverment Interests
STATEMENT OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] This invention was made with government support under Grant
Number AI110259 awarded by the National Institutes of Health and
under Grant Number 1I01BX002358 awarded by the United States
Department of Veterans Affairs. The government has certain rights
in the invention.
Claims
1. An isolated anti-HIV antibody that is capable of neutralizing at
least 95% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 50 .mu.g/mL.
2. (canceled)
3. (canceled)
4. An isolated anti-HIV antibody that neutralizes 100% of the HIV
clade B, G and D viruses listed in Table 1 with an IC50 value of
less than 50 .mu.g/mL.
5. The isolated anti-HIV antibody of claim 1, wherein the anti-HIV
antibody binds to a HIV gp120 epitope comprising outer domain loop
D (which comprises 275-283), the CD4 binding loop (which comprises
354-371), the bridging sheet (which comprises 427-439) and loop V5
(which comprises 455-463) and gp120 inner domain: helix alpha-1 of
Layer 2 (comprising positions 96-106) and 469-480 (loop prior and
helix alpha-5 of Layer 3).
6. The isolated anti-HIV antibody of claim 5, wherein the anti-HIV
antibody binds to a HIV gp120 Layer 2 residues W96, K97, E102,
G124, Loop D residues E275, N276, T278, N279, N280, A281, K282, CD4
binding loop residues P364, 5365, G366, G367, D368, 1371, bridging
sheet residues W427, Q428, G429, Loop V5 residues T455, R456, D457,
G458, G459, A460, N461, T463, and Layer 3 residues R469, P470,
G471, G472, G473, N474, K476, D477, R480.
7. The isolated anti-HIV antibody of claim 6, wherein the antibody
has a Kd for BaL-gp120 of at least about 2.456.times.10.sup.-8 M as
determined by surface plasmon resonance.
8.-11. (canceled)
12. The isolated anti-HIV antibody of claim 4, wherein the anti-HIV
antibody further neutralizes strain CNE5 (clade CRF01_AE) with an
IC50 value of less than 50 .mu.g/mL.
13.-19. (canceled)
20. The isolated anti-HIV antibody of claim 1, wherein anti-HIV
antibody is selected from the group consisting of: a. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYDFIDYV (SEQ ID NO:401), CDR H2 comprises MNPSGGGT (SEQ ID NO:402)
and CDR H3 comprises VRDRANGSGRRRFESVNWFLDL (SEQ ID NO:403); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAFEN (SEQ ID NO:404); b. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPMGGQV (SEQ
ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID
NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); c. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2
comprises MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD
and CDR L3 comprises NTYEF (SEQ ID NO:446); and d. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYL (SEQ ID NO:409), CDR H2 comprises MNPVYGQV (SEQ ID NO:410)
and CDR H3 comprises VRDTGDGSRRHFDSINWFLDL (SEQ ID NO:411); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFD and CDR L3 comprises WAFEA (SEQ ID NO:412).
21. The isolated anti-HIV antibody of claim 1, wherein the anti-HIV
antibody comprises a heavy chain or an antigen binding fragment
thereof and a light chain or an antigen binding fragment thereof,
wherein the heavy chain or antigen binding fragment thereof
comprises a heavy chain variable (VH) region and the light chain or
antigen binding fragment thereof comprises a light chain variable
(VL) region; wherein the anti-HIV antibody is selected from the
group consisting of: a. an antibody wherein the VH region comprises
amino acids 1-128 of SEQ ID NO:153 or a variant thereof comprising
1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:155 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; b. an antibody wherein the VH region comprises amino
acids 1-127 of SEQ ID NO:161 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:163 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; c. an antibody wherein the VH region comprises amino
acids 1-127 of SEQ ID NO:165 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:167 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; d. an antibody wherein the VH region comprises amino
acids 1-128 of SEQ ID NO:225 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:227 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; and e. an antibody wherein the VH region comprises
amino acids 1-120 of SEQ ID NO:293 or a variant thereof comprising
1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-100 of SEQ ID NO:295 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions.
22. The anti-HIV antibody of claim 1, wherein the anti-HIV antibody
is selected from the group consisting of: a. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:153 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:155 or an antigen binding fragment
thereof; b. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:161 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:163 or an antigen binding fragment thereof; c. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:165 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:167 or an antigen binding
fragment thereof; d. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:225 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:227 or an antigen binding fragment thereof; and e. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:293 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:295 or an antigen
binding fragment thereof.
23. An isolated host cell expressing the antibody of claim 21.
24. One or more vectors comprising a nucleic acid encoding the
antibody of claim 21.
25.-27. (canceled)
28. An engineered cell that expresses the antibody of claim 21.
29. (canceled)
30. (canceled)
31. A pharmaceutical composition comprising one or more antibodies
of claim 5 and/or cells of claim 23 and a pharmaceutically
acceptable carrier.
32. A method for treating or preventing HIV infection in a subject,
comprising administering to the subject an effective amount of the
composition of claim 31.
33. A method of functionally curing HIV in a subject comprising
administering to the subject an effective amount of the composition
of claim 31.
34. The method of claim 31, wherein the composition is administered
in combination with another therapy.
35. The method of claim 34, wherein the therapy is an
anti-retroviral therapy.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Appl. No. 62/523,437, filed Jun. 22, 2017, U.S. Provisional Appl.
No. 62/573,764, filed Oct. 18, 2017, U.S. Provisional Appl. No.
62/589,614, filed Nov. 22, 2017, U.S. Provisional Appl. No.
62/591,244, filed Nov. 28, 2017, and U.S. Provisional Appl. No.
62/673,607, filed May 18, 2018, the contents of which are hereby
incorporated by reference in their entirety.
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY
[0003] Incorporated by reference in its entirety herein is a
computer-readable sequence listing submitted concurrently herewith
and identified as follows: One 884,569 Byte ASCII (Text) file named
"Sequence_Listing_ST25.txt," created on Jun. 22, 2018.
FIELD OF THE INVENTION
[0004] The field of the invention relates to medicine, infectious
disease and in particular antibodies which can neutralize HIV-1
virus strains.
BACKGROUND OF THE INVENTION
[0005] HIV is an integrating retrovirus that rapidly establishes
chronic infection in CD4+ T cells. This fundamental characteristic
means that prevention of HIV infection largely depends on humoral
responses and associated effector mechanisms directed against the
HIV envelope proteins (gp120 and gp41) that drive viral attachment
and entry.
[0006] Humoral anti-envelope responses in a minority of
HIV-infected persons comprise neutralizing activity against diverse
viral variants (Scheid et al., Nature 458, 636-640 (2009); Simek et
al., J Virol 83, 7337-7348 (2009); Walker et al., PLoS Pathog 6,
e1001028 (2010); Sajadi et al., J Acquir Immune Defic Syndr 57,
9-15 (2011); Sajadi et al., J Infect Dis 213, 156-164 (2016)).
Broadly neutralizing responses can be used to guide the development
of effective HIV vaccines and/or other immune-based prevention
measures. Three types of information are essential to implementing
this concept. First, conserved sites of extreme neutralization
sensitivity within the HIV envelope structure must be defined.
Significant steps in this direction have been afforded by the
derivation of broadly neutralizing monoclonal anti-envelope
antibodies (mAbs) from the memory B cell pools of certain
HIV-infected individuals. These antibodies reveal a number of
especially potent neutralizing epitopes on gp120, including the CD4
binding site (CD4-BS), V1V2 glycan, V3 glycan, and the gp41
membrane-proximal external region (Haynes et al., J Allergy Clin
Immunol 134, 3-10; quiz 11 (2014). Second, the features of broadly
neutralizing antibodies that arise in multiple individuals, versus
rare subjects, must be fully characterized. A number of serological
studies have made progress in this regard, particularly with
respect to epitopes on gp120 (Scheid et al., Nature 458, 636-640
(2009); Simek et al., J Virol 83, 7337-7348 (2009); Walker et al.,
PLoS Pathog 6, e1001028 (2010); Sajadi et al., J Acquir Immune
Defic Syndr 57, 9-15 (2011); Sajadi et al., J Virol 86, 5014-5025
(2012)). Third, the aggregate nature of the polyclonal humoral
environment in which broadly neutralizing activities evolve,
persist and function must be understood. Collectively, this
information can be used to delineate whether and how certain
epitope presentation patterns should be avoided or targeted in
order to deliberately achieve potent and broad neutralizing
activity.
[0007] To date, the interrelationships between broadly neutralizing
antibodies and the circulating plasma anti-HIV envelope humoral
repertoires that harbor them have been examined mainly by indirect
means. Typical approaches involve protein fractionation, antigen
depletion and/or infectivity analyses using viral envelopes with
targeted mutations (Sather et al., Vaccine 28 Suppl 2, B8-12
(2010); Li et al., J Virol 83, 1045-1059 (2009); Dhillon et al., J
Virol 81, 6548-6562 (2007)). These methods do not fully elucidate
the background milieu of the polyclonal anti-envelope humoral
response and cannot clearly define the neutralizing antibody
species in circulation. For example, various studies indicate that
broad plasma neutralizing activity may be traced to either
pauciclonal or polyclonal antibody species (Scheid et al., Nature
458, 636-640 (2009); Walker et al., PLoS Pathog 6, e1001028 (2010);
Sajadi et al., J Virol 86, 5014-5025 (2012); Bonsignori et al., J
Virol 86, 4688-4692 (2012); Doria-Rose et al., J Virol 84,
1631-1636 (2010)). depending on the source subject. Alternatively,
intensive efforts have been applied toward the derivation of
neutralizing mAbs from memory B cell pools. These antibodies,
albeit important for other purposes, may not reflect the true
nature of neutralizing antibodies in circulation (Guan et al., Proc
Natl Acad Sci USA 106, 3952-3957 (2009); Scheid et al., Nature 458,
636-640 (2009); Walker et al., Science 326, 285-289 (2009); Walker
et al., Nature 477, 466-470 (2011).
[0008] There is a need to develop new therapies for treatment and
prevention of HIV infection in patients.
[0009] This background information is provided for informational
purposes only. No admission is necessarily intended, nor should it
be construed, that any of the preceding information constitutes
prior art against the present invention.
SUMMARY OF THE INVENTION
[0010] It is to be understood that both the foregoing general
description of the embodiments and the following detailed
description are exemplary, and thus do not restrict the scope of
the embodiments.
[0011] In one aspect, the invention provides an isolated anti-HIV
antibody, wherein the antibody is capable of neutralizing at least
95% of the HIV viruses listed in Table 1 with an IC50 value of less
than 50 .mu.g/mL. In some embodiments, the isolated anti-HIV
antibody is capable of neutralizing at least 99% of the HIV
pseudoviruses listed in Table 1 with an IC50 value of less than 50
.mu.g/mL. In some embodiments, the antibody is capable of
neutralizing 100% of the HIV pseudoviruses listed in Table 1 with
an IC50 value of less than 50 .mu.g/mL. In some embodiments, the
antibody is selected from the group consisting of [0012] a. N49P6
or an antigen binding fragment thereof; [0013] b. N49P7 or an
antigen binding fragment thereof; [0014] c. N49P7.1 or an antigen
binding fragment thereof; and [0015] d. N49P11 or an antigen
binding fragment thereof.
[0016] In another aspect, the invention provides an isolated
anti-HIV antibody, wherein the antibody is capable of neutralizing
100% of the HIV clade B, G and D pseudoviruses listed in Table 1
with an IC50 value of less than 50 .mu.g/mL. In some embodiments,
the antibody is selected from the group consisting of [0017] a.
N49P6 or an antigen binding fragment thereof; [0018] b. N49P7 or an
antigen binding fragment thereof; [0019] c. N49P7.1 or an antigen
binding fragment thereof; [0020] d. N49P11 or an antigen binding
fragment thereof; and [0021] e. N49P9 or an antigen binding
fragment thereof.
[0022] In another aspect, the invention provides an isolated
anti-HIV antibody, wherein the antibody is capable of neutralizing
HIV pseudoviruses listed in Table 1 with a median IC50 value of
less than 0.5 .mu.g/mL. In some embodiments, the antibody is
selected from the group consisting of [0023] a. N49P6 or an antigen
binding fragment thereof; [0024] b. N49P7 or an antigen binding
fragment thereof; [0025] c. N49P7.1 or an antigen binding fragment
thereof [0026] d. N49P9 or an antigen binding fragment thereof; and
[0027] e. N49P23 or an antigen binding fragment thereof.
[0028] In another aspect, the invention provides an isolated
anti-HIV antibody selected from the group consisting of: [0029] a.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:1 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:2 or an antigen
binding fragment thereof; [0030] b. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:3 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:4 or an antigen binding fragment thereof;
[0031] c. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:5 or an antigen binding fragment thereof and a
light chain amino acid sequence comprising SEQ ID NO:6 or an
antigen binding fragment thereof [0032] d. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:7 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:8 or an antigen binding fragment
thereof [0033] e. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:9 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:10 or an antigen binding fragment thereof [0034] f. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:11 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:12 or an antigen binding
fragment thereof [0035] g. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:13 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:14 or an antigen binding fragment thereof [0036] h. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:15 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:16 or an antigen
binding fragment thereof [0037] i. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:17 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:18 or an antigen binding fragment thereof;
[0038] j. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:19 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:20 or an
antigen binding fragment thereof; [0039] k. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:21 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:22 or an antigen binding fragment
thereof; [0040] l. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:23 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:24 or an antigen binding fragment thereof; [0041] m. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:25 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:26 or an antigen binding
fragment thereof; [0042] n. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:27 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:28 or an antigen binding fragment thereof; [0043] o. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:29 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:30 or an antigen
binding fragment thereof; [0044] p. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:31 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:32 or an antigen binding fragment thereof;
[0045] q. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:33 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:34 or an
antigen binding fragment thereof; [0046] r. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:35 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:36 or an antigen binding fragment
thereof; [0047] s. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:37 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:38 or an antigen binding fragment thereof; [0048] t. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:39 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:40 or an antigen binding
fragment thereof; [0049] u. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:41 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:42 or an antigen binding fragment thereof; [0050] v. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:43 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:44 or an antigen
binding fragment thereof; [0051] w. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:45 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:46 or an antigen binding fragment thereof;
[0052] x. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:47 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:48 or an
antigen binding fragment thereof; [0053] y. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:49 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:50 or an antigen binding fragment
thereof; [0054] z. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:51 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:52 or an antigen binding fragment thereof; [0055] aa. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:53 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:54 or an antigen
binding fragment thereof; [0056] bb. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:55 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:56 or an antigen binding fragment thereof;
[0057] cc. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:57 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:58 or an
antigen binding fragment thereof; [0058] dd. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:59 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:60 or an antigen binding fragment
thereof; [0059] ee. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:61 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:62 or an antigen binding fragment thereof; [0060] ff. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:63 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:64 or an antigen
binding fragment thereof; [0061] gg. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:65 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:66 or an antigen binding fragment thereof;
[0062] hh. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:67 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:68 or an
antigen binding fragment thereof; [0063] ii. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:69 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:70 or an antigen binding fragment
thereof; [0064] jj. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:71 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:72 or an antigen binding fragment thereof; [0065] kk. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:73 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:74 or an antigen
binding fragment thereof; and [0066] ll. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:75 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:76 or an antigen binding fragment
thereof.
[0067] In another aspect, the invention provides an isolated
anti-HIV antibody selected from the group consisting of: [0068] a.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:153 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:155 or an antigen
binding fragment thereof; [0069] b. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:157 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:159 or an antigen binding fragment thereof;
[0070] c. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:161 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:163 or an
antigen binding fragment thereof; [0071] d. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:165 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:167 or an antigen binding fragment
thereof; [0072] e. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:169 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:171 or an antigen binding fragment thereof; [0073] f. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:173 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:175 or an antigen
binding fragment thereof; [0074] g. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:177 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:179 or an antigen binding fragment thereof;
[0075] h. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:181 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:183 or an
antigen binding fragment thereof; [0076] i. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:185 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:187 or an antigen binding fragment
thereof; [0077] j. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:189 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:191 or an antigen binding fragment thereof; [0078] k. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:193 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:195 or an antigen
binding fragment thereof; [0079] l. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:197 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:199 or an antigen binding fragment thereof;
[0080] m. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:201 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:203 or an
antigen binding fragment thereof; [0081] n. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:205 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:207 or an antigen binding fragment
thereof; [0082] o. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:209 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:211 or an antigen binding fragment thereof; [0083] p. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:213 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:215 or an antigen
binding fragment thereof; [0084] q. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:217 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:219 or an antigen binding fragment thereof;
[0085] r. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:221 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:223 or an
antigen binding fragment thereof; [0086] s. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:225 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:227 or an antigen binding fragment
thereof; [0087] t. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:229 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:231 or an antigen binding fragment thereof; [0088] u. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:233 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:235 or an antigen
binding fragment thereof; [0089] v. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:237 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:239 or an antigen binding fragment thereof;
[0090] w. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:241 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:243 or an
antigen binding fragment thereof; [0091] x. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:245 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:247 or an antigen binding fragment
thereof; [0092] y. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:249 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:251 or an antigen binding fragment thereof; [0093] z. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:253 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:255 or an antigen
binding fragment thereof; [0094] aa. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:257 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:259 or an antigen binding fragment thereof;
[0095] bb. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:261 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:263 or an
antigen binding fragment thereof; [0096] cc. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:265 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:267 or an antigen binding fragment
thereof; [0097] dd. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:269 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:271 or an antigen binding fragment thereof; [0098] ee. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:273 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:275 or an antigen
binding fragment thereof; [0099] ff. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:277 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:279 or an antigen binding fragment thereof;
[0100] gg. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:281 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:283 or an
antigen binding fragment thereof; [0101] hh. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:285 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:287 or an antigen binding fragment
thereof; [0102] ii. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:289 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:291 or an antigen binding fragment thereof; [0103] jj. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:293 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:295 or an antigen
binding fragment thereof; [0104] kk. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:297 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:299 or an antigen binding fragment thereof;
[0105] ll. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:301 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:303 or an
antigen binding fragment thereof; [0106] mm. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:305 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:307 or an antigen binding fragment
thereof; [0107] nn. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:309 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:311 or an antigen binding fragment thereof; [0108] oo. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:313 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:315 or an antigen
binding fragment thereof; [0109] pp. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:317 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:319 or an antigen binding fragment thereof;
[0110] qq. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:321 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:323 or an
antigen binding fragment thereof; [0111] rr. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:325 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:327 or an antigen binding fragment
thereof; [0112] ss. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:329 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:331 or an antigen binding fragment thereof; [0113] tt. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:333 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:335 or an antigen
binding fragment thereof; [0114] uu. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:337 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:339 or an antigen binding fragment thereof;
[0115] vv. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:341 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:343 or an
antigen binding fragment thereof; [0116] ww. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:345 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:347 or an antigen binding fragment
thereof; [0117] xx. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:349 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:351 or an antigen binding fragment thereof; [0118] yy. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:353 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:355 or an antigen
binding fragment thereof; [0119] zz. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:357 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:359 or an antigen binding fragment thereof;
[0120] aaa. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:361 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:363 or an antigen binding fragment thereof; [0121] bbb. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:365 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:367 or an antigen
binding fragment thereof; [0122] ccc. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:369 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:371 or an antigen binding fragment
thereof; [0123] ddd. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:373 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:375 or an antigen binding fragment thereof; [0124] eee.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:377 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:379 or an antigen
binding fragment thereof; [0125] fff. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:381 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:383 or an antigen binding fragment
thereof; [0126] ggg. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:385 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:387 or an antigen binding fragment thereof; [0127] hhh.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:389 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:391 or an antigen
binding fragment thereof; [0128] iii. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:393 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:395 or an antigen binding fragment
thereof; and [0129] jjj. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:397 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:399 or an antigen binding fragment thereof.
[0130] In another aspect, the invention provides an anti-HIV
antibody selected from the group consisting of: [0131] a. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYDFIDYV (SEQ ID NO:401), CDR H2 comprises MNPSGGGT (SEQ
ID NO:402) and CDR H3 comprises VRDRANGSGRRRFESVNWFLDL (SEQ ID
NO:403); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAFEN (SEQ
ID NO:404); [0132] b. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFPDYI (SEQ ID NO:405), CDR H2
comprises INPMGGQV (SEQ ID NO:406) and CDR H3 comprises
VRDRSNGSGRRFESSN (SEQ ID NO:407); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0133] c. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYL (SEQ ID NO:409), CDR H2 comprises MNPVYGQV (SEQ ID NO:410)
and CDR H3 comprises VRDTGDGSRRHFDSINWFLDL (SEQ ID NO:411); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFD and CDR L3 comprises WAFEA (SEQ ID NO:412); [0134] d.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2 comprises IDPPYGQV
(SEQ ID NO:414) and CDR H3 comprises VRDRSNGWGKRFESSNWFLDL (SEQ ID
NO:415); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0135] e. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFVDYF (SEQ ID NO:416), CDR H2
comprises MDPLNGRP (SEQ ID NO:417) and CDR H3 comprises
VRDKSNGSGRRFDSSNWFLDL (SEQ ID NO:418); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFN and CDR
L3 comprises WAYDA (SEQ ID NO:419); [0136] f. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFSDYI (SEQ ID NO:420), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEV (SEQ ID NO:422); [0137] g.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFIDYI (SEQ ID NO:423), CDR H2 comprises IDPMNGRP
(SEQ ID NO:424) and CDR H3 comprises VRDKSNGSGKRFDSSNWFLDL (SEQ ID
NO:425); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAYDA (SEQ
ID NO:419); [0138] h. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFTDYI (SEQ ID NO:426), CDR H2
comprises MNPMGGRT (SEQ ID NO:427) and CDR H3 comprises
VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0139] i. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFVDYL (SEQ ID NO:428), CDR H2 comprises MDPMNGRP (SEQ ID NO:429)
and CDR H3 comprises VRDKSGGSGKLFDSSNWFLDL (SEQ ID NO:430); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAYDA (SEQ ID NO:419); [0140] j.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2 comprises INPGYGQV
(SEQ ID NO:431) and CDR H3 comprises VRDRSNGWGKRFESSNWFLDL (SEQ ID
NO:415); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0141] k. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2
comprises MDPSYGQV (SEQ ID NO:432) and CDR H3 comprises
VRDRSHGSGRQFESSNWFLDL (SEQ ID NO:433); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0142] l. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYV (SEQ ID NO:413), CDR H2 comprises MDPSFGQM (SEQ ID NO:434)
and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0143] m.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYRFTDYV (SEQ ID NO:436), CDR H2 comprises MDPSFGRM
(SEQ ID NO:437) and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL (SEQ ID
NO:435); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0144] n. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFIDYV (SEQ ID NO:438), CDR H2
comprises MDPTYGRM (SEQ ID NO:439) and CDR H3 comprises
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0145] o. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYRFLDYI (SEQ ID NO:440), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0146] p.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2 comprises MNPTYGQV
(SEQ ID NO:443) and CDR H3 comprises ARGPSGENYPFHY (SEQ ID NO:444);
and a light chain variable region, wherein CDR L1 comprises RHII
(SEQ ID NO:445), CDR L2 comprises DDD and CDR L3 comprises NTYEF
(SEQ ID NO:446); [0147] q. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYNFVDSR (SEQ ID NO:447),
CDR H2 comprises INPLQGGV (SEQ ID NO:448) and CDR H3 comprises
ARGIDGKSYPFHF (SEQ ID NO:449); and a light chain variable region,
wherein CDR L1 comprises S, CDR L2 comprises ESS and CDR L3
comprises SILEF (SEQ ID NO:450); [0148] r. an antibody comprising a
heavy chain variable region, wherein CDR H1 comprises GYTFTTHHGHF
(SEQ ID NO:500), CDR H2 comprises MNPMTGQM (SEQ ID NO:462) and CDR
H3 comprises ARGDFGQNYPFHY (SEQ ID NO:463); and a light chain
variable region, wherein CDR L1 comprises NRYL (SEQ ID NO:464), CDR
L2 comprises DDN and CDR L3 comprises ASYER (SEQ ID NO:465); [0149]
s. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYNFMDQF (SEQ ID NO:466), CDR H2 comprises
MNPIYGQV (SEQ ID NO:467) and CDR H3 comprises ARGPSGENYPFHY (SEQ ID
NO:444); and a light chain variable region, wherein CDR L1
comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD and CDR L3
comprises NTYEF (SEQ ID NO:446); [0150] t. an antibody comprising a
heavy chain variable region, wherein CDR H1 comprises GYNFVDSR (SEQ
ID NO:447), CDR H2 comprises INPLHGGV (SEQ ID NO:468) and CDR H3
comprises ARGIDGKSYPFHF (SEQ ID NO:449); and a light chain variable
region, wherein CDR L1 comprises S, CDR L2 comprises ESS and CDR L3
comprises SILEF (SEQ ID NO:450); [0151] u. an antibody comprising a
heavy chain variable region, wherein CDR H1 comprises GYTFTKYF (SEQ
ID NO:451), CDR H2 comprises IHPRTGAV (SEQ ID NO:452) and CDR H3
comprises ARGAFEADSYGSSYPFHH (SEQ ID NO:453); and a light chain
variable region, wherein CDR L1 comprises GNYNP (SEQ ID NO:454),
CDR L2 comprises EDN and CDR L3 comprises ASFEF (SEQ ID NO:455);
[0152] v. an antibody comprising a heavy chain variable region,
wherein CDR H1 comprises GYTFTKYT (SEQ ID NO:456), CDR H2 comprises
IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises ARGAFEADLSGPTYPFHH
(SEQ ID NO:457); and a light chain variable region, wherein CDR L1
comprises GNYNP (SEQ ID NO:454), CDR L2 comprises EDN and CDR L3
comprises ASFEF (SEQ ID NO:455); [0153] w. an antibody comprising a
heavy chain variable region, wherein CDR H1 comprises GFNFIDSV (SEQ
ID NO:458), CDR H2 comprises IKPLRGAV (SEQ ID NO:459) and CDR H3
comprises AKGAFRGGSPFGF (SEQ ID NO:460); and a light chain variable
region, wherein CDR L1 comprises DVT and CDR L2 comprises ASREF
(SEQ ID NO:461); [0154] x. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYTFTSYF (SEQ ID NO:469),
CDR H2 comprises INPLHGAV (SEQ ID NO:470) and CDR H3 comprises
TRGIVADGWPYGH (SEQ ID NO:471); and a light chain variable region,
wherein CDR L1 comprises S, CDR L2 comprises EGA and CDR L3
comprises SSLQF (SEQ ID NO:472); [0155] y. an antibody comprising a
heavy chain variable region, wherein CDR H1 comprises GFTFIDHI (SEQ
ID NO:473), CDR H2 comprises IKPLRGAV (SEQ ID NO:459) and CDR H3
comprises CKAAAPEEAFPLQY (SEQ ID NO:474); and a light chain
variable region, wherein CDR L1 comprises NVD, CDR L2 comprises DNN
and CDR L3 comprises SSRTF (SEQ ID NO:475); [0156] z. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GFKFIDHI (SEQ ID NO:476), CDR H2 comprises IKPLGGVA (SEQ ID NO:477)
and CDR H3 comprises CKAAAPDEAFPLEY (SEQ ID NO:478); and a light
chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DNN and CDR L3 comprises SSTTF (SEQ ID NO:479); [0157]
aa. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFAFLDH (SEQ ID NO:480), CDR H2 comprises VKTIGGVV
(SEQ ID NO:481) and CDR H3 comprises SKAAAPDEAFPLEF (SEQ ID
NO:482); and a light chain variable region, wherein CDR L1
comprises NVD, CDR L2 comprises DNN and CDR L3 comprises SSTTF (SEQ
ID NO:479); [0158] bb. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GFKFTEYF (SEQ ID NO:483),
CDR H2 comprises LNPLRGAV (SEQ ID NO:484) and CDR H3 comprises
ARAVFNEAFPFDY (SEQ ID NO:485); and a light chain variable region,
wherein CDR L1 comprises VS, CDR L2 comprises DGD and CDR L3
comprises ASREF (SEQ ID NO:461); [0159] cc. an antibody comprising
a heavy chain variable region, wherein CDR H1 comprises GFKFIDHI
(SEQ ID NO:476), CDR H2 comprises IKPLGGVA (SEQ ID NO:477) and CDR
H3 comprises CKAAAPDEAFPLEY (SEQ ID NO:478); and a light chain
variable region, wherein CDR L1 comprises NVD, CDR L2 comprises DND
and CDR L3 comprises SSTTF (SEQ ID NO:479); [0160] dd. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GFAFLDHI (SEQ ID NO:486), CDR H2 comprises VKTIGGVV (SEQ ID NO:481)
and CDR H3 comprises SKAAAPDEAFPLEF (SEQ ID NO:482); and a light
chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DNN and CDR L3 comprises SSTTF (SEQ ID NO:479); [0161]
ee. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFKFIDSV (SEQ ID NO:487), CDR H2 comprises
IKPLGGAV (SEQ ID NO:488) and CDR H3 comprises AKGAFGGGSPFGF (SEQ ID
NO:489); and a light chain variable region, wherein CDR L1
comprises DVT and CDR L2 comprises ASREF (SEQ ID NO:461); [0162]
ff. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFNFIDSV (SEQ ID NO:458), CDR H2 comprises
IKPLRGGV (SEQ ID NO:490) and CDR H3 comprises AKGAFGGSSPFGF (SEQ ID
NO:491); and a light chain variable region, wherein CDR L1
comprises DVT and CDR L2 comprises ASREF (SEQ ID NO:461); [0163]
gg. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFTFIKYT (SEQ ID NO:492), CDR H2 comprises
IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises ARGAFEADLYGPTYPFHH
(SEQ ID NO:493); and a light chain variable region, wherein CDR L1
comprises GSYNP (SEQ ID NO:494), CDR L2 comprises DDN and CDR L3
comprises ASFEF (SEQ ID NO:455); [0164] hh. an antibody comprising
a heavy chain variable region, wherein CDR H1 comprises GYNFVDSL
(SEQ ID NO:495), CDR H2 comprises INPLQGGV (SEQ ID NO:448) and CDR
H3 comprises ARGIDGNSYPFHF (SEQ ID NO:496); and a light chain
variable region, wherein CDR L1 comprises S, CDR L2 comprises ESS
and CDR L3 comprises SILEF (SEQ ID NO:450); [0165] ii. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPTYGQV (SEQ ID NO:443)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0166]
jj. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAFEN (SEQ
ID NO:404); [0167] kk. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFD and CDR
L3 comprises WAFEA (SEQ ID NO:412); [0168] ll. an antibody
comprising a heavy chain variable region, wherein CDR comprises
GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises RHII (SEQ ID
NO:445), CDR L2 comprises DDD and CDR L3 comprises NTYEF (SEQ ID
NO:446); [0169] mm. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2
comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFN and CDR
L3 comprises WAYDA (SEQ ID NO:419); [0170] nn. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0171]
oo. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2 comprises
MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises VRDRSNGSGKRFESSN (SEQ
ID NO:498); and a light chain variable region, wherein CDR L1
comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD and CDR L3
comprises NTYEF (SEQ ID NO:446); [0172] pp. an antibody comprising
a heavy chain variable region, wherein CDR H1 comprises GYKFMDQL
(SEQ ID NO:442), CDR H2 comprises MNPTYGQV (SEQ ID NO:443) and CDR
H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light
chain variable region, wherein CDR L1 comprises RHII (SEQ ID
NO:445), CDR L2 comprises DDD and CDR L3 comprises NTYEF (SEQ ID
NO:446); and [0173] qq. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYRFLDYI (SEQ ID NO:440),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408).
[0174] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. It should be understood, however, that the detailed
description and the specific examples, while indicating specific
embodiments of the invention, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
BRIEF DESCRIPTION OF THE FIGURES
[0175] The skilled artisan will understand that the drawings,
described below, are for illustration purposes only. The drawings
are not intended to limit the scope of the present teachings in any
way.
[0176] FIG. 1. ELISA reactivity patterns of fractionated IgG from
NVS60 with broad HIV neutralizing activity. Anti-gp120 IgG1 kappa
(panel A) and lambda (panel B) were fractionated by FFE (see
Materials and Methods). Fractions pH ranges from approximately 6.5
(fraction 25) and increasing to 10 (fraction 68) (not shown on the
graph). Aliquots (0.05 ug) of IgG from each fraction was tested by
ELISA for reactivity against the indicated HIV antigens: (BaL-gp120
monomer, BaL-gp120 monomer with the D368R mutation to abrogate
CD4-BS binding, Yu2 gp120 core with V3 loop, and Yu2 gp120 core,
and full length single chain (FLSC), presenting a full length
CD4-induced gp120 structure in which the CD4 binding site is
occupied). The X axis represents the IEF fractions (spanning a pH
gradient of 6 to 10 from left to right). The Y axis represents
ELISA signals expressed as background-corrected OD450 readings/ug
IgG. The right Y axis shows IgG concentration of each fraction
(ug/ml). Assays were repeated at least twice. Areas of broad and
limited neutralization previously identified based on
neutralization (ability to neutralize Tier 2 viruses at <10
ug/ml of affinity purified antibody). Each fraction contains
antibodies that can distinguish single epitopes. In panel A,
Fractions 55-68 do not bind to D368R envelope mutants but do to the
wild-type virus (BaL-gp120). Likewise, Fractions 25-30 and 35-40 in
Panel A bind to FLSC (fusion protein between CD4 and gp120) but not
monomeric gp120. This strongly suggests antibodies targeting a
single epitope (CD4-binding site antibodies and CoReceptor binding
site, respectively), as a mixed population of CD4-binding site and
non-CD4 binding site antibodies would show some binding to the
D368R mutant, and a mixed population of CoReceptor binding site and
non-CoReceptor binding site would show binding to the monomer. In
Panel B, when the fraction IgG concentrations are compared, the
IgG1 anti-gp120 lambda response is almost entirely limited to
fractions 28-32, suggesting that one or few antibodies are
responsible for the lambda fraction (and by extension up to 60% of
the total anti-gp120 response).
[0177] FIG. 2. Comparison of Heavy chains from 2 antibodies based
on unique peptides. After digestion of affinity purified samples
from N60, samples run through LC-MS and analyzed with patient
specific database (see Example 1 methods). Orange and blue bars
represent unique and non-unique peptide sequences. Grey shading of
the protein sequence shows areas covered by peptide sequence. In
panel A, the peptide matches are restricted to the framework
regions and include only one unique peptide. This mAb did not bind
or neutralize HIV. In contrast, in panel B, the there are multiple
unique peptides, including coverage of the hypervariable region.
This mAb, N60P2.1 bound and neutralized HIV.
[0178] FIG. 3. Free flow electrophoretic fractionation of N60
plasma anti-gp120 polyclonal antibodies and reconstructed
anti-gp120 mAbs. The gray line indicates the pH (right Y axis)
gradient across the fractions created by the FFE procedure.
Anti-gp120 .kappa. light chain (top) or anti-gp120 .lamda. light
chain (bottom) polyclonal plasma antibody preparations were
processed separately (see Example 1 text and methods). The plasma
antibody protein concentrations (left Y axis) detected across
fractions are shown by the black trace. FFE analyses of identified
and reconstructed mAbs (see Example 1) are depicted by horizontal
bars. Bar width spans 75-85% of the total amount of antibodies in
the FFE fraction, as determined by Elisa. Eight mAbs (checkered
bars) were identified by evaluating peptides from individual FFE
fractions of bulk polyclonal anti-gp120 plasma antibodies. The FFE
fraction reflecting the most coverage and unique peptide pairings
is indicted for each mAb by a matched-color arrow. Five additional
mAbs (hatched colored bars) were identified by evaluating peptides
from IEF gel fractionation of the bulk plasma antibodies. Searches
using peptides digested from bulk plasma anti-gp120 antibodies
identified 1 additional mAbs (solid colored bars). One other mAb
(criss-cross colored bars) was identified by homology search of the
Ig gene database. The pH gradient shown is for the polyclonal
N60IgG1 anto-gp120 .kappa. fraction; pH gradients from each
monoclonal run overlapped the trace shown, with a variance of up to
0-5 fractions in either direction.
[0179] FIG. 4. Dendrogram of variable region of all NVS60
antibodies derived from single-cell sequencing from the bone
marrow. The antibodies isolated from 2013 grouped into 7 distinct
families. Two families of CD4-BS antibodies were identified. The
anti-gp120 antibodies represented 3.2% of all antibodies in the
bone marrow database. Lineage 1 and 2 are CD4-binding site
antibodies. Lineages 3-6 are CD4-induced antibodies, while Lineage
7 are variable loop 3 antibodies.
[0180] FIG. 5. ELISA Reactivity of the 7 families of antibodies
isolate. Representative examples of each family is given. Dilutions
of each mAb was tested by ELISA for reactivity against the
indicated HIV antigens: BaL-gp120 monomer, BaL-gp120 monomer with
the D368R mutation to abrogate CD4-BS binding, Yu2 gp120 core, Yu2
gp120 core +V3, and full length single chain (FLSC), presenting a
full length CD4-induced gp120 structure in which the CD4-BS is
occupied. N60P35 and N60P37 were also tested against the Complete
V3 Loop Peptide. X-axis shows mAb concentration in ug/ml, and Y
axis the background-subtracted OD. CD4-BS=CD4-binding site
antibody. CoR--BS=Co--Receptor binding site antibody.
CD4i=CD4-induced.
[0181] FIG. 6. Surface plasmon resonance analysis of N60 Lineage 1
mAbs to HIV envelope antigens. The binding kinetics for BaL-gp120
or D368R with mAb captured on Protein A-coated chips are shown.
Data sets with significant dose response were globally fit to a 1:1
binding model to obtain the kinetic parameters of the binding.
Three of the mAbs tested bound to gp120 monomer but exhibited weak
binding to D368R. The other mAb demonstrated no binding to BaL
gp120 or D368R.
[0182] FIG. 7. Neutralization activity plasma derived anti-Env
antibodies (alone and in combination). A panel of HIV-1 viral
envelope strains (individual viruses listed on the left column)
that were sensitive to the bulk plasma N60 gp120-Ig were tested
against neutralizing anti-CD4-BS antibodies from Lineage 1 and 2.
For Lineage 2, only one mAb N60P22 tested, as the other was a
closely related clone (98% sequence homology). IC.sub.50 values are
color-coded according to the color key on the left: the greater the
neutralization, the darker red the color; grey represents no
neutralization (IC.sub.50>25 ug/ml). Taken together, the
anti-CD4-BS mAbs neutralized 89% of the viruses that were sensitive
to bulk plasma anti-gp120 Ig. An equimolar mix of the mAbs called
N60mAb Mix1 (all CD4-BS, CD4i, and variable loop antibodies with
>5% sequence divergence) were tested at equimolar concentrations
neutralized 79% of the pseudoviruses, and N60mAb Mix2 (all CD4-BS
antibodies with >5% sequence divergence at equimolar
concentrations) neutralized 89% of the pseudoviruses.
IC50=Inhibitory Concentration 50.
[0183] FIG. 8. Neutralization activity of NVS49 plasma and P series
mAbs. A panel of HIV-1 viral envelope strains (individual viruses
listed on the left column) were tested against all N49 plasma and
CD4-BS antibodies. IC50 values are color-coded according to the
color key on the left: the greater the neutralization, the darker
red the color; white represents no neutralization (IC.sub.50>50
ug/ml). The individual mAbs showed extreme breadth with N49P6,
N49P7, and N49P11 exhibiting 100% breadth, N49P7.1 exhibiting 99%
breadth, and N49P9 exhibiting 89% breadth. IC50=Inhibitory
Concentration 50.
[0184] FIG. 9. ELISA Reactivity of the N49 P series mAbs. Dilutions
of each mAb was tested by ELISA for reactivity against the
indicated HIV antigens: BaL-gp120 monomer, BaL-gp120 monomer with
the D368R mutation to abrogate CD4-BS binding, Yu2 gp120 core, Yu2
gp120 core+V3, and full length single chain (FLSC), presenting a
full length CD4-induced gp120 structure in which the CD4-BS is
occupied. X-axis shows mAb concentration in ug/ml, and Y axis the
background-subtracted OD.
[0185] FIG. 10. Surface plasmon resonance analysis of N49 P series
mAbs to HIV-1 envelope antigens. The binding kinetics for BaL-gp120
or D368R with mAb captured on Protein A-coated chips are shown.
Data sets with significant dose response were globally fit to a 1:1
binding model to obtain the kinetic parameters of the binding. All
mAbs tested bound strongly to gp120 monomer but exhibited weak
binding to D368R.
[0186] FIG. 11. Heavy and light chain amino acid sequences. For
heavy and light chains, V(D)J sequences and 1.sup.st position of
constant region are shown. Homology with germline Heavy 1-2, Lambda
2-11 J2/3, and Lambda 2-23 J2/3 are shown. Nucleotide data is given
in a separate excel file (N49 neutralization and sequences).
[0187] FIG. 12. ELISA Reactivity of the N49 antibodies isolated.
Dilutions of each mAb was tested by ELISA for reactivity against
the indicated HIV antigens: BaL-gp120 monomer, BaL-gp120 monomer
with the D368R mutation to abrogate CD4-BS binding, Yu2 gp120 core,
and full length single chain (FLSC), presenting a full length
CD4-induced gp120 structure in which the CD4-BS is occupied. X-axis
shows mAb concentration in ug/ml, and Y axis the
background-subtracted OD.
[0188] FIG. 13. Neutralization activity of N49P7 against a panel of
Clade B pseudoviruses. Purified IgG was tested for neutralizing
activity against the indicated pseudoviruses. SF162.LS is a Tier 1
pseudovirus, the rest fall within the Tier 2 or Tier 3 category.
The monoclonal antibody N49P7 was able to neutralize all 9 viruses
in our Clade B panel.
[0189] FIG. 14. Germline and natural heavy chains. A) Variable
region. IMGT numbering system of germline 1-2 heavy chain shown, as
well as alignment of germline 1-2 to natural sequences 1-38. B)
Constant region. IMGT numbering system of CH1-3 of IgG1 shown as
well as alignment of natural sequences that have point mutations in
the constant region.
[0190] FIG. 15. Germline and natural light chain variable region.
A) IMGT numbering system of germline IgL2-11 shown, as well as
alignment of IgL2-11 with J3 to natural sequences 1-17. B) IMGT
numbering system of germline IgL2-23 shown, as well as alignment of
IgL2-23 with J3 shown to natural sequences 18-38.
[0191] FIG. 16. Germline and natural light chain constant region.
A) IMGT numbering system of germline LC2 as well as alignment to
natural sequences 1-17 that use this gene with point mutation
shown. B) IMGT numbering system of germline LC7, as well as
alignment to natural sequences 18-38 that use this gene, with point
mutation shown.
[0192] FIG. 17. Heavy and light chain amino acid sequences for
N49P6 mutants. Panel A shows heavy chain mutants N49P6 54Y, N49P6
54F, and N49P6 54YT, Panel B light chain mutants N49P6A, N49P6S,
and Panel C the heavy chain constant mutant N49P6 YTE. N49P6 heavy,
light, or heavy constant given as reference.
[0193] FIG. 18. Heavy and light chain amino acid sequences for
N49P7 mutants. Panel A shows heavy chain mutants N49P7 54Y, N49P7
54F, and N49P7 54YT, Panel B light chain mutants N49P7A, N49P7S,
and Panel C the heavy chain constant mutant N49P7 YTE. N49P7 heavy,
light, or heavy constant given as reference.
[0194] FIG. 19. Crystal structure of N60P23 Fab-gp120.sub.93THO57
core.sub.e complex. (A) Ribbon diagram of N60P23
Fab-gp120.sub.93THO57 core.sub.e complex with light and heavy
chains of Fab shown in light and dark green, respectively, and the
complementarity-determining regions (CDRs) shown in blue (CDR L1),
black (CDR L2), orange (CDR L3), pink (CDR H1), green (CDR H2), and
yellow (CDR H3). The gp120 is colored in white. The D (S274-T283),
V5 (T455-N465) and the CD4 binding (Q362-G372) loops are colored in
cyan, violet and magenta, respectively. (B) Structural comparison
of N60P23 Fab-gp120.sub.93THO57 core.sub.e complex and
VRC01-gp120.sub.93THO57 core.sub.e (PDB code 3NGB) complexes.
Complexes were aligned based on the gp120 and are shown as the
ribbon diagrams. The light and heavy chains of VRCO1 Fab are shown
in light and dark cyan and the CDRs are colored as in N60P23
complex. (C) N60P23 and VRCO1 epitope footprints. N60P23/VRCO1
contacts on gp120a3THo57Coree are highlighted in light green/cyan
(light chain) and dark green/cyan (heavy and both chains) on the
gp120 surface. (D) N60P23 and VRCO1 Fabs and gp12093TH057Coree
contact residues on the primary sequence of the Fabs and
gp120.sub.93TH057 core.sub.e, respectively. Residues contributing
to the Fabs and gp12093THos7 core.sub.e are highlighted and
contacts as defined by a 5A cutoff are marked above the sequence.
Side chain (+) and main chain (-) contacts are colored based on
contact type; hydrophobic in blue, hydrophilic in green, or both in
black. Framework and complementary-determining regions are as
indicated in the alignment. N60P23 binds within the CD4BS of gp120
engaging the CD4-binding loop as well as loops D and V5 also known
to interact with the CD4 receptor and the CD4-binding site antibody
VRC01. It recognizes the gp120 antigen with striking similarities
to VRCO1 with epitope footprint almost entirety overlapping the
gp120 surface involved in VRCO1 Fab-CD4-gp120.sub.93TH057
core.sub.e complex and utilizing the same CDR contacts. The close
structural similarity of the complex interfaces is reflected in
relatively low root mean square deviation (RMSD) value of 0.7 .ANG.
for the Ca atoms of the Fab variable domains and the gp120
core.sub.e,
[0195] FIG. 20. Crystal structure of N49P7 Fab-gp120.sub.93TH057
core.sub.e complex. (A) Ribbon diagram of complex with the
complementarity-determining regions (CDRs) of N49P7 Fab
contributing to the gp120 binding (from light chain CDR L1 and CDR
L3 and from heavy chain CDR H1, CDR H2 and CDR H3, see also Table
15) colored as shown. The gp120 outer and inner domains are colored
in black and gray, respectively. The D (S.sup.27-T.sup.283), E5
(F.sup.353-T.sup.358), V5 (T.sup.455-N.sup.465) and the CD4 binding
(Q.sup.362-G.sup.372) loops are colored in cyan, orange, violet and
magenta, respectively. G.sup.54 of N49P7 Fab is highlighted in red
and sugars at positions 276 (Loop D) and 355 (Loop E) are shown as
sticks. (B) A blow up view into the network of interactions of
N49P7 Fab with residues of the inner domain of gp120. Inner domain
Layers 2 and 3 are colored pale green and beige, respectively. Two
hydrogen bonds (CDR H2 Q.sup.56 and Layer 3 N.sup.474; CDR H3
E.sup.100E and Layer 2 K.sup.97) and a salt bridge (CDR H3
E.sup.100C and Layer 3 D.sup.477) are formed at the N49P7 Fab-gp120
inner domain interface. (C) Gp120.sub.93TH057 core.sub.e and N49P7
CDR contact residues mapped onto the primary sequence. Contact
residues are defined by a 5 .ANG. cutoff and marked above the
sequence. Side chain (+) and main chain (-) contacts are colored
based on contact type; hydrophobic in green, hydrophilic in blue,
or both in black. Buried surface residues as determined by PISA are
shaded. (D) Blow up views into the Fab-gp120.sub.93TH057 core.sub.e
interfaces of N49P7 Fab, N60P23 Fab and N6 Fab (PDB code: 5te6).
The molecular surface is displayed over gp120 molecules with outer
domain loops: D, X5, V5 and CD4 binding and inner domain Layers 2
and 3 and the 7-stranded .beta.-sandwich with CDRs colored as in
panels A and B. The Fab residue at the position equivalent to
F.sup.43 of CD4 is shown as sticks (Gly, His and Tyr in N49P7,
N60P23 and N6, respectively). (E) The buried surface area (BSA) of
gp120 residues involved in binding to N49P7, N60P23 and N6 are
shown as bars (bottom panel) and their conservation among HIV-1
isolates (top panel). The conservation of the residue at particular
position is shown as % difference from the Hxbc2 sequence. Only
unique sequences in the database having an equivalent residue at
each position were included in the calculated percentage
representing approximately 32,000 sequences on average. Conserved
inner domain residues uniquely targeted by N49P7 are highlighted in
red.
[0196] FIG. 21. Unique features of gp120 antigen recognition
mediated by N49P7. The overall structure of the N49P7
Fab-gp120.sub.93TH057 core.sub.e complex is shown in the center
with the molecular surface displayed over the Fab molecule to
highlight the shape of the formed antigen binding site. The
complementarity-determining regions (CDRs) are shown in green (CDR
L1), blue (CDR L3), black (CDR H1), yellow (CDR H2), and red (CDR
H3). The gp120 outer and inner domains are colored in black and
gray, respectively. The D (S.sup.274-T.sub.283), E5
(F.sup.353-T.sup.358), V5 (T.sup.455-N.sup.465) and the CD4 binding
(Q.sup.362-G.sup.372) loops are colored in cyan, orange, violet and
magenta, respectively. The bottom panel shows the sequence
alignments of the variable light and heavy regions of N49P7 and N6
(Huang et al., 2016). The unique features of the gp120 antigen
recognition mediated by N49P7 are shown (from 1 to 6) and discussed
in details in the blow up view figures: (1)`Super short` CDR L1The
CDRL1 of N49P7 consists of 8 amino acids (aa), 1 and 3 aa shorter
than the CDRL1 of VRCOI and N6, respectively. The short CDR L1
avoids steric clashes with loop D and Loop E and permits the
accommodation of complex and bulky glycans linked to N.sup.276 and
N.sup.355 of gp120. The figure shows the overlay of the N49P7
Fab-gp120.sub.93TH057 core.sub.e and the N6 Fab-gp120.sub.93TH057
core.sub.e complex (Huang et al., 2016). Structures were
superimposed based upon gp120 to show differences in the length and
position of CDR L1 relative to the gp120 antigen (colored dark
green for N49P7 and light green for N6) (2) Unpaired cysteine
(C.sup.36) in a framework 2 (FW2) of the light chain. Both .kappa.
(as seen in N6) and .lamda. light chains have a tyrosine at
position of 36 of FW2. Replacement of this bulky residue by
cysteine changes the packing of the hydrophobic core formed at the
variable light (V.sub.L) and heavy (V.sub.H) domain interface of
N49P7 as compared to N6. The result of the unique packing is a
difference in the relative orientations (rotation/tilting) of
V.sub.L. and V.sub.H observed in N49P7 relative to N6. The figure
shows the V.sub.L-V.sub.H core packing of N49P7 and N6. Fabs were
superimposed based of V.sub.H domain. N6 is colored light and dark
blue for light and heavy chain, respectively (CD1 L1 as in panel
1). (3) Rotation/tilting of the light chain- the assembly of
V.sub.L and V.sub.H domains of N49P7 forms an asymmetric antigen
binding side, wildly open from the V.sub.L side and protruding from
the V.sub.H side. The open access from the V.sub.L side is due to
the rotation/tilting of the light chain relative to the heavy chain
as described in (2). The figure shows the same superimposition as
in panel 2. The V.sub.L of N49P7 is rotated approximately 12
degrees (measured at the V.sub.L N-termini) away from Loops D and
VS of gp120. This generates a 5A distance between the V.sub.L
N-termini of N49P7 and N6. The wild opening of the V.sub.L side of
the P7 antigen binding site combined with short CDRL1 allows N49P7
to accommodate different lengths of the highly variable loops D, E
and V5. Changes in the length of gp120 loop V5 and the length (and
glycosylation status) of loop E that cause steric clashes with an
antibody CDRL1 were described previously as mechanisms of HIV-1
resistance to VRC01-class antibodies. (4) Long CDRH3 that contacts
to Loop D and the inner domain of gp120. The CDRH3 of N49P7
consists of 19 aa that contact the conserved Loop D of gp120 and
reach deeply into the gp120 inner domain (compared to the 13
aa-long CDRH3 of N6). The CDRH3 contributes 274 .ANG..sup.2 BSA to
the complex interface (28.6% of the BSA of the whole Fab). A
network of interactions is formed which includes hydrogen bonds
formed by Lys of CDRH3 (of a S.sup.100GK motif) and residues of the
al helix of Layer 2 and the .alpha.7-helix of Layer 3 of the inner
domain. (5) `By passing` the Phe43 cavity. The CDRH2 of N49P7 is a
major anchor point in binding to the gp120 antigen contributing 489
.ANG..sup.2 BSA to the complex interface (51% of the BSA of the
whole Fab) but it lacks Glycine at position 54 (Tyrosine in N6)
thus it is unable to anchor deeply inside the Phe43 cavity of the
CD4BS. Instead N49P7 makes important contacts to inner domain
mediated trough M.sup.53 and Q.sup.56 which compensate for lack of
direct contacts to residues of the Phe43 cavity. Overall N49P7
contributes 207 .ANG..sup.2 of its buried surface area (BSA) to the
gp120 inner domain which is the highest among N6 and the VRCO1 Abs
class. The figure shows a blow up view of the CDRH2-gp120 interface
of N49P7 and N6. CDRH2 is colored light and dark yellow for N49P7
and N6, respectively. (6) The P.sup.60W motif in CDRH2. N49P7 is
able to accommodate changes in length and conformation of the gp120
V5 loop through a P.sup.60W motif of its CDRH2 which forms the
framework for an interaction network with the base of the V5 loop.
Figure shows a close-up view of the interaction of CDRH2 of N49P7
and N6 with Loop V5. The P.sup.60W (N49P7) and G.sup.60GG (N6)
motifs are highlighted.
[0197] FIG. 22. Comparison of N49P7 to other bNAbs in the
literature. Viruses resistant to N6, DH511-2, or 10E8 are shown.
N49P7 shows the greatest breadth and overall potency.
DETAILED DESCRIPTION OF THE INVENTION
[0198] The nature of humoral immunity generated by HIV infection
provides critical insights for developing antibody-based prevention
measures. While most studies are based on memory B-cell derived
antibodies, in this disclosure the circulating polyclonal responses
of two HIV-infected subjects with super-neutralizing HIV activity
were deconvoluted through purification, fractionation, and direct
sequencing of plasma antibodies. These analyses revealed that
plasma anti-gp120 responses comprise a limited number of coexistent
antibody lineages; only one of which (CD4-binding site) explains
the bulk of the neutralizing activity. Members of one lineage (N49P
series) comprised of several members, each able to neutralize 100%
of isolates tested in a multitier, multiclade 117 pseudovirus
panel, including all strains resistant to other broadly
neutralizing antibodies. The derivation of such native antibodies
with very broad cross-reactivity and potency from the plasma
repertoires of multiple individuals should facilitate better
understanding of the evolution of HIV humoral immunity, and inform
envelope-based immunoprophylaxis strategies.
[0199] Reference will now be made in detail to the presently
preferred embodiments of the invention which, together with the
drawings and the following examples, serve to explain the
principles of the invention. These embodiments describe in
sufficient detail to enable those skilled in the art to practice
the invention, and it is understood that other embodiments may be
utilized, and that structural, biological, and chemical changes may
be made without departing from the spirit and scope of the present
invention. Unless defined otherwise, all technical and scientific
terms used herein have the same meanings as commonly understood by
one of ordinary skill in the art.
[0200] The practice of the present invention employs, unless
otherwise indicated, conventional techniques of molecular biology
(including recombinant techniques), microbiology, cell biology,
biochemistry and immunology, which are within the skill of the art.
Such techniques are explained fully in the literature. See, e.g.,
Sambrook et al. Molecular Cloning: A Laboratory Manual, 2.sup.nd
edition (1989); Current Protocols in Molecular Biology (F. M.
Ausubel et al. eds. (1987)); the series Methods in Enzymology
(Academic Press, Inc.); PCR: A Practical Approach (M. MacPherson et
al. IRL Press at Oxford University Press (1991)); PCR 2: A
Practical Approach (M. J. MacPherson, B. D. Hames and G. R. Taylor
eds. (1995)); Antibodies, A Laboratory Manual (Harlow and Lane eds.
(1988)); Using Antibodies, A Laboratory Manual (Harlow and Lane
eds. (1999)); and Animal Cell Culture (R. I. Freshney ed. (1987)).
Definitions of common terms in molecular biology may be found, for
example, in Benjamin Lewin, Genes VII, published by Oxford
University Press, 2000 (ISBN 019879276X); Kendrew et al. (eds.);
The Encyclopedia of Molecular Biology, published by Blackwell
Publishers, 1994 (ISBN 0632021829); and Robert A. Meyers (ed.),
Molecular Biology and Biotechnology: a Comprehensive Desk
Reference, published by Wiley, John & Sons, Inc., 1995 (ISBN
0471186341).
[0201] For the purpose of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice versa.
In the event that any definition set forth below conflicts with the
usage of that word in any other document, including any document
incorporated herein by reference, the definition set forth below
shall always control for purposes of interpreting this
specification and its associated claims unless a contrary meaning
is clearly intended (for example in the document where the term is
originally used). The use of "or" means "and/or" unless stated
otherwise. As used in the specification and claims, the singular
form "a," "an" and "the" include plural references unless the
context clearly dictates otherwise. For example, the term "a cell"
includes a plurality of cells, including mixtures thereof. The use
of "comprise," "comprises," "comprising," "include," "includes,"
and "including" are interchangeable and not intended to be
limiting. Furthermore, where the description of one or more
embodiments uses the term "comprising," those skilled in the art
would understand that, in some specific instances, the embodiment
or embodiments can be alternatively described using the language
"consisting essentially of" and/or "consisting of."
[0202] Abbreviations for amino acids are used throughout this
disclosure and follow the standard nomenclature known in the art.
For example, as would be understood by those of ordinary skill in
the art, Alanine is Ala or A; Arginine is Arg or R; Asparagine is
Asn or N; Aspartic Acid is Asp or D; Cysteine is Cys or C; Glutamic
acid is Glu or E; Glutamine is Gln or Q; Glycine is Gly or G;
Histidine is His or H; Isoleucine is Ile or I; Leucine is Leu or L;
Lysine is Lys or K; Methionine is Met or M; Phenylalanine is Phe or
F; Proline is Pro or P; Serine is Ser or S; Threonine is Thr or T;
Tryptophan is Trp or W; Tyrosine is Tyr or Y; and Valine is Val or
V.
[0203] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
[0204] The term "antibody" means an immunoglobulin molecule that
recognizes and specifically binds to a target, such as a protein,
polypeptide, peptide, carbohydrate, polynucleotide, lipid, or
combinations of the foregoing through at least one antigen
recognition site within the variable region of the immunoglobulin
molecule. As used herein, the term "antibody" encompasses intact
polyclonal antibodies, intact monoclonal antibodies, antibody
fragments (such as Fab, Fab', F(ab')2, and Fv fragments, dual
affinity retargeting antibodies (DART)), single chain Fv (scFv)
mutants, multispecific antibodies such as bispecific and
trispecific antibodies generated from at least two intact
antibodies, chimeric antibodies, humanized antibodies, human
antibodies, fusion proteins comprising an antigen determination
portion of an antibody, and any other modified immunoglobulin
molecule comprising an antigen recognition site so long as the
antibodies exhibit the desired biological activity.
[0205] In some embodiments, an antibody can be of any the five
major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or
subclasses (isotypes) thereof (e.g. IgG1, IgG2, IgG3, IgG4, IgA1
and IgA2), based on the identity of their heavy-chain constant
domains referred to as alpha, delta, epsilon, gamma, and mu,
respectively. The different classes of immunoglobulins have
different and well known subunit structures and three-dimensional
configurations. Antibodies can be naked or conjugated to other
molecules such as toxins, radioisotopes, etc.
[0206] The basic four-chain antibody unit is a heterotetrameric
glycoprotein composed of two identical light (L) chains and two
identical heavy (H) chains. An IgM antibody consists of 5 basic
heterotetramer units along with an additional polypeptide called J
chain, and therefore contain 10 antigen binding sites, while
secreted IgA antibodies can polymerize to form polyvalent
assemblages comprising 2-5 of the basic 4-chain units along with J
chain. In the case of IgGs, the 4-chain unit is generally about
150,000 daltons. Each L chain is linked to an H chain by one
covalent disulfide bond, while the two H chains are linked to each
other by one or more disulfide bonds depending on the H chain
isotype. Each H and L chain also has regularly spaced intrachain
disulfide bridges. Each H chain has at the N-terminus, a variable
region (V.sub.H) followed by three constant domains (C.sub.H) for
each of the .alpha. and .gamma. chains and four C.sub.H domains for
.mu. and .epsilon. isotypes. Each L chain has at the N-terminus, a
variable region (V.sub.L) followed by a constant domain (C.sub.L)
at its other end. The V.sub.L is aligned with the V.sub.H and the
C.sub.L is aligned with the first constant domain of the heavy
chain (C.sub.H1). Particular amino acid residues are believed to
form an interface between the light chain and heavy chain variable
regions. The pairing of a V.sub.H and V.sub.L together forms a
single antigen-binding site. For the structure and properties of
the different classes of antibodies, see, e.g., Basic and Clinical
Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and
Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn.,
1994, page 71, and Chapter 6.
[0207] The L chain from any vertebrate species can be assigned to
one of two clearly distinct types, called kappa (.kappa.) and
lambda (.lamda.), based on the amino acid sequences of their
constant domains (C.sub.L). Depending on the amino acid sequence of
the constant domain of their heavy chains (C.sub.H),
immunoglobulins can be assigned to different classes or isotypes.
There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and
IgM, having heavy chains designated alpha (.alpha.), delta
(.delta.), epsilon (.epsilon.), gamma (.gamma.) and mu (.mu.)
respectively. The .gamma. and .alpha. classes are further divided
into subclasses on the basis of relatively minor differences in
C.sub.H sequence and function, e.g., humans express the following
subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.
[0208] The terms "antigen" or "immunogen" are used interchangeably
to refer to a substance, typically a protein, which is capable of
inducing an immune response in a subject. The term also refers to
proteins that are immunologically active in the sense that once
administered to a subject (either directly or by administering to
the subject a nucleotide sequence or vector that encodes the
protein) is able to evoke an immune response of the humoral and/or
cellular type directed against that protein.
[0209] The term "antigen binding fragment" or antibody fragment
refers to a portion of an intact antibody and comprises the
antigenic determining variable regions of an intact antibody.
Examples of antigen binding fragment include, but are not limited
to Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single
chain antibodies, and multispecific antibodies formed from antibody
fragments.
[0210] A "monoclonal antibody" refers to a homogeneous antibody
population involved in the highly specific recognition and binding
of a single antigenic determinant, or epitope. This is in contrast
to polyclonal antibodies that typically include different
antibodies directed against different antigenic determinants. The
term "monoclonal antibody" encompasses both intact and full-length
monoclonal antibodies as well as antibody fragments (such as Fab,
Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins
comprising an antibody portion, and any other modified
immunoglobulin molecule comprising an antigen recognition site.
Furthermore, "monoclonal antibody" refers to such antibodies made
in any number of manners including but not limited to by hybridoma,
phage selection, recombinant expression, and transgenic
animals.
[0211] The term "humanized antibody" refers to forms of non-human
(e.g. murine) antibodies that are specific immunoglobulin chains,
chimeric immunoglobulins, or fragments thereof that contain minimal
non-human (e.g., murine) sequences. Typically, humanized antibodies
are human immunoglobulins in which residues from the complementary
determining region (CDR) are replaced by residues from the CDR of a
non-human species (e.g. mouse, rat, rabbit, hamster) that have the
desired specificity, affinity, and capability (Jones et al., 1986,
Nature, 321:522-525; Riechmann et al., 1988, Nature, 332:323-327;
Verhoeyen et al., 1988, Science, 239:1534-1536). In some instances,
the Fv framework region (FR) residues of a human immunoglobulin are
replaced with the corresponding residues in an antibody from a
non-human species that has the desired specificity, affinity, and
capability. The humanized antibody can be further modified by the
substitution of additional residues either in the Fv framework
region and/or within the replaced non-human residues to refine and
optimize antibody specificity, affinity, and/or capability. In
general, the humanized antibody will comprise substantially all of
at least one, and typically two or three, variable domains
containing all or substantially all of the CDR regions that
correspond to the non-human immunoglobulin whereas all or
substantially all of the FR regions are those of a human
immunoglobulin consensus sequence. The humanized antibody can also
comprise at least a portion of an immunoglobulin constant region or
domain (Fc), typically that of a human immunoglobulin. Examples of
methods used to generate humanized antibodies are described in U.S.
Pat. No. 5,225,539 or 5,639,641.
[0212] A "variable region" of an antibody refers to the variable
region of the antibody light chain or the variable region of the
antibody heavy chain, either alone or in combination. The variable
regions of the heavy and light chain each consist of four framework
regions (FR) connected by three complementarity determining regions
(CDRs) also known as hypervariable regions. The CDRs in each chain
are held together in close proximity by the FRs and, with the CDRs
from the other chain, contribute to the formation of the
antigen-binding site of antibodies. The term "hypervariable region"
when used herein refers to the amino acid residues of an antibody
that are responsible for antigen binding. The hypervariable region
generally comprises amino acid residues from a "complementarity
determining region" or "CDR" (e.g., around about residues 24-34
(L1), 50-56 (L2) and 89-97 (L3) in the V.sub.L, and around about
31-35 (H1), 50-65 (H2) and 95-102 (H3) in the V.sub.H when numbered
in accordance with the Kabat numbering system; Kabat et al.,
Sequences of Proteins of Immunological Interest, 5th Ed. Public
Health Service, National Institutes of Health, Bethesda, Md.
(1991)); and/or those residues from a "hypervariable loop" (e.g.,
residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the V.sub.L, and
26-32 (H1), 52-56 (H2) and 95-101 (H3) in the V.sub.H when numbered
in accordance with the Chothia numbering system; Chothia and Lesk,
J. Mol. Biol. 196:901-917 (1987)); and/or those residues from a
"hypervariable loop"/CDR (e.g., residues 27-38 (L1), 56-65 (L2) and
105-120 (L3) in the V.sub.L, and 27-38 (H1), 56-65 (H2) and 105-120
(H3) in the V.sub.H when numbered in accordance with the IMGT
numbering system; Lefranc, M. P. et al. Nucl. Acids Res. 27:209-212
(1999), Ruiz, M. e al. Nucl. Acids Res. 28:219-221 (2000)).
[0213] The IMGT unique numbering has been defined to compare the
variable domains whatever the antigen receptor, the chain type, or
the species [Lefranc M.-P., Immunology Today 18, 509 (1997)/Lefranc
M.-P., The Immunologist, 7, 132-136 (1999)/Lefranc, M.-P., Pommie,
C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L.,
Thouvenin-Contet, V. and Lefranc, Dev. Comp. Immunol., 27, 55-77
(2003)]. In the IMGT unique numbering, the conserved amino acids
always have the same position, for instance cysteine 23 (1st-CYS),
tryptophan 41 (CONSERVED-TRP), hydrophobic amino acid 89, cysteine
104 (2nd-CYS), phenylalanine or tryptophan 118 (J-PHE or J-TRP).
The IMGT unique numbering provides a standardized delimitation of
the framework regions (FR1-IMGT: positions 1 to 26, FR2-IMGT: 39 to
55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to 128) and of the
complementarity determining regions: CDR1-IMGT: 27 to 38,
CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps represent
unoccupied positions, the CDR-IMGT lengths (shown between brackets
and separated by dots, e.g. [8.8.13]) become crucial information.
The IMGT unique numbering is used in 2D graphical representations,
designated as IMGT Colliers de Perles (Ruiz, M. and Lefranc, M.-P.,
Immunogenetics, 53, 857-883 (2002)/Kaas, Q. and Lefranc, M.-P.,
Current Bioinformatics, 2, 21-30 (2007)), and in 3D structures in
IMGT/3Dstructure-DB (Kaas, Q., Ruiz, M. and Lefranc, M.-P., T cell
receptor and MHC structural data. Nucl. Acids. Res., 32, D208-D210
(2004)).
[0214] In some embodiments, CDRs are determined based on
cross-species sequence variability (i.e., Kabat et al. Sequences of
Proteins of Immunological Interest, (5th ed., 1991, National
Institutes of Health, Bethesda Md.)). In some embodiments, CDRs are
determined based on crystallographic studies of antigen-antibody
complexes (Al-lazikani et al (1997) J. Molec. Biol. 273:927-948)).
In addition, combinations of these two approaches can be used to
determine CDRs. In some embodiments, the CDRs are determined based
on AHo (Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670;
2001). In some embodiments, CDRs are determined based on the IMGT
system.
[0215] The term "human antibody" means an antibody produced by a
human or an antibody having an amino acid sequence corresponding to
an antibody produced by a human made using any technique known in
the art. This definition of a human antibody includes intact or
full-length antibodies, fragments thereof, and/or antibodies
comprising at least one human heavy and/or light chain polypeptide
such as, for example, an antibody comprising murine light chain and
human heavy chain polypeptides.
[0216] A "neutralizing antibody" may inhibit the entry of HIV-1
virus for example SF162 and/or JR-CSF with a neutralization index
>1.5 or >2.0. (Kostrikis L G et al. J Virol. 1996; 70(1):
445-458.). By "broad and potent neutralizing antibodies" are meant
antibodies that neutralize more than one HIV-1 virus species (from
diverse clades and different strains within a clade) in a
neutralization assay. A broad neutralizing antibody may neutralize
at least 2, 3, 4, 5, 6, 7, 8, 9 or more different strains of HIV-1,
the strains belonging to the same or different clades. A broad
neutralizing antibody may neutralize multiple HIV-1 species
belonging to at least 2, 3, 4, 5, or 6 different clades. In some
embodiments, the \concentration of the monoclonal antibody able to
neutralize at 50% of the input virus in the neutralization assay
can be less than about 50 .mu.g/ml.
[0217] An "intact" antibody is one that comprises an
antigen-binding site as well as a C.sub.L and at least heavy chain
constant domains, C.sub.H1, C.sub.H2 and C.sub.H3. The constant
domains may be native sequence constant domains (e.g., human native
sequence constant domains) or amino acid sequence variants
thereof.
[0218] The term "chimeric antibodies" refers to antibodies wherein
the amino acid sequence of the immunoglobulin molecule is derived
from two or more species. Typically, the variable region of both
light and heavy chains corresponds to the variable region of
antibodies derived from one species of mammals (e.g. mouse, rat,
rabbit, etc) with the desired specificity, affinity, and capability
while the constant regions are homologous to the sequences in
antibodies derived from another (usually human) to avoid eliciting
an immune response in that species.
[0219] The antibodies herein also include antibodies in which a
portion of the heavy and/or light chain is identical with or
homologous to corresponding sequences in antibodies belonging to a
particular antibody class or subclass, while the remainder of the
chain(s) is identical with or homologous to corresponding sequences
in antibodies derived from another species or belonging to another
antibody class or subclass, as well as fragments of such
antibodies.
[0220] In some embodiments, the antibody comprises variable region
antigen-binding sequences derived from human antibodies (e.g.,
CDRs) and containing one or more sequences derived from a non-human
antibody, e.g., an FR or C region sequence. In some embodiments,
the antibody includes those comprising a human variable region
antigen binding sequence of one antibody class or subclass and
another sequence, e.g., FR or C region sequence, derived from
another antibody class or subclass.
[0221] In some embodiments, chimeric antibodies may comprise
residues that are not found in the recipient antibody or in the
donor antibody. In some embodiments, modifications are made to
further refine antibody performance. For further details, see Jones
et al., Nature 321:522-525 (1986); Riechmann et al., Nature
332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596
(1992).
[0222] The term "epitope" or "antigenic determinant" are used
interchangeably herein and refer to that portion of an antigen
capable of being recognized and specifically bound by a particular
antibody. When the antigen is a polypeptide, epitopes can be formed
both from contiguous amino acids and noncontiguous amino acids
juxtaposed by tertiary folding of a protein. Epitopes formed from
contiguous amino acids are typically retained upon protein
denaturing, whereas epitopes formed by tertiary folding are
typically lost upon protein denaturing. An epitope typically
includes at least 3, and more usually, at least 5 or 8-10 amino
acids in a unique spatial conformation.
[0223] "Binding affinity" generally refers to the strength of the
sum total of noncovalent interactions between a single binding site
of a molecule (e.g., an antibody) and its binding partner (e.g., an
antigen). Unless indicated otherwise, as used herein, "binding
affinity" refers to intrinsic binding affinity which reflects a 1:1
interaction between members of a binding pair (e.g., antibody and
antigen). The affinity of a molecule X for its partner Y can
generally be represented by the dissociation constant (Kd).
Low-affinity antibodies generally bind antigen slowly and tend to
dissociate readily, whereas high-affinity antibodies generally bind
antigen faster and tend to remain bound longer.
[0224] The affinity or avidity of an antibody for an antigen can be
determined experimentally using any suitable method well known in
the art, e.g. flow cytometry, enzyme-linked immunoabsorbent assay
(ELISA), or radioimmunoassay (RIA), or kinetics (e.g.,
BIACORE'analysis). Direct binding assays as well as competitive
binding assay formats can be readily employed. (See, for example,
Berzofsky, et al., "Antibody-Antigen Interactions," In Fundamental
Immunology, Paul, W. E., Ed., Raven Press: New York, N.Y. (1984);
Kuby, Janis Immunology, W.H. Freeman and Company: New York, N.Y.
(1992); and methods described herein. The measured affinity of a
particular antibody-antigen interaction can vary if measured under
different conditions (e.g., salt concentration, pH, temperature).
Thus, measurements of affinity and other antigen-binding parameters
(e.g., KD or Kd, K.sub.on, K.sub.off) are made with standardized
solutions of antibody and antigen, and a standardized buffer, as
known in the art and such as the buffer described herein.
[0225] The phrase "substantially similar," or "substantially the
same", as used herein, denotes a sufficiently high degree of
similarity between two numeric values (generally one associated
with an antibody of the invention and the other associated with a
reference/comparator antibody) such that one of skill in the art
would consider the difference between the two values to be of
little or no biological and/or statistical significance within the
context of the biological characteristics measured by said values
(e.g., Kd values). The difference between said two values is less
than about 500%, less than about 40%, less than about 300%, less
than about 200%, or less than about 10% as a function of the value
for the reference/comparator antibody.
[0226] A polypeptide, antibody, polynucleotide, vector, cell, or
composition which is "isolated" is a polypeptide, antibody,
polynucleotide, vector, cell, or composition which is in a form not
found in nature. Isolated polypeptides, antibodies,
polynucleotides, vectors, cell or compositions include those which
have been purified to a degree that they are no longer in a form in
which they are found in nature. In some embodiments, an antibody,
polynucleotide, vector, cell, or composition which is isolated is
substantially pure.
[0227] An "isolated nucleic acid" is a nucleic acid that is
substantially separated from other genome DNA sequences as well as
proteins or complexes such as ribosomes and polymerases, which
naturally accompany a native sequence. The term embraces a nucleic
acid sequence that has been removed from its naturally occurring
environment, and includes recombinant or cloned DNA isolates and
chemically synthesized analogues or analogues biologically
synthesized by heterologous systems. A substantially pure nucleic
acid includes isolated forms of the nucleic acid. Of course, this
refers to the nucleic acid as originally isolated and does not
exclude genes or sequences later added to the isolated nucleic acid
by the hand of man.
[0228] An "isolated polypeptide" is one that has been identified
and separated and/or recovered from a component of its natural
environment. In preferred embodiments, the isolated polypeptide
will be purified (1) to greater than 95% by weight of polypeptide
as determined by the Lowry method, and most preferably more than
99% by weight, (2) to a degree sufficient to obtain at least 15
residues of N-terminal or internal amino acid sequence by use of a
spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under
reducing or non-reducing conditions using Coomassie blue or,
preferably, silver stain. Isolated polypeptide includes the
polypeptide in situ within recombinant cells since at least one
component of the polypeptide's natural environment will not be
present.
[0229] A "native sequence" polynucleotide is one that has the same
nucleotide sequence as a polynucleotide derived from nature. A
"native sequence" polypeptide is one that has the same amino acid
sequence as a polypeptide (e.g., antibody) derived from nature
(e.g., from any species). Such native sequence polynucleotides and
polypeptides can be isolated from nature. A polynucleotide
"variant," as the term is used herein, is a polynucleotide that
typically differs from a polynucleotide specifically disclosed
herein in one or more substitutions, deletions, additions and/or
insertions. Such variants may be naturally occurring or may be
synthetically generated, for example, by modifying one or more of
the polynucleotide sequences of the invention and evaluating one or
more biological activities of the encoded polypeptide as described
herein and/or using any of a number of techniques well known in the
art.
[0230] A polypeptide "variant," as the term is used herein, is a
polypeptide that typically differs from a polypeptide specifically
disclosed herein in one or more substitutions, deletions, additions
and/or insertions. Such variants may be naturally occurring or may
be synthetically generated, for example, by modifying one or more
of the above polypeptide sequences of the invention and evaluating
one or more biological activities of the polypeptide as described
herein and/or using any of a number of techniques well known in the
art. or can be produced by recombinant or synthetic means.
[0231] As used herein, "substantially pure" refers to material
which is at least 50% pure (i.e., free from contaminants), at least
90% pure, at least 95% pure, at least 98% pure, or at least 99%
pure.
[0232] The term "subject" refers to any animal (e.g., a mammal),
including, but not limited to humans, non-human primates, rodents,
and the like, which is to be the recipient of a particular
treatment. Typically, the terms "subject" and "patient" are used
interchangeably herein in reference to a human subject.
[0233] Administration "in combination with" one or more further
therapeutic agents includes simultaneous (concurrent) and
consecutive administration in any order.
[0234] The term "pharmaceutical formulation" refers to a
preparation which is in such form as to permit the biological
activity of the active ingredient to be effective, and which
contains no additional components which are unacceptably toxic to a
subject to which the formulation would be administered. Such
formulation can be sterile.
[0235] An "effective amount" of an antibody as disclosed herein is
an amount sufficient to carry out a specifically stated purpose. An
"effective amount" can be determined empirically and in a routine
manner, in relation to the stated purpose.
[0236] The term "therapeutically effective amount" refers to an
amount of an antibody or other drug effective to "treat" or prevent
a disease or disorder in a subject or mammal.
[0237] Terms such as "treating" or "treatment" or "to treat" or
"alleviating" or "to alleviate" refer to both 1) therapeutic
measures that cure, slow down, lessen symptoms of, and/or halt
progression of a diagnosed pathologic condition or disorder and 2)
prophylactic or preventative measures that prevent and/or slow the
development of a targeted pathologic condition or disorder. Thus,
those in need of treatment include those already with the disorder;
those prone to have the disorder; and those in whom the disorder is
to be prevented.
[0238] "Polynucleotide," or "nucleic acid," as used interchangeably
herein, refer to polymers of nucleotides of any length, and include
DNA and RNA. The nucleotides can be deoxyribonucleotides,
ribonucleotides, modified nucleotides or bases, and/or their
analogs, or any substrate that can be incorporated into a polymer
by DNA or RNA polymerase. A polynucleotide can comprise modified
nucleotides, such as methylated nucleotides and their analogs. If
present, modification to the nucleotide structure can be imparted
before or after assembly of the polymer. The sequence of
nucleotides can be interrupted by non-nucleotide components. A
polynucleotide can be further modified after polymerization, such
as by conjugation with a labeling component. Other types of
modifications include, for example, "caps", substitution of one or
more of the naturally occurring nucleotides with an analog,
internucleotide modifications such as, for example, those with
uncharged linkages (e.g., methyl phosphonates, phosphotriesters,
phosphoamidates, cabamates, etc.) and with charged linkages (e.g.,
phosphorothioates, phosphorodithioates, etc.), those containing
pendant moieties, such as, for example, proteins (e.g., nucleases,
toxins, antibodies, signal peptides, ply-L-lysine, etc.), those
with intercalators (e.g., acridine, psoralen, etc.), those
containing chelators (e.g., metals, radioactive metals, boron,
oxidative metals, etc.), those containing alkylators, those with
modified linkages (e.g., alpha anomeric nucleic acids, etc.), as
well as unmodified forms of the polynucleotide(s). Further, any of
the hydroxyl groups ordinarily present in the sugars can be
replaced, for example, by phosphonate groups, phosphate groups,
protected by standard protecting groups, or activated to prepare
additional linkages to additional nucleotides, or can be conjugated
to solid supports. The 5' and 3' terminal OH can be phosphorylated
or substituted with amines or organic capping group moieties of
from 1 to 20 carbon atoms. Other hydroxyls can also be derivatized
to standard protecting groups. Polynucleotides can also contain
analogous forms of ribose or deoxyribose sugars that are generally
known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl,
2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs,
alpha.-anomeric sugars, epimeric sugars such as arabinose, xyloses
or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses,
acyclic analogs and abasic nucleoside analogs such as methyl
riboside. One or more phosphodiester linkages can be replaced by
alternative linking groups. These alternative linking groups
include, but are not limited to, embodiments wherein phosphate is
replaced by P(O)S ("thioate"), P(S)S ("dithioate"), "(O)NR.sub.2
("amidate"), P(O)R, P(O)OR', CO or CH.sub.2 ("formacetal"), in
which each R or R' is independently H or substituted or
unsubstituted alkyl (1-20 C) optionally containing an ether (--O--)
linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not
all linkages in a polynucleotide need be identical. The preceding
description applies to all polynucleotides referred to herein,
including RNA and DNA.
[0239] The terms "polypeptide," "peptide," and "protein" are used
interchangeably herein to refer to polymers of amino acids of any
length. The polymer can be linear or branched, it can comprise
modified amino acids, and it can be interrupted by non-amino acids.
The terms also encompass an amino acid polymer that has been
modified naturally or by intervention; for example, disulfide bond
formation, glycosylation, lipidation, acetylation, phosphorylation,
or any other manipulation or modification, such as conjugation with
a labeling component. Also included within the definition are, for
example, polypeptides containing one or more analogs of an amino
acid (including, for example, unnatural amino acids, etc.), as well
as other modifications known in the art. It is understood that,
because the polypeptides of this invention are based upon
antibodies, in certain embodiments, the polypeptides can occur as
single chains or associated chains.
[0240] The terms "identical" or percent "identity" in the context
of two or more nucleic acids or polypeptides, refer to two or more
sequences or subsequences that are the same or have a specified
percentage of nucleotides or amino acid residues that are the same,
when compared and aligned (introducing gaps, if necessary) for
maximum correspondence, not considering any conservative amino acid
substitutions as part of the sequence identity. The percent
identity can be measured using sequence comparison software or
algorithms or by visual inspection. Various algorithms and software
are known in the art that can be used to obtain alignments of amino
acid or nucleotide sequences. One such non-limiting example of a
sequence alignment algorithm is the algorithm described in Karlin
et al, 1990, Proc. Natl. Acad. Sci., 87:2264-2268, as modified in
Karlin et al., 1993, Proc. Natl. Acad. Sci., 90:5873-5877, and
incorporated into the NBLAST and XBLAST programs (Altschul et al.,
1991, Nucleic Acids Res., 25:3389-3402). In certain embodiments,
Gapped BLAST can be used as described in Altschul et al., 1997,
Nucleic Acids Res. 25:3389-3402. BLAST-2, WU-BLAST-2 (Altschul et
al., 1996, Methods in Enzymology, 266:460-480), ALIGN, ALIGN-2
(Genentech, South San Francisco, Calif.) or Megalign (DNASTAR) are
additional publicly available software programs that can be used to
align sequences. In certain embodiments, the percent identity
between two nucleotide sequences is determined using the GAP
program in GCG software (e.g., using a NWSgapdna.CMP matrix and a
gap weight of 40, 50, 60, 70, or 90 and a length weight of 1, 2, 3,
4, 5, or 6). In certain alternative embodiments, the GAP program in
the GCG software package, which incorporates the algorithm of
Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) can be
used to determine the percent identity between two amino acid
sequences (e.g., using either a Blossum 62 matrix or a PAM250
matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length
weight of 1, 2, 3, 4, 5). Alternatively, in certain embodiments,
the percent identity between nucleotide or amino acid sequences is
determined using the algorithm of Myers and Miller (CABIOS, 4:11-17
(1989)). For example, the percent identity can be determined using
the ALIGN program (version 2.0) and using a PAM120 with residue
table, a gap length penalty of 12 and a gap penalty of 4.
Appropriate parameters for maximal alignment by particular
alignment software can be determined by one skilled in the art. In
certain embodiments, the default parameters of the alignment
software are used. In certain embodiments, the percentage identity
"X" of a first amino acid sequence to a second sequence amino acid
is calculated as 100.times.(Y/Z), where Y is the number of amino
acid residues scored as identical matches in the alignment of the
first and second sequences (as aligned by visual inspection or a
particular sequence alignment program) and Z is the total number of
residues in the second sequence. If the length of a first sequence
is longer than the second sequence, the percent identity of the
first sequence to the second sequence will be longer than the
percent identity of the second sequence to the first sequence.
[0241] As a non-limiting example, whether any particular
polynucleotide has a certain percentage sequence identity (e.g., is
at least 80% identical, at least 85% identical, at least 90%
identical, and in some embodiments, at least 95%, 96%, 97%, 98%, or
99% identical) to a reference sequence can, in certain embodiments,
be determined using the Bestfit program (Wisconsin Sequence
Analysis Package, Version 8 for Unix, Genetics Computer Group,
University Research Park, 575 Science Drive, Madison, Wis. 53711).
Bestfit uses the local homology algorithm of Smith and Waterman.
Advances in Applied Mathematics 2: 482 489 (1981), to find the best
segment of homology between two sequences. When using Bestfit or
any other sequence alignment program to determine whether a
particular sequence is, for instance, 95% identical to a reference
sequence according to the present invention, the parameters are set
such that the percentage of identity is calculated over the full
length of the reference nucleotide sequence and that gaps in
homology of up to 5% of the total number of nucleotides in the
reference sequence are allowed.
[0242] In some embodiments, two nucleic acids or polypeptides of
the invention are substantially identical, meaning they have at
least 70%, at least 75%, at least 80%, at least 85%, at least 90%,
and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide
or amino acid residue identity, when compared and aligned for
maximum correspondence, as measured using a sequence comparison
algorithm or by visual inspection. In certain embodiments, identity
exists over a region of the sequences that is at least about 10,
about 20, about 40-60 residues in length or any integral value
therebetween, or over a longer region than 60-80 residues, at least
about 90-100 residues, or the sequences are substantially identical
over the full length of the sequences being compared, such as the
coding region of a nucleotide sequence for example.
[0243] A "conservative amino acid substitution" is one in which one
amino acid residue is replaced with another amino acid residue
having a similar side chain. Families of amino acid residues having
similar side chains have been defined in the art, including basic
side chains (e.g., lysine, arginine, histidine), acidic side chains
(e.g., aspartic acid, glutamic acid), uncharged polar side chains
(e.g., asparagine, glutamine, serine, threonine, tyrosine,
cysteine), nonpolar side chains (e.g., glycine, alanine, valine,
leucine, isoleucine, proline, phenylalanine, methionine,
tryptophan), beta-branched side chains (e.g., threonine, valine,
isoleucine) and aromatic side chains (e.g., tyrosine,
phenylalanine, tryptophan, histidine). For example, substitution of
a phenylalanine for a tyrosine is a conservative substitution. In
certain embodiments, conservative substitutions in the sequences of
the polypeptides and antibodies of the invention do not abrogate
the binding of the polypeptide or antibody containing the amino
acid sequence, to the antigen(s), i.e., the gp120 to which the
polypeptide or antibody binds. Methods of identifying nucleotide
and amino acid conservative substitutions which do not eliminate
antigen binding are well-known in the art (see, e.g., Brummell et
al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng.
12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA
94:412-417 (1997)).
Anti-HIV Antibodies
[0244] In some embodiments, the invention provides antibodies that
are broadly neutralizing antibodies against HIV.
[0245] HIV-1 is among the most genetically diverse viral pathogens.
Of the three main branches of the HIV-1 phylogenetic tree, the M
(main), N (new), and 0 (outlier) groups, group M viruses are the
most widespread, accounting for over 99% of global infections. This
group is presently divided into nine distinct genetic subtypes, or
clades (A through K), based on full-length sequences. Env is the
most variable HIV-1 gene, with up to 35% sequence diversity between
clades, 20% sequence diversity within clades, and up to 10%
sequence diversity in a single infected person (Shankarappa, R. et
al. 1999. J. Virol. 73:10489-10502). Clade B is dominant in Europe,
the Americas, and Australia. Clade C is common in southern Africa,
China, and India and presently infects more people worldwide than
any other clade (McCutchan, F E. 2000. Understanding the genetic
diversity of HIV-1. AIDS 14(Suppl. 3):S31-S44). Clades A and D are
prominent in central and eastern Africa.
[0246] In some embodiments, the invention provides antibodies that
are broadly neutralizing against HIV. In some embodiments, the
antibody has a particularly high potency in neutralizing HIV
infection in vitro across multiple clades as shown in the Figures
and Tables 5, 6, and 16-21 herein. Such antibodies are desirable,
as only low concentrations are required in order to neutralize a
given amount of virus. This facilitates higher levels of protection
while administering lower amounts of antibody.
[0247] In some embodiments, the invention provides a broadly
neutralizing anti-HIV antibody wherein the antibody neutralizes
HIV-1 species belonging to two or more clades.
[0248] In some embodiments, the anti-HIV antibody neutralizes at
least 95%, at least 96%, at least 97%, at least 98%, at least 99%
or 100% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 50 .mu.g/mL. In some embodiments, the antibody
is selected from N49P6 or an antigen binding fragment thereof,
N49P7 or an antigen binding fragment thereof, N49P7.1 or an antigen
binding fragment thereof, or N49P11 or an antigen binding fragment
thereof. In some embodiments, the antibody comprises the V.sub.H
and V.sub.L regions of N49P6, N49P7, N49P7.1 or N49P11 as described
herein. In some embodiments, the antibody comprises the CDRs of the
V.sub.H and V.sub.L regions of N49P6, N49P7, N49P7.1 or N49P11 as
described herein.
[0249] In some embodiments, the anti-HIV antibody neutralizes 100%
of the HIV clade B, G and D viruses listed in Table 1 with an IC50
value of less than 50 .mu.g/mL. See also FIG. 8 and Tables 16-21
herein. In some embodiments, the antibody is selected from N49P6 or
an antigen binding fragment thereof, N49P7 or an antigen binding
fragment thereof, N49P7.1 or an antigen binding fragment thereof,
N49P11 or an antigen binding fragment thereof, or N49P9 or an
antigen binding fragment thereof. In some embodiments, the antibody
comprises the V.sub.H and/or V.sub.L regions of N49P6, N49P7,
N49P7.1, N49P11 or N49P9 as described herein. In some embodiments,
the antibody comprises the CDRs of the V.sub.H and V.sub.L regions
of N49P6, N49P7, N49P7.1, N49P11 or N49P9 as described herein.
[0250] In some embodiments, the anti-HIV antibody neutralizes 100%
of the HIV pseudoviruses listed in Table 1 with an IC50 value of
less than 50 .mu.g/mL. In some embodiments, the anti-HIV antibody
neutralizes at least 95%, at least 96%, at least 97%, at least 98%,
at least 99% or 100% of the HIV pseudoviruses encompassed by Table
1 and strain CNE5 (clade CRF01_AE) with an IC50 value of less than
50 .mu.g/mL. In some embodiments, the antibody is selected from
N49P6 or an antigen binding fragment thereof, N49P7 or an antigen
binding fragment thereof, N49P7.1 or an antigen binding fragment
thereof, or N49P11 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P6, N49P7, N49P7.1 or N49P11 as described herein. In some
embodiments, the antibody comprises the CDRs of the V.sub.H and
V.sub.L regions of N49P6, N49P7, N49P7.1 or N49P11 as described
herein.
[0251] In embodiment aspect, the invention provides an isolated
anti-HIV antibody, wherein the antibody is capable of neutralizing
HIV pseudoviruses listed in Table 1 with a median IC50 value of
less than 0.5 .mu.g/mL. In some embodiments, the antibody is
selected from the group consisting of [0252] a. N49P6 or an antigen
binding fragment thereof; [0253] b. N49P7 or an antigen binding
fragment thereof; [0254] c. N49P7.1 or an antigen binding fragment
thereof [0255] d. N49P9 or an antigen binding fragment thereof; and
[0256] e. N49P23 or an antigen binding fragment thereof.
[0257] In some embodiments, the anti-HIV antibody neutralizes at
least 50%, at least 55%, at least 60%, at least 65%, at least 70%,
at least 75%, at least 80%, at least 85%, at least 90%, at least
95%, or at least 99% of the HIV pseudoviruses listed in Table 1
with an IC50 value of less than about 1 .mu.g/ml, between about 1-5
.mu.g/ml or greater than about 5 .mu.g/ml.
[0258] In some embodiments, the anti-HIV antibody neutralizes at
least about 86.4% of the HIV pseudoviruses listed in Table 1 with
an IC50 value of less than 1 .mu.g/mL. In some embodiments, the
antibody is N49P7 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P7 as described herein. In some embodiments, the antibody
comprises the CDRs of the V.sub.H and V.sub.L regions of N49P7 as
described herein.
[0259] In some embodiments, the anti-HIV antibody neutralizes at
least 88.7% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P7.1 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P7.1 as described herein. In some embodiments, the antibody
comprises the CDRs of the V.sub.H and V.sub.L regions of N49P7.1 as
described herein.
[0260] In some embodiments, the anti-HIV antibody neutralizes at
least 84.5% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P7.2 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P7.2 as described herein. In some embodiments, the antibody
comprises the CDRs of the V.sub.H and V.sub.L regions of N49P7.2 as
described herein.
[0261] In some embodiments, the anti-HIV antibody neutralizes at
least 71.8% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P6 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P6 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions of N49P6 as described
herein.
[0262] In some embodiments, the anti-HIV antibody neutralizes at
least 93.3% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P9 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P9 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions of N49P9 as described
herein.
[0263] In some embodiments, the anti-HIV antibody neutralizes at
least 91.1% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P9.1 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P9.1 as described herein. In some embodiments, the antibody
comprises the CDRs of the V.sub.H and V.sub.L regions of N49P9.1 as
described herein.
[0264] In some embodiments, the anti-HIV antibody neutralizes at
least 41.9% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P11 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P11 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions of N49P11 as described
herein.
[0265] In some embodiments, the anti-HIV antibody neutralizes at
least 2.1% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P18.1 or an antigen binding fragment thereof. In some
embodiments, the antibody comprises the V.sub.H and V.sub.L regions
of N49P18.1 as described herein. In some embodiments, the antibody
comprises the CDRs of the V.sub.H and V.sub.L regions of N49P18.1
as described herein.
[0266] In some embodiments, the anti-HIV antibody neutralizes at
least 60% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P19 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P19 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions of N49P19 as described
herein.
[0267] In some embodiments, the anti-HIV antibody neutralizes at
least 58.3% of the HIV viruses listed in Table 1 with an IC50 value
of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P22 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P22 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions regions of N49P22 as
described herein.
[0268] In some embodiments, the anti-HIV antibody neutralizes at
least 88.6% of the HIV viruses listed in Table 1 with an IC50 value
of less than 1 .mu.g/mL. In some embodiments, the antibody is
N49P23 or an antigen binding fragment thereof. In some embodiments,
the antibody comprises the V.sub.H and V.sub.L regions of N49P23 as
described herein. In some embodiments, the antibody comprises the
CDRs of the V.sub.H and V.sub.L regions of N49P23 as described
herein.
[0269] The neutralization can be performed using a luciferase-based
assay in TZM.b1 cells as described by M. M. Sajadi et al., J Acquir
Immune Defic Syndr 57, 9-15 (2011) and M. Li et al., J Virol 79,
10108-10125 (2005)). This assay measures the reduction in
luciferase expression following a single round of virus
infection.
TABLE-US-00001 TABLE 1 HIV Env pseudovirus panel. Virus ID Clade*
6535.3 B QH0692.42 B SC422661.8 B PVO.4 B TRO.11 B AC10.0.29 B
RHPA4259.7 B THRO4156.18 B REJO4541.67 B TRJO4551.58 B WITO4160.33
B CAAN5342.A2 B WEAU_d15_410_787 B (T/F) 1006_11_C3_1601 B (T/F)
1054_07_TC4_1499 B (T/F) 1056_10_TA11_1826 B (T/F)
1012_11_TC21_3257 B (T/F) 6240_08_TA5_4622 B (T/F) 6244_13_B5_4576
B (T/F) 62357_14_D3_4589 B (T/F) SC05_8C11_2344 B (T/F) Du156.12 C
Du172.17 C Du422.1 C ZM197M.PB7 C ZM214M.PL15 C ZM233M.PB6 C
ZM249M.PL1 C ZM53M.PB12 C ZM109F.PB4 C ZM135M.PL10a C CAP45.2.00.G3
C CAP210.2.00.E8 C HIV-001428-2.42 C HIV-0013095-2.11 C
HIV-16055-2.3 C HIV-16845-2.22 C Ce1086_B2 C (T/F) Ce0393_C3 C
(T/F) Cel176_A3 C (T/F) Ce2010_F5 C (T/F) Ce0682_E4 C (T/F)
Ce1172_H1 C (T/F) Ce2060_G9 C (T/F) Ce703010054_2A2 C (T/F)
BF1266.431a C (T/F) 246F C1G C (T/F) 249M B10 C (T/F) ZM247v1(Rev-)
C (T/F) 7030102001E5(Rev-) C (T/F) 1394C9G1(Rev-) C (T/F)
Ce704809221_1B3 C (T/F) CNE19 BC CNE20 BC CNE21 BC CNE17 BC CNE30
BC CNE52 BC CNE53 BC CNE58 BC MS208.A1 A Q23.17 A Q461.e2 A
Q769.d22 A Q259.d2.17 A Q842.d12 A 3415.v1.c1 A 3365.v2.c2 A
0260.v5.c36 A 191955_A11 A (T/F) 191084 B7-19 A (T/F) 9004SS_A3_4 A
(T/F) T257-31 CRF02_AG 928-28 CRF02_AG 263-8 CRF02_AG T250-4
CRF02_AG T251-18 CRF02_AG T278-50 CRF02_AG T255-34 CRF02_AG 211-9
CRF02_AG 235-47 CRF02_AG 620345.c01 CRF01_AE CNE8 CRF01_AE
C1080.c03 CRF01_AE R2184.c04 CRF01_AE R1166.c01 CRF01_AE R3265.c06
CRF01_AE C2101.c01 CRF01_AE C3347.c11 CRF01_AE C4118.c09 CRF01_AE
BJOX009000.02.4 CRF01_AE BJOX015000.11.5 CRF01_AE (T/F)
BJOX010000.06.2 CRF01_AE (T/F) BJOX025000.01.1 CRF01_AE (T/F)
BJOX028000.10.3 CRF01_AE (T/F) X1193_c1 G P0402_c2_c11 G X1254_c3 G
X2088_c9 G X2131_C1_B5 G P1981_C5_3 G X1632_S2_B10 G 3016.v5.c45 D
A07412M1.vrc12 D 231965.c01 D 231966.c02 D 3817.v2.c59 CD
6480.v4.c25 CD 6952.v1.c20 CD 6811.v7.c18 CD 89-F1_2_25 CD
3301.v1.c24 AC 6041.v3.c23 AC 6540.v4.c1 AC 6545.v4.c1 AC
0815.v3.c3 ACD 3103.v3.c10 ACD * (T/F): Transmitted/Founder
Virus
[0270] Methods for producing antibodies, such as those disclosed
herein, are known in the art. For example, DNA molecules encoding
light chain variable regions and/or heavy chain variable regions
can be chemically synthesized using the sequence information
provided herein. Synthetic DNA molecules can be ligated to other
appropriate nucleotide sequences, including, e.g., expression
control sequences, to produce conventional gene expression
constructs encoding the desired antibodies. Production of defined
gene constructs is within routine skill in the art. Alternatively,
the sequences provided herein can be cloned out of hybridomas by
conventional hybridization techniques or polymerase chain reaction
(PCR) techniques, using synthetic nucleic acid probes whose
sequences are based on sequence information provided herein, or
prior art sequence information regarding genes encoding the heavy
and light chains.
[0271] Standard techniques of molecular biology may be used to
prepare DNA sequences coding for the antibodies or fragments of the
antibodies of the present invention. Desired DNA sequences may be
synthesized completely or in part using oligonucleotide synthesis
techniques. Site-directed mutagenesis and polymerase chain reaction
(PCR) techniques may be used as appropriate.
[0272] Any suitable host cell/vector system may be used for
expression of the DNA sequences encoding the antibody molecules of
the present invention or fragments thereof. Bacterial, for example
E. coli, and other microbial systems may be used, in part, for
expression of antibody fragments such as Fab and F(ab')2 fragments,
and especially Fv fragments and single chain antibody fragments,
for example, single chain Fvs. Eukaryotic, e.g. mammalian, host
cell expression systems may be used for production of larger
antibody molecules, including complete antibody molecules. Suitable
mammalian host cells include CHO, HEK293T, PER.C6, myeloma or
hybridoma cells.
[0273] In some embodiments, antibodies according to the invention
may be produced by i) expressing a nucleic acid sequence according
to the invention in a cell, and ii) isolating the expressed
antibody product. Additionally, the method may include iii)
purifying the antibody.
[0274] For the antibodies of the present invention to be expressed,
the protein coding sequence should be "operably linked" to
regulatory or nucleic acid control sequences that direct
transcription and translation of the protein. As used herein, a
coding sequence and a nucleic acid control sequence or promoter are
said to be "operably linked" when they are covalently linked in
such a way as to place the expression or transcription and/or
translation of the coding sequence under the influence or control
of the nucleic acid control sequence. The "nucleic acid control
sequence" can be any nucleic acid element, such as, but not limited
to promoters, enhancers, IRES, introns, and other elements
described herein that direct the expression of a nucleic acid
sequence or coding sequence that is operably linked thereto. The
term "promoter" will be used herein to refer to a group of
transcriptional control modules that are clustered around the
initiation site for RNA polymerase II and that when operationally
linked to the protein coding sequences of the invention lead to the
expression of the encoded protein. The expression of the antibodies
of the present invention can be under the control of a constitutive
promoter or of an inducible promoter, which initiates transcription
only when exposed to some particular external stimulus, such as,
without limitation, antibiotics such as tetracycline, hormones such
as ecdysone, or heavy metals. The promoter can also be specific to
a particular cell-type, tissue or organ. Many suitable promoters
and enhancers are known in the art, and any such suitable promoter
or enhancer may be used for expression of the antibodies of the
invention. For example, suitable promoters and/or enhancers can be
selected from the Eukaryotic Promoter Database (EPDB).
[0275] Nucleic acids encoding desired antibodies can be
incorporated (ligated) into expression vectors, which can be
introduced into host cells through conventional transfection or
transformation techniques. Exemplary host cells are E. coli cells,
Chinese hamster ovary (CHO) cells, human embryonic kidney 293 (HEK
293) cells, HeLa cells, baby hamster kidney (BHK) cells, monkey
kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep
G2), and myeloma cells that do not otherwise produce IgG protein.
Transformed host cells can be grown under conditions that permit
the host cells to express the genes that encode the immunoglobulin
light and/or heavy chain variable regions. Specific expression and
purification conditions will vary depending upon the expression
system employed.
[0276] Following expression, the antibodies and/or antigens of the
invention can be isolated and/or purified or concentrated using any
suitable technique known in the art. For example, anion or cation
exchange chromatography, phosphocellulose chromatography,
hydrophobic interaction chromatography, affinity chromatography,
immuno-affinity chromatography, hydroxyapatite chromatography,
lectin chromatography, molecular sieve chromatography, isoelectric
focusing, gel electrophoresis, or any other suitable method or
combination of methods can be used.
[0277] In some embodiments, the antibodies can be made using
recombinant DNA methods as described in U.S. Pat. No. 4,816,567.
The polynucleotides encoding a monoclonal antibody can be isolated
from mature B-cells or hybridoma cell, such as by RT-PCR using
oligonucleotide primers that specifically amplify the genes
encoding the heavy and light chains of the antibody, and their
sequence is determined using conventional procedures. The isolated
polynucleotides encoding the heavy and light chains are then cloned
into suitable expression vectors, which when transfected into host
cells such as E. coli cells, simian COS cells, Chinese hamster
ovary (CHO) cells, or myeloma cells that do not otherwise produce
immunoglobulin protein, monoclonal antibodies are generated by the
host cells.
[0278] The anti-HIV antibodies can also include insertions,
deletions, substitutions, or other selected modifications of
particular regions or specific amino acids residues. It should be
understood that the antibodies of the invention may differ from the
exact sequences illustrated and described herein. Thus, the
invention contemplates deletions, additions and substitutions to
the sequences shown, so long as the sequences function in
accordance with the methods of the invention. In this regard,
particularly preferred substitutions will generally be conservative
in nature, i.e., those substitutions that take place within a
family of amino acids. For example, amino acids are generally
divided into four families: (1) acidic--aspartate and glutamate;
(2) basic--lysine, arginine, histidine; (3) non-polar--alanine,
valine, leucine, isoleucine, proline, phenylalanine, methionine,
tryptophan; and (4) uncharged polar--glycine, asparagine,
glutamine, cystine, serine threonine, tyrosine. Phenylalanine,
tryptophan, and tyrosine are sometimes classified as aromatic amino
acids. For example, leucine can be replaced with isoleucine or
valine, or vice versa; an aspartate with a glutamate or vice versa;
a threonine with a serine or vice versa; or a similar conservative
replacement of an amino acid with a structurally related amino acid
can be made.
[0279] The polynucleotide(s) encoding a monoclonal antibody can
further be modified in a number of different manners using
recombinant DNA technology to generate alternative antibodies. In
some embodiments, the constant domains of the light and heavy
chains of, for example, a mouse monoclonal antibody can be
substituted 1) for those regions of, for example, a human antibody
to generate a chimeric antibody or 2) for a non-immunoglobulin
polypeptide to generate a fusion antibody. In some embodiments, the
constant regions are truncated or removed to generate the desired
antibody fragment of a monoclonal antibody. Site-directed or
high-density mutagenesis of the variable region can be used to
optimize specificity, affinity, etc. of a monoclonal antibody.
[0280] For the purposes of the present invention, it should be
appreciated that modified antibodies can comprise any type of
variable region that provides for the association of the antibody
with the polypeptides of HIV such as gp120.
[0281] In some embodiments, the variable regions or domains in both
the heavy and light chains are altered by at least partial
replacement of one or more CDRs and, if necessary, by partial
framework region replacement and sequence changing. Although the
CDRs can be derived from an antibody of the same class or even
subclass as the antibody from which the framework regions are
derived, in some embodiments the CDRs will be derived from an
antibody of different class.
[0282] Alterations to the variable region notwithstanding, those
skilled in the art will appreciate that the modified antibodies of
this invention can comprise antibodies (e.g., full-length
antibodies or immunoreactive fragments thereof) in which at least a
fraction of one or more of the constant region domains has been
deleted or otherwise altered so as to provide desired biochemical
characteristics such as increased localization, increased serum
half-life or reduced serum half-life when compared with an antibody
of approximately the same immunogenicity comprising a native or
unaltered constant region. In some embodiments, the constant region
of the modified antibodies will comprise a human constant region.
Modifications to the constant region compatible with this invention
comprise additions, deletions or substitutions of one or more amino
acids in one or more domains. That is, the modified antibodies
disclosed herein can comprise alterations or modifications to one
or more of the three heavy chain constant domains (CH1, CH2 or CH3)
and/or to the light chain constant domain (CL). In some
embodiments, modified constant regions wherein one or more domains
are partially or entirely deleted are contemplated. In some
embodiments, the modified antibodies will comprise domain deleted
constructs or variants wherein the entire CH2 domain has been
removed (.DELTA.CH2 constructs). In some embodiments, the omitted
constant region domain will be replaced by a short amino acid
spacer (e.g. 10 residues) that provides some of the molecular
flexibility typically imparted by the absent constant region.
[0283] Besides their configuration, it is known in the art that the
constant region mediates several effector functions. For example,
binding of the C1 component of complement to antibodies activates
the complement system. Activation of complement is important in the
opsonisation and lysis of cell pathogens. The activation of
complement also stimulates the inflammatory response and can also
be involved in autoimmune hypersensitivity. Further, antibodies
bind to cells via the Fc region, with a Fc receptor site on the
antibody Fc region binding to a Fc receptor (FcR) on a cell. There
are a number of Fc receptors which are specific for different
classes of antibody, including IgG (gamma receptors), IgE (eta
receptors), IgA (alpha receptors) and IgM (mu receptors). Binding
of antibody to Fc receptors on cell surfaces triggers a number of
important and diverse biological responses including engulfment and
destruction of antibody-coated particles, clearance of immune
complexes, lysis of antibody-coated target cells by killer cells
(called antibody-dependent cell-mediated cytotoxicity, or ADCC),
release of inflammatory mediators, placental transfer and control
of immunoglobulin production.
[0284] In certain embodiments, the anti-HIV antibodies provide for
altered effector functions that, in turn, affect the biological
profile of the administered antibody. For example, the deletion or
inactivation (through point mutations or other means) of a constant
region domain can reduce Fc receptor binding of the circulating
modified antibody thereby increasing tumor localization. In other
cases it may be that constant region modifications, consistent with
this invention, moderate complement binding and thus reduce the
serum half life and nonspecific association of a conjugated
cytotoxin. Yet other modifications of the constant region can be
used to eliminate disulfide linkages or oligosaccharide moieties
that allow for enhanced localization due to increased antigen
specificity or antibody flexibility. Similarly, modifications to
the constant region in accordance with this invention can easily be
made using well known biochemical or molecular engineering
techniques well within the purview of the skilled artisan.
[0285] In certain embodiments, the invention provides antibodies or
antigen binding fragments that specifically bind to an HIV antigen,
such as gp120. In some embodiments, the invention is directed to a
broadly neutralizing antibody against HIV wherein the antibody
binds an epitope on gp120. In some embodiments, the invention is
directed to a broadly neutralizing antibody against HIV wherein the
antibody binds an epitope on the CD4 binding site (CD4-BS). In some
embodiments, the invention is directed to a broadly neutralizing
antibody against HIV wherein the antibody binds an epitope on V1V2
glycan. In some embodiments, the invention is directed to a broadly
neutralizing antibody against HIV wherein the antibody binds an
epitope on V3 glycan. In some embodiments, the invention is
directed to a broadly neutralizing antibody against HIV wherein the
antibody binds an epitope on the gp41 membrane-proximal external
region.
[0286] X-ray crystallography analysis of pan-neutralizing
monoclonal, N49P7, identified its unique ability to bypass the
CD4-binding site Phe43 cavity while reaching deep into the highly
conserved residues of Layer 3 of the gp120 inner domain, likely
accounting for its pan-neutralization. Deletion in the CDR L1 (not
found in N6) combined with the rotation/tilting of the light chain
`opens` the variable light (V1) side of the N49P7 antigen binding
site to accommodate different lengths of the highly variable loops
D, E and VS (FIG. 21). Changes in the length of gp120 loop VS and
the length (and glycosylation status) of loop E that cause steric
clashes with an antibody light chain were described previously as
mechanisms of HIV-I resistance to VRC01-class antibodies (Lynch et
al., 2015). These signatures, along with a long CDRH3 (21 aa) and
unique sequence signatures within CDR.B2 (not seen in VRCO1 and N6,
FIG. 21), allow N49P7 to bypass the Phe43 cavity affording it an
unusual capacity to contact the gp120 inner domain at residues 97,
102 and 124 of Layer 2, and 472-480 of Layer 3.
[0287] In some embodiments, the conformational interdomain CD4
binding site epitope is formed by combination of residues of both
outer and inner domain of gp120 of HIV Env. These generally involve
residues of gp120 outer domain at position (HXBc2 numbering):
275-283 (Loop D), 354-371 (CD4 binding loop), 427-439 (bridging
sheet) and 455-463 (loop V5) and residues of gp120 inner domain at
positions: 96-106 (helix alpha-1 of Layer 2) and 469-480 (loop
prior and helix alpha-5 of Layer 3).
[0288] In some embodiments, the anti-HIV antibody binds to a HIV
gp120 epitope comprising outer domain loop D (which comprises
275-283), the CD4 binding loop (which comprises 354-371), the
bridging sheet (which comprises 427-439) and loop V5 (which
comprises 455-463) and gp120 inner domain at positions 96-106
(helix alpha-1 of Layer 2) and 469-480 (loop prior and helix
alpha-5 of Layer 3). In some embodiments, the anti-HIV antibody
binding the aforementioned epitope is from the antibody lineage as
shown in FIG. 15A. In some embodiments, the anti-HIV antibody is
selected from N49P6 or an antigen binding fragment thereof, N49P7
or an antigen binding fragment thereof, N49P7.1 or an antigen
binding fragment thereof, and N49P11 or an antigen binding fragment
thereof. In some embodiments, the antibody comprises the VH and VL
regions of N49P6, N49P7, N49P7.1 or N49P11 as described herein. In
some embodiments, the antibody comprises the CDRs of the VH and VL
regions of N49P6, N49P7, N49P7.1 or N49P11 as described herein. In
some embodiments, the antibody has a Kd for BaL-gp120 of at least
about 1.59.times.10.sup.-8M. In some embodiments, the antibody has
a Kd for BaL-gp120 of at least about 1.562.times.10.sup.-8M. In
some embodiments, the antibody has a Kd for BaL-gp120 of at least
about 1.143.times.10.sup.-9M. In some embodiments, the antibody has
a Kd for BaL-gp120 of at least about 8.602.times.10.sup.-10 M. In
some embodiments, the binding affinity is determined by surface
plasmon resonance. See FIG. 10.
[0289] In some embodiments, the anti-HIV antibody binds to a HIV
gp120 epitope comprising the specific residues as described in FIG.
20E. In some embodiments, the anti-HIV antibody binds to gp120
Layer 2 residues W96, K97, E102, G124, Loop D residues E275, N276,
T278, N279, N280, A281, K282, CD4 binding loop residues P364, 5365,
G366, G367, D368, 1371, bridging sheet residues W427, Q428, G429,
Loop V5 residues T455, R456, D457, G458, G459, A460, N461, T463),
and Layer 3 residues R469, P470, G471, G472, G473, N474, K476,
D477, R480. In some embodiments, the anti-HIV antibody binding the
aforementioned epitope is from the antibody lineage as shown in
FIG. 15A. In some embodiments, the anti-HIV antibody is selected
from N49P6 or an antigen binding fragment thereof, N49P7 or an
antigen binding fragment thereof, N49P7.1 or an antigen binding
fragment thereof, and N49P11 or an antigen binding fragment
thereof. In some embodiments, the antibody comprises the VH and VL
regions of N49P6, N49P7, N49P7.1 or N49P11 as described herein. In
some embodiments, the antibody comprises the CDRs of the VH and VL
regions of N49P6, N49P7, N49P7.1 or N49P11 as described herein. In
some embodiments, the antibody has a Kd for BaL-gp120 of at least
about 1.59.times.10.sup.-8M. In some embodiments, the antibody has
a Kd for BaL-gp120 of at least about 1.562.times.10.sup.-8M. In
some embodiments, the antibody has a Kd for BaL-gp120 of at least
about 1.143.times.10.sup.-9M. In some embodiments, the antibody has
a Kd for BaL-gp120 of at least about 8.602.times.10.sup.-10 M. In
some embodiments, the binding affinity is determined by surface
plasmon resonance. See FIG. 10.
[0290] In some embodiments, the anti-HIV antibody binds to the same
epitope as antibody N49P6, N49P7, N49P7.1, and/or N49P11.
[0291] In some embodiments, the anti-HIV antibody is an antibody
that binds to the same epitope as an antibody selected from the
group consisting of N49P6; N49P6.2; N49P7; N49P7.1; N49P7A; N49P7S;
N49P7F; N49P7Y; N49P7-54TY; N49P7LS-1; N49P7LS-2; N49P7YTE;
N49P7L6; N49P7L11; N49P7.1L9; N49P7.1L19; R49P7; N49P7.2; N49P11;
N49P18; N49P18.2; N49P18.1; N49P19; N49P37; N49P38; N49P38.1; and
N49P55.
[0292] In some embodiments, the anti-HIV antibody is an antibody
that binds to the same epitope as antibody N49P7.
[0293] In some embodiments, the anti-HIV antibody is an antibody
that binds to the same epitope as antibody N49P6.
[0294] In some embodiments, the anti-HIV antibody is an antibody
that binds to the same epitope as antibody N49P7.1.
[0295] In some embodiments, the anti-HIV antibody is an antibody
that binds to the same epitope as antibody N49P11.
[0296] In some embodiments, the anti-HIV antibody comprises a heavy
chain comprising an amino acid sequence selected from the group
consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,
25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,
59, 61, 63, 65, 67, 69, 71, 73 and 75.
[0297] In some embodiments, the anti-HIV antibody comprises an
antigen binding fragment of an amino acid sequence selected from
the group consisting of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17,
19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51,
53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73 and 75.
[0298] In some embodiments, the anti-HIV antibody comprises a light
chain comprising an amino acid sequence selected from the group
consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,
24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56,
58, 60, 62, 64, 66, 68, 70, 72, 74 and 76.
[0299] In some embodiments, the anti-HIV antibody comprises an
antigen binding fragment of an amino acid sequence selected from
the group consisting of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,
20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52,
54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74 and 76.
[0300] In some embodiments, the anti-HIV antibody comprises a heavy
chain comprising an amino acid sequence selected from the group
consisting of SEQ ID NOS:153, 157, 161, 165, 169, 173, 177, 181,
185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233,
237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285,
289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337,
341, 345, 349, 353, 357, 361, 365, 369, 373, 377, 381, 385, 389,
393 and 397.
[0301] In some embodiments, the anti-HIV antibody comprises an
antigen binding fragment of an amino acid sequence selected from
the group consisting of SEQ ID NOS:153, 157, 161, 165, 169, 173,
177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225,
229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277,
281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329,
333, 337, 341, 345, 349, 353, 357, 361, 365, 369, 373, 377, 381,
385, 389, 393 and 397.
[0302] In some embodiments, the anti-HIV antibody comprises a light
chain comprising an amino acid sequence selected from the group
consisting of SEQ ID NOS:155, 159, 163, 167, 171, 175, 179, 183,
187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235,
239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287,
291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339,
343, 347, 351, 355, 359, 363, 367, 371, 375, 379, 383, 387, 391,
395 and 399.
[0303] In some embodiments, the anti-HIV antibody comprises an
antigen binding fragment of an amino acid sequence selected from
the group consisting of SEQ ID NOS:155, 159, 163, 167, 171, 175,
179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227,
231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279,
283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331,
335, 339, 343, 347, 351, 355, 359, 363, 367, 371, 375, 379, 383,
387, 391, 395 and 399.
[0304] In some embodiments, the anti-HIV antibody is selected from
the group consisting of: [0305] a. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:1 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:2 or an antigen binding fragment thereof;
[0306] b. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:3 or an antigen binding fragment thereof and a
light chain amino acid sequence comprising SEQ ID NO:4 or an
antigen binding fragment thereof; [0307] c. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:5 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:6 or an antigen binding fragment
thereof; [0308] d. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:7 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:8 or an antigen binding fragment thereof; [0309] e. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID NO:9
or an antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:10 or an antigen binding fragment
thereof; [0310] f. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:11 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:12 or an antigen binding fragment thereof; [0311] g. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:13 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:14 or an antigen binding
fragment thereof; [0312] h. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:15 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:16 or an antigen binding fragment thereof; [0313] i. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:17 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:18 or an antigen
binding fragment thereof; [0314] j. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:19 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:20 or an antigen binding fragment thereof;
[0315] k. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:21 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:22 or an
antigen binding fragment thereof; [0316] l. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:23 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:24 or an antigen binding fragment
thereof; [0317] m. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:25 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:26 or an antigen binding fragment thereof; [0318] n. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:27 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:28 or an antigen binding
fragment thereof; [0319] o. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:29 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:30 or an antigen binding fragment thereof; [0320] p. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:31 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:32 or an antigen
binding fragment thereof; [0321] q. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:33 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:34 or an antigen binding fragment thereof;
[0322] r. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:35 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:36 or an
antigen binding fragment thereof; [0323] s. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:37 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:38 or an antigen binding fragment
thereof; [0324] t. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:39 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:40 or an antigen binding fragment thereof; [0325] u. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:41 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:42 or an antigen binding
fragment thereof; [0326] v. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:43 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:44 or an antigen binding fragment thereof; [0327] w. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:45 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:46 or an antigen
binding fragment thereof; [0328] x. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:47 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:48 or an antigen binding fragment thereof;
[0329] y. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:49 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:50 or an
antigen binding fragment thereof; [0330] z. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:51 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:52 or an antigen binding fragment
thereof; [0331] aa. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:53 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:54 or an antigen binding fragment thereof; [0332] bb. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:55 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:56 or an antigen
binding fragment thereof; [0333] cc. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:57 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:58 or an antigen binding fragment thereof;
[0334] dd. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:59 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:60 or an
antigen binding fragment thereof; [0335] ee. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:61 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:62 or an antigen binding fragment
thereof; [0336] ff. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:63 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:64 or an antigen binding fragment thereof; [0337] gg. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:65 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:66 or an antigen
binding fragment thereof; [0338] hh. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:67 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:68 or an antigen binding fragment thereof;
[0339] ii. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:69 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:70 or an
antigen binding fragment thereof; [0340] jj. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:71 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:72 or an antigen binding fragment
thereof; [0341] kk. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:73 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:74 or an antigen binding fragment thereof; [0342] ll. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:75 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:76 or an antigen
binding fragment thereof; [0343] mm. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:153 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:155 or an antigen binding fragment thereof;
[0344] nn. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:157 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:159 or an
antigen binding fragment thereof; [0345] oo. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:161 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:163 or an antigen binding fragment
thereof; [0346] pp. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:165 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:167 or an antigen binding fragment thereof; [0347] qq. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:169 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:171 or an antigen
binding fragment thereof; [0348] rr. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:173 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:175 or an antigen binding fragment thereof;
[0349] ss. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:177 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:179 or an
antigen binding fragment thereof; [0350] tt. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:181 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:183 or an antigen binding fragment
thereof; [0351] uu. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:185 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:187 or an antigen binding fragment thereof; [0352] vv. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:189 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:191 or an antigen
binding fragment thereof; [0353] ww. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:193 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:195 or an antigen binding fragment thereof;
[0354] xx. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:197 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:199 or an
antigen binding fragment thereof; [0355] yy. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:201 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:203 or an antigen binding fragment
thereof; [0356] zz. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:205 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:207 or an antigen binding fragment thereof; [0357] aaa. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:209 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:211 or an antigen
binding fragment thereof; [0358] bbb. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:213 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:215 or an antigen binding fragment
thereof; [0359] ccc. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:217 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:219 or an antigen binding fragment thereof; [0360] ddd.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:221 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:223 or an antigen
binding fragment thereof; [0361] eee. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:225 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:227 or an antigen binding fragment
thereof; [0362] fff. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:229 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:231 or an antigen binding fragment thereof; [0363] ggg.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:233 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:235 or an antigen
binding fragment thereof; [0364] hhh. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:237 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:239 or an antigen binding fragment
thereof; [0365] iii. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:241 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:243 or an antigen binding fragment thereof; [0366] jjj.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:245 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:247 or an antigen
binding fragment thereof; [0367] kkk. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:249 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:251 or an antigen binding fragment
thereof; [0368] lll. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:253 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:255 or an antigen binding fragment thereof;
[0369] mmm. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:257 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:259 or an antigen binding fragment thereof; [0370] nnn. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:261 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:263 or an antigen
binding fragment thereof; [0371] ooo. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:265 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:267 or an antigen binding fragment
thereof; [0372] ppp. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:269 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:271 or an antigen binding fragment thereof; [0373] qqq.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:273 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:275 or an antigen
binding fragment thereof; [0374] rrr. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:277 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:279 or an antigen binding fragment
thereof; [0375] sss. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:281 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:283 or an antigen binding fragment thereof; [0376] ttt.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:285 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:287 or an antigen
binding fragment thereof; [0377] uuu. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:289 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:291 or an antigen binding fragment
thereof; [0378] vvv. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:293 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:295 or an antigen binding fragment thereof; [0379] www.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:297 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:299 or an antigen
binding fragment thereof; [0380] xxx. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:301 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:303 or an antigen binding fragment
thereof; [0381] yyy. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:305 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:307 or an antigen binding fragment thereof; [0382] zzz.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:309 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:311 or an antigen
binding fragment thereof; [0383] aaaa. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:313 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:315 or an antigen binding fragment
thereof; [0384] bbbb. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:317 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:319 or an antigen binding fragment thereof; [0385] cccc.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:321 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:323 or an antigen
binding fragment thereof; [0386] dddd. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:325 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:327 or an antigen binding fragment
thereof; [0387] eeee. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:329 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:331 or an antigen binding fragment thereof; [0388] ffff.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:333 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:335 or an antigen
binding fragment thereof; [0389] gggg. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:337 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:339 or an antigen binding fragment
thereof; [0390] hhhh. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:341 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:343 or an antigen binding fragment thereof; [0391] iiii.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:345 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:347 or an antigen
binding fragment thereof; [0392] jjjj. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:349 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:351 or an antigen binding fragment
thereof; [0393] kkkk. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:353 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:355 or an antigen binding fragment thereof; [0394] llll.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:357 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:359 or an antigen
binding fragment thereof; [0395] mmmm. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:361 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:363 or an antigen binding fragment
thereof; [0396] nnnn. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:365 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:367 or an antigen binding fragment thereof; [0397] oooo.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:369 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:371 or an antigen
binding fragment thereof; [0398] pppp. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:373 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:375 or an antigen binding fragment
thereof; [0399] qqqq. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:377 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:379 or an antigen binding fragment thereof; [0400] rrrr.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:381 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:383 or an antigen
binding fragment thereof; [0401] ssss. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:385 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:387 or an antigen binding fragment
thereof; [0402] tttt. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:389 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:391 or an antigen binding fragment thereof; [0403] uuuu.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:393 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:395 or an antigen
binding fragment thereof; and [0404] vvvv. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:397 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:399 or an antigen binding fragment
thereof.
[0405] In some embodiments, the anti-HIV antibody is isolated
and/or substantially pure.
[0406] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain
comprises a heavy chain variable (VH) region and the light chain
comprises a light chain variable (VL) region; wherein the VL region
comprises one or more VL complementary determining regions (CDRs)
and wherein the VH region comprises one or more VH complementary
determining regions (CDRs), wherein the VL CDRs correspond to the
CDRs found within any of SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18,
20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52,
54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 155, 159, 163, 167,
171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219,
223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271,
275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323,
327, 331, 335, 339, 343, 347, 351, 355, 359, 363, 367, 371, 375,
379, 383, 387, 391, 395 and 399.
[0407] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain
comprises a heavy chain variable (VH) region and the light chain
comprises a light chain variable (VL) region; wherein the VL region
comprises one or more VL complementary determining regions (CDRs)
and wherein the VH region comprises one or more VH complementary
determining regions (CDRs), wherein the VH CDRs correspond to the
CDRs found within any of SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17,
19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51,
53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 153, 157, 161, 165,
169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217,
221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269,
273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321,
325, 329, 333, 337, 341, 345, 349, 353, 357, 361, 365, 369, 373,
377, 381, 385, 389, 393 and 397.
[0408] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain
comprises a heavy chain variable (VH) region and the light chain
comprises a light chain variable (VL) region; wherein the VL region
comprises one or more VL complementary determining regions (CDRs)
and wherein the VH region comprises one or more VH complementary
determining regions (CDRs), wherein the VL CDRs correspond to the
CDRs found within any of SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16,
18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50,
52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 155, 159, 163,
167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215,
219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267,
271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319,
323, 327, 331, 335, 339, 343, 347, 351, 355, 359, 363, 367, 371,
375, 379, 383, 387, 391, 395 and 399 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions, and
wherein the VH CDRs correspond to the CDRs found within any of SEQ
ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,
33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65,
67, 69, 71, 73, 75, 153, 157, 161, 165, 169, 173, 177, 181, 185,
189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237,
241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289,
293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341,
345, 349, 353, 357, 361, 365, 369, 373, 377, 381, 385, 389, 393 and
397 or a variant thereof comprising 1, 2, 3, or 4 conservative
amino acid substitutions.
[0409] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain
comprises a heavy chain variable (VH) region and the light chain
comprises a light chain variable (VL) region; wherein the VL region
comprises an amino acid sequence selected from the group consisting
of: amino acids 1-99 of SEQ ID NO:2; amino acids 1-99 of SEQ ID
NO:4; amino acids 1-99 of SEQ ID NO:6; amino acids 1-99 of SEQ ID
NO:8; amino acids 1-99 of SEQ ID NO:10; amino acids 1-99 of SEQ ID
NO:12; amino acids 1-99 of SEQ ID NO:14; amino acids 1-99 of SEQ ID
NO:16; amino acids 1-99 of SEQ ID NO:18; amino acids 1-99 of SEQ ID
NO:20; amino acids 1-99 of SEQ ID NO:22; amino acids 1-99 of SEQ ID
NO:24; amino acids 1-99 of SEQ ID NO:26; amino acids 1-99 of SEQ ID
NO:28; amino acids 1-99 of SEQ ID NO:30; amino acids 1-99 of SEQ ID
NO:32; amino acids 1-99 of SEQ ID NO:34; amino acids 1-100 of SEQ
ID NO:36; amino acids 1-97 of SEQ ID NO:38; amino acids 1-100 of
SEQ ID NO:40; amino acids 1-100 of SEQ ID NO:42; amino acids 1-97
of SEQ ID NO:44; amino acids 1-101 of SEQ ID NO:46; amino acids
1-101 of SEQ ID NO:48; amino acids 1-96 of SEQ ID NO:50; amino
acids 1-97 of SEQ ID NO:52; amino acids 1-99 of SEQ ID NO:54; amino
acids 1-99 of SEQ ID NO:56; amino acids 1-99 of SEQ ID NO:58; amino
acids 1-99 of SEQ ID NO:60; amino acids 1-98 of SEQ ID NO:62; amino
acids 1-99 of SEQ ID NO:64; amino acids 1-99 of SEQ ID NO:66; amino
acids 1-96 of SEQ ID NO:68; amino acids 1-96 of SEQ ID NO:70; amino
acids 1-96 of SEQ ID NO:72; amino acids 1-101 of SEQ ID NO:74;
amino acids 1-97 of SEQ ID NO:76; amino acids 1-99 of SEQ ID
NO:155; amino acids 1-99 of SEQ ID NO:159; amino acids 1-99 of SEQ
ID NO:163; amino acids 1-99 of SEQ ID NO:167; amino acids 1-99 of
SEQ ID NO:171; amino acids 1-99 of SEQ ID NO:175; amino acids 1-99
of SEQ ID NO:179; amino acids 1-99 of SEQ ID NO:183; amino acids
1-99 of SEQ ID NO:187; amino acids 1-99 of SEQ ID NO:191; amino
acids 1-99 of SEQ ID NO:195; amino acids 1-99 of SEQ ID NO:199;
amino acids 1-99 of SEQ ID NO:203; amino acids 1-99 of SEQ ID
NO:207; amino acids 1-100 of SEQ ID NO:211; amino acids 1-99 of SEQ
ID NO:215; amino acids 1-99 of SEQ ID NO:219; amino acids 1-99 of
SEQ ID NO:223; amino acids 1-99 of SEQ ID NO:227; amino acids 1-99
of SEQ ID NO:231; amino acids 1-99 of SEQ ID NO:235; amino acids
1-99 of SEQ ID NO:239; amino acids 1-99 of SEQ ID NO:243; amino
acids 1-99 of SEQ ID NO:247; amino acids 1-99 of SEQ ID NO:251;
amino acids 1-99 of SEQ ID NO:255; amino acids 1-99 of SEQ ID
NO:259; amino acids 1-99 of SEQ ID NO:263; amino acids 1-99 of SEQ
ID NO:267; amino acids 1-99 of SEQ ID NO:271; amino acids 1-99 of
SEQ ID NO:275; amino acids 1-99 of SEQ ID NO:279; amino acids 1-99
of SEQ ID NO:283; amino acids 1-99 of SEQ ID NO:287; amino acids
1-99 of SEQ ID NO:291; amino acids 1-100 of SEQ ID NO:295; amino
acids 1-100 of SEQ ID NO:299; amino acids 1-100 of SEQ ID NO:303;
amino acids 1-100 of SEQ ID NO:307; amino acids 1-100 of SEQ ID
NO:311; amino acids 1-100 of SEQ ID NO:315; amino acids 1-97 of SEQ
ID NO:319; amino acids 1-100 of SEQ ID NO:323; amino acids 1-100 of
SEQ ID NO:327; amino acids 1-100 of SEQ ID NO:331; amino acids 1-97
of SEQ ID NO:335; amino acids 1-101 of SEQ ID NO:339; amino acids
1-101 of SEQ ID NO:343; amino acids 1-96 of SEQ ID NO:347; amino
acids 1-97 of SEQ ID NO:351; amino acids 1-99 of SEQ ID NO:355;
amino acids 1-99 of SEQ ID NO:359; amino acids 1-99 of SEQ ID
NO:363; amino acids 1-99 of SEQ ID NO:367; amino acids 1-98 of SEQ
ID NO:371; amino acids 1-99 of SEQ ID NO:375; amino acids 1-99 of
SEQ ID NO:379; amino acids 1-96 of SEQ ID NO:383; amino acids 1-96
of SEQ ID NO:387; amino acids 1-96 of SEQ ID NO:391; amino acids
1-101 of SEQ ID NO:395; and amino acids 1-97 of SEQ ID NO:399 or a
variant thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions.
[0410] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain
comprises a heavy chain variable (VH) region and the light chain
comprises a light chain variable (VL) region; wherein the VH region
comprises an amino acid sequence selected from the group consisting
of: amino acids 1-128 of SEQ ID NO:1; amino acids 1-127 of SEQ ID
NO:3; amino acids 1-127 of SEQ ID NO:5; amino acids 1-128 of SEQ ID
NO:7; amino acids 1-127 of SEQ ID NO:9; amino acids 1-127 of SEQ ID
NO:11; amino acids 1-127 of SEQ ID NO:13; amino acids 1-127 of SEQ
ID NO:15; amino acids 1-127 of SEQ ID NO:17; amino acids 1-127 of
SEQ ID NO:19; amino acids 1-127 of SEQ ID NO:21; amino acids 1-127
of SEQ ID NO:23; amino acids 1-127 of SEQ ID NO:25; amino acids
1-127 of SEQ ID NO:27; amino acids 1-127 of SEQ ID NO:29; amino
acids 1-127 of SEQ ID NO:31; amino acids 1-127 of SEQ ID NO:33;
amino acids 1-120 of SEQ ID NO:35; amino acids 1-120 of SEQ ID
NO:37; amino acids 1-123 of SEQ ID NO:39; amino acids 1-120 of SEQ
ID NO:41; amino acids 1-120 of SEQ ID NO:43; amino acids 1-125 of
SEQ ID NO:45; amino acids 1-125 of SEQ ID NO:47; amino acids 1-120
of SEQ ID NO:49; amino acids 1-120 of SEQ ID NO:51; amino acids
1-121 of SEQ ID NO:53; amino acids 1-121 of SEQ ID NO:55; amino
acids 1-121 of SEQ ID NO:57; amino acids 1-121 of SEQ ID NO:59;
amino acids 1-120 of SEQ ID NO:61; amino acids 1-121 of SEQ ID
NO:63; amino acids 1-121 of SEQ ID NO:65; amino acids 1-120 of SEQ
ID NO:67; amino acids 1-120 of SEQ ID NO:69; amino acids 1-120 of
SEQ ID NO:71; amino acids 1-125 of SEQ ID NO:73; amino acids 1-120
of SEQ ID NO:75; amino acids 1-128 of SEQ ID NO:153; amino acids
1-128 of SEQ ID NO:157; amino acids 1-127 of SEQ ID NO:161; amino
acids 1-127 of SEQ ID NO:165; amino acids 1-127 of SEQ ID NO:169;
amino acids 1-127 of SEQ ID NO:173; amino acids 1-127 of SEQ ID
NO:177; amino acids 1-127 of SEQ ID NO:181; amino acids 1-127 of
SEQ ID NO:185; amino acids 1-127 of SEQ ID NO:189; amino acids
1-127 of SEQ ID NO:193; amino acids 1-127 of SEQ ID NO:197; amino
acids 1-127 of SEQ ID NO:201; amino acids 1-127 of SEQ ID NO:205;
amino acids 1-127 of SEQ ID NO:209; amino acids 1-127 of SEQ ID
NO:213; amino acids 1-127 of SEQ ID NO:217; amino acids 1-127 of
SEQ ID NO:221; amino acids 1-128 of SEQ ID NO:225; amino acids
1-127 of SEQ ID NO:229; amino acids 1-127 of SEQ ID NO:233; amino
acids 1-127 of SEQ ID NO:237; amino acids 1-127 of SEQ ID NO:241;
amino acids 1-127 of SEQ ID NO:245; amino acids 1-127 of SEQ ID
NO:249; amino acids 1-127 of SEQ ID NO:253; amino acids 1-127 of
SEQ ID NO:257; amino acids 1-127 of SEQ ID NO:261; amino acids
1-127 of SEQ ID NO:265; amino acids 1-127 of SEQ ID NO:269; amino
acids 1-127 of SEQ ID NO:273; amino acids 1-127 of SEQ ID NO:277;
amino acids 1-127 of SEQ ID NO:281; amino acids 1-127 of SEQ ID
NO:285; amino acids 1-127 of SEQ ID NO:289; amino acids 1-120 of
SEQ ID NO:293; amino acids 1-120 of SEQ ID NO:297; amino acids
1-120 of SEQ ID NO:301; amino acids 1-123 of SEQ ID NO:305; amino
acids 1-128 of SEQ ID NO:309; amino acids 1-128 of SEQ ID NO:313;
amino acids 1-120 of SEQ ID NO:317; amino acids 1-123 of SEQ ID
NO:321; amino acids 1-120 of SEQ ID NO:325; amino acids 1-120 of
SEQ ID NO:329; amino acids 1-120 of SEQ ID NO:333; amino acids
1-125 of SEQ ID NO:337; amino acids 1-125 of SEQ ID NO:341; amino
acids 1-120 of SEQ ID NO:345; amino acids 1-120 of SEQ ID NO:349;
amino acids 1-121 of SEQ ID NO:353; amino acids 1-121 of SEQ ID
NO:357; amino acids 1-121 of SEQ ID NO:361; amino acids 1-121 of
SEQ ID NO:365; amino acids 1-120 of SEQ ID NO:369; amino acids
1-121 of SEQ ID NO:373; amino acids 1-121 of SEQ ID NO:377; amino
acids 1-120 of SEQ ID NO:381; amino acids 1-120 of SEQ ID NO:385;
amino acids 1-120 of SEQ ID NO:389; amino acids 1-125 of SEQ ID
NO:393; and amino acids 1-120 of SEQ ID NO:397 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions.
[0411] In some embodiments, the anti-HIV antibody comprises a heavy
chain or an antigen binding fragment thereof and a light chain or
an antigen binding fragment thereof, wherein the heavy chain or
antigen binding fragment thereof comprises a heavy chain variable
(VH) region and the light chain or antigen binding fragment thereof
comprises a light chain variable (VL) region; wherein the anti-HIV
antibody is selected from the group consisting of an antibody:
[0412] i) wherein the VH region comprises amino acids 1-128 of SEQ
ID NO:1 or a variant thereof comprising 1, 2, 3, or 4 conservative
amino acid substitutions; wherein the VL region comprises amino
acids 1-99 of SEQ ID NO:2 or a variant thereof comprising 1, 2, 3,
or 4 conservative amino acid substitutions; [0413] ii) wherein the
VH region comprises amino acids 1-127 of SEQ ID NO:3 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:4 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0414] iii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:5 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:6 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0415] iv) wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:7 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:8 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0416] v) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:9 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:10 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0417] vi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:11 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:12 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0418] vii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:13 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:14 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0419] viii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:15 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:16 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0420] ix) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:17 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:18 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0421] x) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:19 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:20 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0422] xi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:21 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:22 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0423] xii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:23 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:24 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0424] xiii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:25 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:26 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0425] xiv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:27 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:28 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0426] xv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:29 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:30 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0427] xvi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:31 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:32 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0428] xvii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:33 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:34 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0429] xviii) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:35 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:36 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0430] xix) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:37 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:38 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0431] xx) wherein the VH
region comprises amino acids 1-123 of SEQ ID NO:39 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:40 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0432] xxi) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:41 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:42 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0433] xxii) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:43 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:44 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0434] xxiii) wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:45 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:46 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0435] xxiv) wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:47 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:48 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0436] xxv) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:49 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:50 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0437] xxvi) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:51 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:52 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0438] xxvii) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:53 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:54 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0439] xxviii) wherein the
VH region comprises amino acids 1-121 of SEQ ID NO:55 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:56 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0440] xxix) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:57 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:58 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0441] xxx) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:59 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:60 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0442] xxxi) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:61 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-98 of
SEQ ID NO:62 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0443] xxxii) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:63 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:64 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0444] xxxiii) wherein the
VH region comprises amino acids 1-121 of SEQ ID NO:65 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:66 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0445] xxxiv) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:67 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:68 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0446] xxxv) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:69 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:70 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0447] xxxvi) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:71 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:72 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0448] xxxvii) wherein the
VH region comprises amino acids 1-125 of SEQ ID NO:73 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:74 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0449] xxxviii) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:75 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:76 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0450] xxxix) wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:153 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:155 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0451] xl) wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:157 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:159 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0452] xli) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:161 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:163 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0453] xlii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:165 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:167 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0454] xliii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:169 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:171 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0455] xliv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:173 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:175 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0456] xlv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:177 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:179 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0457] xlvi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:181 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:183 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0458] xlvii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:185 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:187 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions;
[0459] xlviii) wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:189 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:191 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0460] xlix) wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:193 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:195 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0461] l) wherein the VH region comprises amino acids 1-127 of SEQ
ID NO:197 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:199 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0462] li) wherein the VH region comprises amino acids 1-127 of SEQ
ID NO:201 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:203 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0463] lii) wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:205 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:207 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0464] liii) wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:209 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:211 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0465] liv) wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:213 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:215 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
wherein the VH region comprises amino acids 1-127 of SEQ ID NO:217
or a variant thereof comprising 1, 2, 3, or 4 conservative amino
acid substitutions; wherein the VL region comprises amino acids
1-99 of SEQ ID NO:219 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0466] lv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:221 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:223 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0467] lvi) wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:225 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:227 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0468] lvii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:229 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:231 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0469] lviii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:233 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:235 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0470] lix) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:237 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:239 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0471] lx) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:241 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:243 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0472] lxi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:245 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:247 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0473] lxii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:249 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:251 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0474] lxiii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:253 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:255 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0475] lxiv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:257 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:259 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0476] lxv) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:261 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:263 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0477] lxvi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:265 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:267 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0478] lxvii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:269 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:271 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0479] lxviii) wherein the
VH region comprises amino acids 1-127 of SEQ ID NO:273 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:275 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0480] lxix) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:277 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:279 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0481] lxx) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:281 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:283 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0482] lxxi) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:285 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:287 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0483] lxxii) wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:289 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:291 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0484] lxxiii) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:293 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:295 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0485] lxxiv) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:297 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:299 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0486] lxxv) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:301 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:303 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0487] lxxvi) wherein the VH
region comprises amino acids 1-123 of SEQ ID NO:305 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:307 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0488] lxxvii) wherein the
VH region comprises amino acids 1-128 of SEQ ID NO:309 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:311 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0489] lxxviii) wherein the
VH region comprises amino acids 1-128 of SEQ ID NO:313 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:315 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0490] lxxix) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:317 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:319 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0491] lxxx) wherein the VH
region comprises amino acids 1-123 of SEQ ID NO:321 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:323 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0492] lxxxi) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:325 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:327 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0493] lxxxii) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:329 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:331 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0494] lxxxiii) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:333 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:335 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0495] lxxxiv) wherein the
VH region comprises amino acids 1-125 of SEQ ID NO:337 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:339 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0496] lxxxv) wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:341 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:343 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0497] lxxxvi) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:345 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:347 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0498] lxxxvii) wherein the
VH region comprises amino acids 1-120 of SEQ ID NO:349 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:351 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0499] lxxxviii) wherein the
VH region comprises amino acids 1-121 of SEQ ID NO:353 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:355 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0500] lxxxix) wherein the
VH region comprises amino acids 1-121 of SEQ ID NO:357 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:359 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0501] xc) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:361 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:363 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0502] xci) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:365 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:367 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0503] xcii) wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:369 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-98 of
SEQ ID NO:371 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0504] xciii) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:373 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:375 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0505] xciv) wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:377 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:379 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions;
[0506] xcv) wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:381 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:383 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0507] xcvi) wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:385 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:387 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0508] xcvii) wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:389 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:391 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0509] xcviii) wherein the VH region comprises amino acids 1-125 of
SEQ ID NO:393 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-101 of SEQ ID NO:395 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0510] xcix) wherein the VH region comprises and amino acids 1-120
of SEQ ID NO:397 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; and wherein the VL region
comprises amino acids 1-97 of SEQ ID NO:399 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions.
[0511] In some embodiments, the anti-HIV antibody is selected from
the group consisting of: [0512] i) an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYDFIDYV (SEQ ID NO:401), MNPSGGGT (SEQ ID NO:402) and
VRDRANGSGRRRFESVNWFLDL (SEQ ID NO:403); [0513] ii) an antibody
comprising a light chain variable region, wherein the CDRs comprise
amino acid sequences HNY, DFN and WAFEN (SEQ ID NO:404); [0514]
iii) an antibody comprising a heavy chain variable region, wherein
the CDRs comprise amino acid sequences GYRFPDYI (SEQ ID NO:497),
MNPMGGQV (SEQ ID NO:421) and VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441);
[0515] iv) an antibody comprising a light chain variable region,
wherein the CDRs comprise amino acid sequences HNL, DFN and WAYEA
(SEQ ID NO:408); [0516] v) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GYKFPDYI (SEQ ID NO:405), INPMGGQV (SEQ ID NO:406) and
VRDRSNGSGRRFESSN (SEQ ID NO:407); [0517] vi) an antibody comprising
a heavy chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYL (SEQ ID NO:409), MNPVYGQV (SEQ ID NO:410) and
VRDTGDGSRRHFDSINWFLDL (SEQ ID NO:411); [0518] vii) an antibody
comprising a light chain variable region, wherein the CDRs comprise
amino acid sequences HNY, DFD and WAFEA (SEQ ID NO:412); [0519]
viii) an antibody comprising a heavy chain variable region, wherein
the CDRs comprise amino acid sequences GYTFTDYV (SEQ ID NO:413),
IDPPYGQV (SEQ ID NO:414) and VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415);
[0520] ix) an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GYTFTDYV (SEQ ID
NO:413), INPGYGQV (SEQ ID NO:431) and VRDRSNGWGKRFESSNWFLDL (SEQ ID
NO:415); [0521] x) an antibody comprising a heavy chain variable
region, wherein the CDRs comprise amino acid sequences GYTFVDYF
(SEQ ID NO:416), MDPLNGRP (SEQ ID NO:417) and VRDKSNGSGRRFDSSNWFLDL
(SEQ ID NO:418); [0522] xi) an antibody comprising a light chain
variable region, wherein the CDRs comprise amino acid sequences
HNY, DFN and WAYDA (SEQ ID NO:419); [0523] xii) an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYTFSDYI (SEQ ID NO:420), MNPMGGQV (SEQ ID
NO:421) and VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); [0524] xiii) an
antibody comprising a light chain variable region, wherein the CDRs
comprise amino acid sequences HNL, DFN and WAYEV (SEQ ID NO:422);
[0525] xiv) an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GYTFIDYI (SEQ ID
NO:423), IDPMNGRP (SEQ ID NO:424) and VRDKSNGSGKRFDSSNWFLDL (SEQ ID
NO:425); [0526] xv) an antibody comprising a heavy chain variable
region, wherein the CDRs comprise amino acid sequences GYTFTDYI
(SEQ ID NO:426), MNPMGGRT (SEQ ID NO:427) and VRDKSNGSGKRFDSSNWFLDL
(SEQ ID NO:425); [0527] xvi) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GYTFVDYL (SEQ ID NO:428), MDPMNGRP (SEQ ID NO:429) and
VRDKSGGSGKLFDSSNWFLDL (SEQ ID NO:430); [0528] xvii) an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYTFTDYV (SEQ ID NO:413), MDPSYGQV (SEQ ID
NO:432) and VRDRSHGSGRQFESSNWFLDL (SEQ ID NO:433); [0529] xviii) an
antibody comprising a heavy chain variable region, wherein the CDRs
comprise amino acid sequences GYTFTDYV (SEQ ID NO:413), MDPSFGQM
(SEQ ID NO:434) and VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); [0530]
xix) an antibody comprising a heavy chain variable region, wherein
the CDRs comprise amino acid sequences GYRFTDYV (SEQ ID NO:436),
MDPSFGRM (SEQ ID NO:437) and VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435);
[0531] xx) an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GYTFIDYV (SEQ ID
NO:438), MDPTYGRM (SEQ ID NO:439) and VRDRSHGSGRLFESSNWFLDL (SEQ ID
NO:435); [0532] xxi) an antibody comprising a heavy chain variable
region, wherein the CDRs comprise amino acid sequences GYRFLDYI
(SEQ ID NO:440), MNPMGGQV (SEQ ID NO:421) and VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); [0533] xxii) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GYKFMDQL (SEQ ID NO:442), MNPTYGQV (SEQ ID NO:443) and
ARGPSGENYPFHY (SEQ ID NO:444); [0534] xxiii) an antibody comprising
a light chain variable region, wherein the CDRs comprise amino acid
sequences RHII (SEQ ID NO:445), DDD and NTYEF (SEQ ID NO:446);
[0535] xxiv) an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GYNFVDSR (SEQ ID
NO:447), INPLQGGV (SEQ ID NO:448) and ARGIDGKSYPFHF (SEQ ID
NO:449); [0536] xxv) an antibody comprising a light chain variable
region, wherein the CDRs comprise amino acid sequences S, ESS and
SILEF (SEQ ID NO:450); [0537] xxvi) an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTTHHGHF (SEQ ID NO:500), MNPMTGQM (SEQ ID NO:462) and
ARGDFGQNYPFHY (SEQ ID NO:463); [0538] xxvii) an antibody comprising
a light chain variable region, wherein the CDRs comprise amino acid
sequences NRYL (SEQ ID NO:464), DDN and ASYER (SEQ ID NO:465);
[0539] xxviii) an antibody comprising a heavy chain variable
region, wherein the CDRs comprise amino acid sequences GYNFMDQF
(SEQ ID NO:466), MNPIYGQV (SEQ ID NO:467) and ARGPSGENYPFHY (SEQ ID
NO:444); [0540] xxix) an antibody comprising a light chain variable
region, wherein the CDRs comprise amino acid sequences RHII (SEQ ID
NO:445), DDD and NTYEF (SEQ ID NO:446); [0541] xxx) an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYNFVDSR (SEQ ID NO:447), INPLHGGV (SEQ ID
NO:468) and ARGIDGKSYPFHF (SEQ ID NO:449); [0542] xxxi) an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYTFTKYF (SEQ ID NO:451), IHPRTGAV (SEQ ID
NO:452) and ARGAFEADSYGSSYPFHH (SEQ ID NO:453); [0543] xxxii) an
antibody comprising a light chain variable region, wherein the CDRs
comprise amino acid sequences GNYNP (SEQ ID NO:454), EDN and ASFEF
(SEQ ID NO:455); [0544] xxxiii) an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTKYT (SEQ ID NO:456), IHPRTGAV (SEQ ID NO:452) and
ARGAFEADLSGPTYPFHH (SEQ ID NO:457); [0545] xxxiv) an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFNFIDSV (SEQ ID NO:458), IKPLRGAV (SEQ ID
NO:459) and AKGAFRGGSPFGF (SEQ ID NO:460); [0546] xxxv) an antibody
comprising a light chain variable region, wherein the CDRs comprise
amino acid sequences DVT and ASREF (SEQ ID NO:461); [0547] xxxvi)
an antibody comprising a heavy chain variable region, wherein the
CDRs comprise amino acid sequences GYTFTSYF (SEQ ID NO:469),
INPLHGAV (SEQ ID NO:470) and TRGIVADGWPYGH (SEQ ID NO:471); [0548]
xxxvii) an antibody comprising a light chain variable region,
wherein the CDRs comprise amino acid sequences S, EGA and SSLQF
(SEQ ID NO:472); [0549] xxxviii) an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GFTFIDHI (SEQ ID NO:473), IKPLRGAV (SEQ ID NO:459) and
CKAAAPEEAFPLQY (SEQ ID NO:474); [0550] xxxix) an antibody
comprising a light chain variable region, wherein the CDRs comprise
amino acid sequences NVD, DNN and SSRTF (SEQ ID NO:475); [0551] xl)
an antibody comprising a heavy chain variable region, wherein the
CDRs comprise amino acid sequences GFKFIDHI (SEQ ID NO:476),
IKPLGGVA (SEQ ID NO:477) and CKAAAPDEAFPLEY (SEQ ID NO:478); [0552]
xli) an antibody comprising a light chain variable region, wherein
the CDRs comprise amino acid sequences NVD, DNN and SSTTF (SEQ ID
NO:479); [0553] xlii) an antibody comprising a heavy chain variable
region, wherein the CDRs comprise amino acid sequences GFAFLDH (SEQ
ID NO:480), VKTIGGVV (SEQ ID NO:481) and SKAAAPDEAFPLEF (SEQ ID
NO:482); [0554] xliii) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFAFLDHI (SEQ ID NO:486), VKTIGGVV (SEQ ID NO:481) and
SKAAAPDEAFPLEF (SEQ ID NO:482); [0555] xliv) an antibody comprising
a heavy chain variable region, wherein the CDRs comprise amino acid
sequences GFKFTEYF (SEQ ID NO:483), LNPLRGAV (SEQ ID NO:484),
ARAVFNEAFPFDY (SEQ ID NO:485); [0556] xlv) an antibody comprising a
light chain variable region, wherein the CDRs comprise amino acid
sequences VS, DGD and ASREF (SEQ ID NO:461); [0557] xlvi) an
antibody comprising a light chain variable region, wherein the CDRs
comprise amino acid sequences NVD, DND and SSTTF (SEQ ID NO:479);
[0558] xlvii) an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GFNFIDSV (SEQ ID
NO:458), IKPLRGGV (SEQ ID NO:490) and AKGAFGGSSPFGF (SEQ ID
NO:491); [0559] xlviii) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFKFIDSV (SEQ ID NO:487), IKPLGGAV (SEQ ID NO:488) and
AKGAFGGGSPFGF (SEQ ID NO:489); [0560] xlix) an antibody comprising
a heavy chain variable region, wherein the CDRs comprise amino acid
sequences GFTFIKYT (SEQ ID NO:492), IHPRTGAV (SEQ ID NO:452) and
ARGAFEADLYGPTYPFHH (SEQ ID NO:493); [0561] l) an antibody
comprising a light chain variable region, wherein the CDRs comprise
amino acid sequences GSYNP (SEQ ID NO:494), DDN and ASFEF (SEQ ID
NO:455); and [0562] li) an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GYNFVDSL (SEQ ID NO:495), INPLQGGV (SEQ ID NO:448) and
ARGIDGNSYPFHF (SEQ ID NO:496).
[0563] In some embodiments, the anti-HIV antibody is selected from
the group consisting of: [0564] a. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYDFIDYV (SEQ ID NO:401), MNPSGGGT (SEQ ID NO:402) and
VRDRANGSGRRRFESVNWFLDL (SEQ ID NO:403); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNY, DFN and
WAFEN (SEQ ID NO:404); [0565] b. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYRFPDYI (SEQ ID NO:497), MNPMGGQV (SEQ ID NO:421) and
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0566] c. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYKFPDYI (SEQ ID NO:405), INPMGGQV (SEQ ID NO:406) and
VRDRSNGSGRRFESSN (SEQ ID NO:407); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0567] d. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYL (SEQ ID NO:409), MNPVYGQV (SEQ ID NO:410) and
VRDTGDGSRRHFDSINWFLDL (SEQ ID NO:411); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNY, DFD and
WAFEA (SEQ ID NO:412); [0568] e. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYV (SEQ ID NO:413), IDPPYGQV (SEQ ID NO:414) and
VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0569] f. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYV (SEQ ID NO:413), INPGYGQV (SEQ ID NO:431) and
VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0570] g. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFVDYF (SEQ ID NO:416), MDPLNGRP (SEQ ID NO:417) and
VRDKSNGSGRRFDSSNWFLDL (SEQ ID NO:418); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNY, DFN and
WAYDA (SEQ ID NO:419); [0571] h. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFSDYI (SEQ ID NO:420), MNPMGGQV (SEQ ID NO:421) and
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEV (SEQ ID NO:422); [0572] i. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFIDYI (SEQ ID NO:423), IDPMNGRP (SEQ ID NO:424) and
VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNY, DFN and
WAYDA (SEQ ID NO:419); [0573] j. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYI (SEQ ID NO:426), MNPMGGRT (SEQ ID NO:427) and
VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0574] k. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFVDYL (SEQ ID NO:428), MDPMNGRP (SEQ ID NO:429) and
VRDKSGGSGKLFDSSNWFLDL (SEQ ID NO:430); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNY, DFN and
WAYDA (SEQ ID NO:419); [0575] l. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYV (SEQ ID NO:413), INPGYGQV (SEQ ID NO:431) and
VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0576] m. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYV (SEQ ID NO:413), MDPSYGQV (SEQ ID NO:432) and
VRDRSHGSGRQFESSNWFLDL (SEQ ID NO:433); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0577] n. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTDYV (SEQ ID NO:413), MDPSFGQM (SEQ ID NO:434) and
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0578] o. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYRFTDYV (SEQ ID NO:436), MDPSFGRM (SEQ ID NO:437) and
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0579] p. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYTFIDYV (SEQ ID NO:438), MDPTYGRM (SEQ ID NO:439) and
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0580] q. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYRFLDYI (SEQ ID NO:440), MNPMGGQV (SEQ ID NO:421) and
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein the CDRs comprise amino acid sequences HNL, DFN and
WAYEA (SEQ ID NO:408); [0581] r. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GYKFMDQL (SEQ ID NO:442), MNPTYGQV (SEQ ID NO:443) and
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein the CDRs comprise amino acid sequences RHII (SEQ ID
NO:445), DDD and NTYEF (SEQ ID NO:446); [0582] s. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYNFVDSR (SEQ ID NO:447), INPLQGGV (SEQ ID
NO:448) and ARGIDGKSYPFHF (SEQ ID NO:449); and a light chain
variable region, wherein the CDRs comprise amino acid sequences S,
ESS and SILEF (SEQ ID NO:450); [0583] t. an antibody comprising a
heavy chain variable region, wherein the CDRs comprise amino acid
sequences GYTFTTHHGHF (SEQ ID NO:500), MNPMTGQM (SEQ ID NO:462) and
ARGDFGQNYPFHY (SEQ ID NO:463); and a light chain variable region,
wherein the CDRs comprise amino acid sequences NRYL (SEQ ID
NO:464), DDN and ASYER (SEQ ID NO:465); [0584] u. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYNFMDQF (SEQ ID NO:466), MNPIYGQV (SEQ ID
NO:467) and ARGPSGENYPFHY (SEQ ID NO:444); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
RHII (SEQ ID NO:445), DDD and NTYEF (SEQ ID NO:446); [0585] v. an
antibody comprising a heavy chain variable region, wherein the CDRs
comprise amino acid sequences GYNFVDSR (SEQ ID NO:447), INPLHGGV
(SEQ ID NO:468) and ARGIDGKSYPFHF (SEQ ID NO:449); and a light
chain variable region, wherein the CDRs comprise amino acid
sequences S, ESS and SILEF (SEQ ID NO:450); [0586] w. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYTFTKYF (SEQ ID NO:451), IHPRTGAV (SEQ ID
NO:452) and ARGAFEADSYGSSYPFHH (SEQ ID NO:453); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
GNYNP (SEQ ID NO:454), EDN and ASFEF (SEQ ID NO:455); [0587] x. an
antibody comprising a heavy chain variable region, wherein the CDRs
comprise amino acid sequences GYTFTKYT (SEQ ID NO:456), IHPRTGAV
(SEQ ID NO:452) and ARGAFEADLSGPTYPFHH (SEQ ID NO:457); and a light
chain variable region, wherein the CDRs comprise amino acid
sequences GNYNP (SEQ ID NO:454), EDN and ASFEF (SEQ ID NO:455);
[0588] y. an antibody comprising a heavy chain variable region,
wherein the CDRs comprise amino acid sequences GFNFIDSV (SEQ ID
NO:458), IKPLRGAV (SEQ ID NO:459) and AKGAFRGGSPFGF (SEQ ID
NO:460); and a light chain variable region, wherein the CDRs
comprise amino acid sequences DVT and ASREF (SEQ ID NO:461); [0589]
z. an antibody comprising a heavy chain variable region, wherein
the CDRs comprise amino acid sequences GYTFTSYF (SEQ ID NO:469),
INPLHGAV (SEQ ID NO:470) and TRGIVADGWPYGH (SEQ ID NO:471); and a
light chain variable region, wherein the CDRs comprise amino acid
sequences S, EGA and SSLQF (SEQ ID NO:472); [0590] aa. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFTFIDHI (SEQ ID NO:473), IKPLRGAV (SEQ ID
NO:459) and CKAAAPEEAFPLQY (SEQ ID NO:474); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
NVD, DNN and SSRTF (SEQ ID NO:475); [0591] bb. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFKFIDHI (SEQ ID NO:476), IKPLGGVA (SEQ ID
NO:477) and CKAAAPDEAFPLEY (SEQ ID NO:478); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
NVD, DNN and SSTTF (SEQ ID NO:479); [0592] cc. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFAFLDH (SEQ ID NO:480), VKTIGGVV (SEQ ID
NO:481) and SKAAAPDEAFPLEF (SEQ ID NO:482); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
NVD, DNN and SSTTF (SEQ ID NO:479); [0593] dd. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFAFLDHI (SEQ ID NO:486), VKTIGGVV (SEQ ID
NO:481) and SKAAAPDEAFPLEF (SEQ ID NO:482); and a light chain
variable region, wherein the CDRs comprise amino acid sequences
NVD, DNN and SSTTF (SEQ ID NO:479); [0594] ee. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GFKFTEYF (SEQ ID NO:483), LNPLRGAV (SEQ ID
NO:484), ARAVFNEAFPFDY (SEQ ID NO:485); and a light chain variable
region, wherein the CDRs comprise amino acid sequences VS, DGD and
ASREF (SEQ ID NO:461); [0595] ff. an antibody comprising a heavy
chain variable region, wherein the CDRs comprise amino acid
sequences GFKFIDHI (SEQ ID NO:476), IKPLGGVA (SEQ ID NO:477) and
CKAAAPDEAFPLEY (SEQ ID NO:478); and a light chain variable region,
wherein the CDRs comprise amino acid sequences NVD, DND and SSTTF
(SEQ ID NO:479); [0596] gg. an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFAFLDHI (SEQ ID NO:486), VKTIGGVV (SEQ ID NO:481) and
SKAAAPDEAFPLEF (SEQ ID NO:482); and a light chain variable region,
wherein the CDRs comprise amino acid sequences NVD, DNN and SSTTF
(SEQ ID NO:479); [0597] hh. an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFNFIDSV (SEQ ID NO:458), IKPLRGGV (SEQ ID NO:490) and
AKGAFGGSSPFGF (SEQ ID NO:491); and a light chain variable region,
wherein the CDRs comprise amino acid sequences DVT and ASREF (SEQ
ID NO:461); [0598] ii. an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFKFIDSV (SEQ ID NO:487), IKPLGGAV (SEQ ID NO:488) and
AKGAFGGGSPFGF (SEQ ID NO:489); and a light chain variable region,
wherein the CDRs comprise amino acid sequences DVT and ASREF (SEQ
ID NO:461); [0599] jj. an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFNFIDSV (SEQ ID NO:458), IKPLRGGV (SEQ ID NO:490) and
AKGAFGGSSPFGF (SEQ ID NO:491); and a light chain variable region,
wherein the CDRs comprise amino acid sequences DVT and ASREF (SEQ
ID NO:461); [0600] kk. an antibody comprising a heavy chain
variable region, wherein the CDRs comprise amino acid sequences
GFTFIKYT (SEQ ID NO:492), IHPRTGAV (SEQ ID NO:452) and
ARGAFEADLYGPTYPFHH (SEQ ID NO:493); and a light chain variable
region, wherein the CDRs comprise amino acid sequences GSYNP (SEQ
ID NO:494), DDN and ASFEF (SEQ ID NO:455); [0601] ll. an antibody
comprising a heavy chain variable region, wherein the CDRs comprise
amino acid sequences GYNFVDSL (SEQ ID NO:495), INPLQGGV (SEQ ID
NO:448) and ARGIDGNSYPFHF (SEQ ID NO:496); and a light chain
variable region, wherein the CDRs comprise amino acid sequences S,
ESS and SILEF (SEQ ID NO:450).
[0602] In some embodiments, the anti-HIV antibody is selected from
the group consisting of: [0603] a. an antibody comprising a heavy
chain variable region, wherein CDR H1 comprises GYDFIDYV (SEQ ID
NO:401), CDR H2 comprises MNPSGGGT (SEQ ID NO:402) and CDR H3
comprises VRDRANGSGRRRFESVNWFLDL (SEQ ID NO:403); and a light chain
variable region, wherein CDR L1 comprises HNY, CDR L2 comprises DFN
and CDR L3 comprises WAFEN (SEQ ID NO:404); [0604] b. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYKFPDYI (SEQ ID NO:405), CDR H2 comprises INPMGGQV (SEQ ID NO:406)
and CDR H3 comprises VRDRSNGSGRRFESSN (SEQ ID NO:407); and a light
chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0605] c.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFTDYL (SEQ ID NO:409), CDR H2 comprises MNPVYGQV
(SEQ ID NO:410) and CDR H3 comprises VRDTGDGSRRHFDSINWFLDL (SEQ ID
NO:411); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFD and CDR L3 comprises WAFEA (SEQ
ID NO:412); [0606] d. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2
comprises IDPPYGQV (SEQ ID NO:414) and CDR H3 comprises
VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0607] e. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFVDYF (SEQ ID NO:416), CDR H2 comprises MDPLNGRP (SEQ ID NO:417)
and CDR H3 comprises VRDKSNGSGRRFDSSNWFLDL (SEQ ID NO:418); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAYDA (SEQ ID NO:419); [0608] f.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFSDYI (SEQ ID NO:420), CDR H2 comprises MNPMGGQV
(SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID
NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEV (SEQ
ID NO:422); [0609] g. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFIDYI (SEQ ID NO:423), CDR H2
comprises IDPMNGRP (SEQ ID NO:424) and CDR H3 comprises
VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFN and CDR
L3 comprises WAYDA (SEQ ID NO:419); [0610] h. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYI (SEQ ID NO:426), CDR H2 comprises MNPMGGRT (SEQ ID NO:427)
and CDR H3 comprises VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0611] i.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFVDYL (SEQ ID NO:428), CDR H2 comprises MDPMNGRP
(SEQ ID NO:429) and CDR H3 comprises VRDKSGGSGKLFDSSNWFLDL (SEQ ID
NO:430); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAYDA (SEQ
ID NO:419); [0612] j. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2
comprises INPGYGQV (SEQ ID NO:431) and CDR H3 comprises
VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0613] k. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYV (SEQ ID NO:413), CDR H2 comprises MDPSYGQV (SEQ ID NO:432)
and CDR H3 comprises VRDRSHGSGRQFESSNWFLDL (SEQ ID NO:433); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0614] l.
an antibody comprising a heavy chain variable region, wherein CDR
comprises GYTFTDYV (SEQ ID NO:413), CDR H2 comprises MDPSFGQM (SEQ
ID NO:434) and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL (SEQ ID
NO:435); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0615] m. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYRFTDYV (SEQ ID NO:436), CDR H2
comprises MDPSFGRM (SEQ ID NO:437) and CDR H3 comprises
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0616] n. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFIDYV (SEQ ID NO:438), CDR H2 comprises MDPTYGRM (SEQ ID NO:439)
and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0617] o.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYRFLDYI (SEQ ID NO:440), CDR H2 comprises MNPMGGQV
(SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID
NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0618] p. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2
comprises MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD
and CDR L3 comprises NTYEF (SEQ ID NO:446); [0619] q. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYNFVDSR (SEQ ID NO:447), CDR H2 comprises INPLQGGV (SEQ ID NO:448)
and CDR H3 comprises ARGIDGKSYPFHF (SEQ ID NO:449); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
ESS and CDR L3 comprises SILEF (SEQ ID NO:450); [0620] r. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYTFTTHHGHF (SEQ ID NO:500), CDR H2 comprises MNPMTGQM
(SEQ ID NO:462) and CDR H3 comprises ARGDFGQNYPFHY (SEQ ID NO:463);
and a light chain variable region, wherein CDR L1 comprises NRYL
(SEQ ID NO:464), CDR L2 comprises DDN and CDR L3 comprises ASYER
(SEQ ID NO:465); [0621] s. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYNFMDQF (SEQ ID NO:466),
CDR H2 comprises MNPIYGQV (SEQ ID NO:467) and CDR H3 comprises
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD
and CDR L3 comprises NTYEF (SEQ ID NO:446); [0622] t. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYNFVDSR (SEQ ID NO:447), CDR H2 comprises INPLHGGV (SEQ ID NO:468)
and CDR H3 comprises ARGIDGKSYPFHF (SEQ ID NO:449); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
ESS and CDR L3 comprises SILEF (SEQ ID NO:450); [0623] u. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYTFTKYF (SEQ ID NO:451), CDR H2 comprises IHPRTGAV (SEQ
ID NO:452) and CDR H3 comprises ARGAFEADSYGSSYPFHH (SEQ ID NO:453);
and a light chain variable region, wherein CDR L1 comprises GNYNP
(SEQ ID NO:454), CDR L2 comprises EDN and CDR L3 comprises ASFEF
(SEQ ID NO:455); [0624] v. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYTFTKYT (SEQ ID NO:456),
CDR H2 comprises IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises
ARGAFEADLSGPTYPFHH (SEQ ID NO:457); and a light chain variable
region, wherein CDR L1 comprises GNYNP (SEQ ID NO:454), CDR L2
comprises EDN and CDR L3 comprises ASFEF (SEQ ID NO:455); [0625] w.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GFNFIDSV (SEQ ID NO:458), CDR H2 comprises IKPLRGAV
(SEQ ID NO:459) and CDR H3 comprises AKGAFRGGSPFGF (SEQ ID NO:460);
and a light chain variable region, wherein CDR L1 comprises DVT and
CDR L2 comprises ASREF (SEQ ID NO:461); [0626] x. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTSYF (SEQ ID NO:469), CDR H2 comprises INPLHGAV (SEQ ID NO:470)
and CDR H3 comprises TRGIVADGWPYGH (SEQ ID NO:471); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
EGA and CDR L3 comprises SSLQF (SEQ ID NO:472); [0627] y. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GFTFIDHI (SEQ ID NO:473), CDR H2 comprises IKPLRGAV (SEQ
ID NO:459) and CDR H3 comprises CKAAAPEEAFPLQY (SEQ ID NO:474); and
a light chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DNN and CDR L3 comprises SSRTF (SEQ ID NO:475); [0628] z.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GFKFIDHI (SEQ ID NO:476), CDR H2 comprises IKPLGGVA
(SEQ ID NO:477) and CDR H3 comprises CKAAAPDEAFPLEY (SEQ ID
NO:478); and a light chain variable region, wherein CDR L1
comprises NVD, CDR L2 comprises DNN and CDR L3 comprises SSTTF (SEQ
ID NO:479); [0629] aa. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GFAFLDH (SEQ ID NO:480),
CDR H2 comprises VKTIGGVV (SEQ ID NO:481) and CDR H3 comprises
SKAAAPDEAFPLEF (SEQ ID NO:482); and a light chain variable region,
wherein CDR L1 comprises NVD, CDR L2 comprises DNN and CDR L3
comprises SSTTF (SEQ ID NO:479); [0630] bb. an antibody comprising
a heavy chain variable region, wherein CDR H1 comprises GFKFTEYF
(SEQ ID NO:483), CDR H2 comprises LNPLRGAV (SEQ ID NO:484) and CDR
H3 comprises ARAVFNEAFPFDY (SEQ ID NO:485); and a light chain
variable region, wherein CDR L1 comprises VS, CDR L2 comprises DGD
and CDR L3 comprises ASREF (SEQ ID NO:461); [0631] cc. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GFKFIDHI (SEQ ID NO:476), CDR H2 comprises IKPLGGVA (SEQ ID NO:477)
and CDR H3 comprises CKAAAPDEAFPLEY (SEQ ID NO:478); and a light
chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DND and CDR L3 comprises SSTTF (SEQ ID NO:479); [0632]
dd. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFAFLDHI (SEQ ID NO:486), CDR H2 comprises
VKTIGGVV (SEQ ID NO:481) and CDR H3 comprises SKAAAPDEAFPLEF (SEQ
ID NO:482); and a light chain variable region, wherein CDR L1
comprises NVD, CDR L2 comprises DNN and CDR L3 comprises SSTTF (SEQ
ID NO:479); [0633] ee. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GFKFIDSV (SEQ ID NO:487),
CDR H2 comprises IKPLGGAV (SEQ ID NO:488) and CDR H3 comprises
AKGAFGGGSPFGF (SEQ ID NO:489); and a light chain variable region,
wherein CDR L1 comprises DVT and CDR L2 comprises ASREF (SEQ ID
NO:461); [0634] ff. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GFNFIDSV (SEQ ID NO:458), CDR H2
comprises IKPLRGGV (SEQ ID NO:490) and CDR H3 comprises
AKGAFGGSSPFGF (SEQ ID NO:491); and a light chain variable region,
wherein CDR L1 comprises DVT and CDR L2 comprises ASREF (SEQ ID
NO:461); [0635] gg. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GFTFIKYT (SEQ ID NO:492), CDR H2
comprises IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises
ARGAFEADLYGPTYPFHH (SEQ ID NO:493); and a light chain variable
region, wherein CDR L1 comprises GSYNP (SEQ ID NO:494), CDR L2
comprises DDN and CDR L3 comprises ASFEF (SEQ ID NO:455); [0636]
hh. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYNFVDSL (SEQ ID NO:495), CDR H2 comprises
INPLQGGV (SEQ ID NO:448) and CDR H3 comprises ARGIDGNSYPFHF (SEQ ID
NO:496); and a light chain variable region, wherein CDR L1
comprises S, CDR L2 comprises ESS and CDR L3 comprises SILEF (SEQ
ID NO:450); [0637] ii. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0638] jj. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAFEN (SEQ ID NO:404); [0639]
kk. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFD and CDR L3 comprises WAFEA (SEQ
ID NO:412); [0640] ll. an antibody comprising a heavy chain
variable region, wherein CDR comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2
comprises DDD and CDR L3 comprises NTYEF (SEQ ID NO:446); [0641]
mm. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAYDA (SEQ
ID NO:419); [0642] nn. an antibody comprising a heavy chain
variable region, wherein CDR comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0643] oo. an antibody
comprising a heavy chain variable region, wherein CDR comprises
GYKFMDQL (SEQ ID NO:442), CDR H2 comprises MNPTYGQV (SEQ ID NO:443)
and CDR H3 comprises VRDRSNGSGKRFESSN (SEQ ID NO:498); and a light
chain variable region, wherein CDR L1 comprises RHII (SEQ ID
NO:445), CDR L2 comprises DDD and CDR L3 comprises NTYEF (SEQ ID
NO:446); [0644] pp. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2
comprises (SEQ ID NO:443) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2
comprises DDD and CDR L3 comprises NTYEF (SEQ ID NO:446); and
[0645] qq. an antibody comprising a heavy chain variable region,
wherein CDR H1 comprises GYRFLDYI (SEQ ID NO:440), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408).
[0646] In some embodiments, the anti-HIV antibody is a
non-naturally occurring antibody. In some embodiments, the anti-HIV
antibody is selected from the group consisting of: N49P6; N49P6.2;
N49P7; N49P7.1; N49P7A; N49P7S; N49P7F; N49P7Y; N49P7-54TY;
N49P7LS-1; N49P7LS-2; N49P7YTE; N49P7L6; N49P7L11; N49P7.1L9;
N49P7.1L19 R49P7; N49P7.2; N49P11; N49P18; N49P18.2; N49P18.1;
N49P19; N49P37; N49P38; N49P38.1; N49P55; N49P56; N49P57; N49P58;
N49P59; N49P73; N49P74; N49P75; N49P75.1; N49P9; N49P9.1; N49P9.2;
N49P9i7; N49P9i7H1; N49P9i7H2; N49P22; N49P23; N49P9.3; N49P9.4;
N49P51; N49P52; N49P53; N49P54; N49P60; N49P61; N49P62; N49P63;
N49P64; N49P65; N49P66; N49P67; N49P68; N49P69; N49P70; N49P71; and
N49P72.
[0647] In some embodiments, the invention provides antibodies or
antigen binding fragments comprise the CDRs as shown in the Table 2
below with up to four (i.e. 0, 1, 2, 3, or 4) conservative amino
acid substitutions per CDR.
TABLE-US-00002 TABLE 2 Amino acid sequence of natural antibodies.
Natural antibody Related variants Amino Acid sequence Sequence 1
N49P6, N49P6.2 ##STR00001## ##STR00002##
YYCVRDRANGSGRRRFESVNWFLDLWGRGTQITVVSPSTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTC
PPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN
WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 1
--------------------------------------------------- ##STR00003##
##STR00004## LRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSP
VKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECS SEQ ID
NO: 2 Sequence 2 N49P7, N49P7.1 ##STR00005## N49P7A ##STR00006##
N49P7S CVRDRSNGSGKRFESSNWFLDLWGRGTAVTIQSSSTKGPSVFPLAPSS N49P7F
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY N49P7Y
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC N49P7.54TY
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY N49P7-LS1
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS N49P7-L52
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP N49P7/6L
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV N49P7/11L
FSCSVMHEALHNHYTQKSLSLSPGK R49P7 SEQ ID NO: 3
--------------------------------------------------- ##STR00007##
##STR00008## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 4 Sequence 3 N49P7.2 ##STR00009## ##STR00010##
CVRDRSNGSGRRFESSNWFLDLWGRGTAVTVHSPSKSTSGGTAALGC
LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL
FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK
PREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK
AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK SEQ
ID NO: 5 ---------------------------------------------------
##STR00011## ##STR00012##
VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 6 Sequence 4 N49P11 ##STR00013## ##STR00014##
YYCVRDTGDGSRRHFDSINWFLDLWGRGTWIRVAPASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG
LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP
PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN
WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF
YPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 7
--------------------------------------------------- ##STR00015##
##STR00016## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 8 Sequence 5 N49P18 ##STR00017## N49P18.2 ##STR00018##
VRDRSNGWGKRFESSNWFLDLWGRGTVVTVHSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 9
--------------------------------------------------- ##STR00019##
##STR00020## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 10 Sequence 6 N49P18.1 ##STR00021## ##STR00022##
VRDRSNGWGKRFESSNWFLDLWGRGTVVTVHSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 11
--------------------------------------------------- ##STR00023##
##STR00024## LRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSP
VKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECS SEQ ID
NO: 12 Sequence 7 N49P19 ##STR00025## ##STR00026##
CVRDKSNGSGRRFDSSNWFLDLWGRGTRVSIFSASTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 13
--------------------------------------------------- ##STR00027##
##STR00028## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 14 Sequence 8 N49P37 ##STR00029## ##STR00030##
YCVRDRSNGSGKRFESSNWFLDLWGRGTAVTISSPSTKGPSVFPLAPS
SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP
CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW
YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV
SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 15
--------------------------------------------------- ##STR00031##
##STR00032## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 16 Sequence 9 N49P38 ##STR00033## N49P38.1 ##STR00034##
RDKSNGSGKRFDSSNWFLDLWGRGTRVSISSASTKGPSVFPLAPSSKS
TSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP
ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 17
--------------------------------------------------- ##STR00035##
##STR00036## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 18 Sequence 10 N49P55 ##STR00037## ##STR00038##
CVRDKSNGSGKRFDSSNWFLDLWGRGTPVTISSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 19
--------------------------------------------------- ##STR00039##
##STR00040## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 20 Sequence 11 N49P56 ##STR00041## ##STR00042##
CVRDKSGGSGKLFDSSNWFLDLWGRGTRVSISSASTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 21
--------------------------------------------------- ##STR00043##
##STR00044## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 22 Sequence 12 N49P57 ##STR00045## ##STR00046##
VRDRSNGWGKRFESSNWFLDLWGRGTVITVHSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 23
--------------------------------------------------- ##STR00047##
##STR00048## LRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSP
VKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTV EKTVAPTECS SEQ ID
NO: 24 Sequence 13 N49P58 ##STR00049## ##STR00050##
CVRDRSHGSGRQFESSNWFLDLWGRGTVVNVQSPSTKGPSVFPLAPS
SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP
CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW
YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV
SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 25
--------------------------------------------------- ##STR00051##
##STR00052## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS
SEQ ID NO: 26 Sequence 14 N49P59 ##STR00053## ##STR00054##
CVRDRSHGSGRLFESSNWFLDLWGRGTVVTVQSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 27
--------------------------------------------------- ##STR00055##
##STR00056## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 28 Sequence 15 N49P73 ##STR00057## ##STR00058##
CVRDRSHGSGRLFESSNWFLDLWGRGTVVTVQSPSTKGPSVFPLAPSS
KSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC
PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY
VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS
NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP
SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV
FSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 29
--------------------------------------------------- ##STR00059##
##STR00060## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 30 Sequence 16 N49P74 ##STR00061## ##STR00062##
VRDRSHGSGRLFESSNWFLDLWGRGTVVTVQSPSTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
CSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 31
--------------------------------------------------- ##STR00063##
##STR00064## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 32 Sequence 17 N49P75 ##STR00065## ##STR00066##
YCVRDRSNGSGKRFESSNWFLDLWGRGTAVTIHSPSTKGPSVFPLAPS
SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP
CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW
YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV
SNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN
VFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 33
--------------------------------------------------- ##STR00067##
##STR00068## VLRQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSS
PVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGST VEKTVAPTECS SEQ ID
NO: 34 Sequence 18 N49P9 ##STR00069## N49P9.1 ##STR00070## N49P9.2
AVYYCARGPSGENYPFHYWGQGVRVVVSSPSTKGPSVFPLAPSSKSTS N49P9i7
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 35
--------------------------------------------------- ##STR00071##
##STR00072## SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 36 Sequence 19 N49P22 ##STR00073## ##STR00074##
ARGIDGKSYPFHFWGHGTRVTVFSASTKGPSVFPLAPSSKSTSGGTAA
LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK
SEQ ID NO: 37 ---------------------------------------------------
##STR00075## ##STR00076##
APSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGV
ETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP AECS SEQ ID NO:
38 Sequence 20 N49P23 ##STR00077## ##STR00078##
GDTGTYYCARGDFGQNYPFHYWGQGSLVIVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPA
PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS
CSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 39
--------------------------------------------------- ##STR00079##
##STR00080## VLSQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADG
SPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGS TVEKTVAPAECS SEQ
ID NO: 40 Sequence 21 N49P9.3 ##STR00081## N49P9.4 ##STR00082##
VYYCARGPSGENYPFHYWGQGVRVVVSSPSTKGPSVFPLAPSSKSTSG
GTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL
LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV
EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALP
APIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV
MHEALHNHYTQKSLSLSPGK SEQ ID NO: 41
--------------------------------------------------- ##STR00083##
##STR00084## SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 42 Sequence 22 N49P51 ##STR00085## ##STR00086##
ARGIDGKSYPFHFWGHGTRVTVFSASTKGPSVFPLAPSSKSTSGGTAA
LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK
SEQ ID NO: 43 ---------------------------------------------------
##STR00087## ##STR00088##
APSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGV
ETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP AECS SEQ ID NO:
44 Sequence 23 N49P52 ##STR00089## ##STR00090##
CARGAFEADSYGSSYPFHHWGQGTLVTVSSASTKGPSVFPLAPSSKST
SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 45
--------------------------------------------------- ##STR00091##
##STR00092## LTVLSQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKA
DGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHE GSTVEKTVAPAECS SEQ
ID NO: 46 Sequence 24 N49P53 ##STR00093## ##STR00094##
CARGAFEADLSGPTYPFHHWGQGTLVIVSAASTKGPSVFPLAPSSKST
SGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 47
--------------------------------------------------- ##STR00095##
##STR00096## LIVLSQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKAD
GSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEG STVEKTVAPAECS SEQ
ID NO: 48 Sequence 25 N49P54 ##STR00097## ##STR00098##
CAKGAFRGGSPFGFWGQGTLLTVSPASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 49 ---------------------------------------------------
##STR00099## ##STR00100##
AAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVG
VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTV APAECS SEQ ID NO:
50 Sequence 26 N49P60 ##STR00101## ##STR00102##
FCTRGIVADGWPYGHWGQGTQVTVSPASTKGPSVFPLAPSSKSTSGGT
AALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV
HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW
ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK
SEQ ID NO: 51 ---------------------------------------------------
##STR00103## ##STR00104##
PKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVK
VGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEK TVAPAECS SEQ ID
NO: 52 Sequence 27 N49P61 ##STR00105## ##STR00106##
AAAPEEAFPLQYWGQGTQLIVSSASTKGPSVFPLAPSSKSTSGGTAALG
CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF
LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT
KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS
KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG
QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK SEQ
ID NO: 53 ---------------------------------------------------
##STR00107## ##STR00108##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 54 Sequence 28 N49P62 ##STR00109## ##STR00110##
CKAAAPDEAFPLEYWGQGTQLIVSPASTKGPSVFPLAPSSKSTSGGTAA
LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK
SEQ ID NO: 55 ---------------------------------------------------
##STR00111## ##STR00112##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 56 Sequence 29 N49P63 ##STR00113## ##STR00114##
CSKAAAPDEAFPLEFWGQGTQVIVSSASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 57 ---------------------------------------------------
##STR00115## ##STR00116##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 58 Sequence 30 N49P64 ##STR00117## ##STR00118##
SKAAAPDEAFPLEFWGQGTQVIVSSASTKGPSVFPLAPSSKSTSGGTAA
LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK
SEQ ID NO: 59 ---------------------------------------------------
##STR00119## ##STR00120##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 60 Sequence 31 N49P65 ##STR00121## ##STR00122##
YYCARAVFNEAFPFDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGG
TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG
GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV
HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEW
ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMH EALHNHYTQKSLSLSPGK
SEQ ID NO: 61 ---------------------------------------------------
##STR00123## ##STR00124##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 62 Sequence 32 N49P66 ##STR00125## ##STR00126##
CKAAAPDEAFPLEYWGQGTQLIVSPASTKGPSVFPLAPSSKSTSGGTAA
LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT
ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGK
SEQ ID NO: 63 ---------------------------------------------------
##STR00127## ##STR00128##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 64 Sequence 33 N49P67 ##STR00129## ##STR00130##
CSKAAAPDEAFPLEFWGQGTQVIVSSASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 65 ---------------------------------------------------
##STR00131## ##STR00132##
SQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSP
VKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV EKTVAPAECS SEQ ID
NO: 66 Sequence 34 N49P68 ##STR00133## ##STR00134##
CAKGAFGGSSPFGFWGQGTLLTVSPASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 67 ---------------------------------------------------
##STR00135## ##STR00136##
AAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVG
VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTV APAECS SEQ ID NO:
68 Sequence 35 N49P69 ##STR00137## ##STR00138##
CAKGAFGGGSPFGFWGQGTLLTVSPASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 69 ---------------------------------------------------
##STR00139## ##STR00140##
AAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVG
VETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTV APAECS SEQ ID NO:
70 Sequence 36 N49P70 ##STR00141## ##STR00142##
CAKGAFGGSSPFGFWGQGTLLTVSPASTKGPSVFPLAPSSKSTSGGTA
ALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
SSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP
SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK
TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK
SEQ ID NO: 71 ---------------------------------------------------
##STR00143## ##STR00144##
APSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGV
ETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP AECS SEQ ID NO:
72 Sequence 37 N49P71 ##STR00145## ##STR00146##
ARGAFEADLYGPTYPFHHWGQGTQVTVSAASTKGPSVFPLAPSSKSTS
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE
LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDG
VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
VMHEALHNHYTQKSLSLSPGK SEQ ID NO: 73
--------------------------------------------------- ##STR00147##
##STR00148## LTVLSQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKA
DGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHE GSTVEKTVAPAECS SEQ
ID NO: 74 Sequence 38 N49P72 ##STR00149## ##STR00150##
ARGIDGNSYPFHFWGHGTRVTVFSASTKGPSVFPLAPSSKSTSGGTAAL
GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI
SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG
QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK SEQ
ID NO: 75 ---------------------------------------------------
##STR00151## ##STR00152##
APSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGV
ETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP AECS SEQ ID NO:
76 Heavy chain is shown first (above dotted line), followed by the
light chain (below dotted line). Sequences of CDRH1, CDRH2, CDRH3,
CDRL1, CDRL2, and CDRL3 are in bold. Note that there is a predicted
blank CDR in the light chain for Sequences 25, 34 and 36.
TABLE-US-00003 TABLE 3 Nucleotide sequences of natural antibodies.
Heavy chain is shown first (above dotted line), followed by the
light chain (below dotted line). Natural Related antibody variants
Nucleotide sequence Sequence 1 N49P6,
gcgggactgatgcagtctggggctgtgatgaagaattcgggggcctcagtgagggtctct
N49P6.2
tgtcaggctgatggatacgacttcattgactatgtcattcactggtttcgacaaagacgt N49P6-
ggagaaggtcttgagtggctgggatggatgaatccctcgggaggcggcacaaactatccg LS1
cgaccatttcagggcaaagtcaccatgaccagggacacgtccaccgagacagcctattta N49P6-
gatgtcagaggacttacatatgacgacacggccgtctattattgtgtgagagacagggcc LS2
aacggttcgggaagaagacgttttgagtcggtgaattggttcctggatctgtggggccgc N49P6A
ggcacccaaataacagtcgtctcgccctccaccaagggcccatcggtcttccccctggca N49P6S
ccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactac N49P6F
ttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacc N49P6Y
ttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccc
N49P6.54
tccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacacc TY
aaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgc
ccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggac
accctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaa
gaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagaca
aagccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctg
caccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctccca
gcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtac
accctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtc
aaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaac
aactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaag
ctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcat
gaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO:
77 ------------------------------------------------------------
cagtctgccctaactcagcctcgctcagtgtccgcatctcctggtcagtcagtcaccatc
tcctgcactggaacacacaattatgtgtcctggtgtcaacagaaaccgggccaagccccc
aaattattaatttacgatttcaataaacggccctcaggggtctctgatcgcttctctggc
tccacgtctggcaacacggcctccctgaccatctctggactccaggctgacgatgagggt
cattatttttgttgggcgtttgaaaatatcggcggagggaccaagctgaccgtcctgcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 78 Sequence 2 N49P7,
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgaggatctcc
N49P7.1
tgtgaggctcaaggatatagatttcctgactacatcattcactggattcgacgggcccct N49P7A
ggacaaggccctgaatggatgggatggatgaatccaatgggcggacaagtaaatattcca N49P7S
tggaaatttcagggtagggtctccatgacccgggacacgtccatcgaaacagcatttctg N49P7F
gacttaagaggactaaagtctgacgacacggccgtctattattgcgtgagagatcgcagt N49P7Y
aatggatcgggaaagcgattcgagtcctccaattggttcctcgatctgtggggccgtggg
N49P7.54 actgcggtcacaattcaatca TY
tcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg N49P7-
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg LS1
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca N49P7-
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc LS2
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
N49P7/6L
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
N49P7/11L
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct R49P7
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 79
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcagccaggcagagccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcactggactccaggatgacgatgacgcc
gaatatttttgttgggcgtatgaagcttttggcggagggaccaagttgaccgttcttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 80 Sequence 3 N49P7.2
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgaggatctcc
tgtgaggctcaaggatacaaatttcctgactacatcattcactggattcgacgggcccct
ggacaaggccttgagtggatggggtggattaatccaatgggcggacaagtaaacattcca
tggcagtttcagggcagggtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagaggactaaagtctgacgacacggccctctattattgcgtgagagatcgaagt
aatggatcgggaaggcgattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgcggtcactgttcattcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtgatgcatgagg
ctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 81
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagagccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcagtggactccaggatgacgatgacgcc
gaatatttttgttgggcgtatgaagcttttggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 82 Sequence 4 N49P11
tcggcggaattggtgcaatctggggctgtggtgaagaagcctgggacctccgtgaaggtc
tcttgtcaggcttatggatacacttttaccgactaccttattcattggcttcgacaggcc
cctggacaaggacttgaatggatgggatggatgaatcctgtttatggacaagtaaattat
gcccaaaactttcagggcagggtctccatgaccagggacatttacagggaaacagcattt
ctagaggtgcgcgacctgaagactgacgacacaggcacttattattgtgtgagagacaca
ggcgacggttcgcggagacactttgactccatcaattggtttctcgatctttggggccgc
gggacatggataagggtcgccccagcctccaccaagggcccatcggtcttccccctggca
ccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactac
ttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacc
ttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccc
tccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacacc
aaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgc
ccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggac
accctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaa
gaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagaca
aagccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctg
caccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctccca
gcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtac
accctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtc
aaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaac
aactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaag
ctcaccgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtgatgcatg
aggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 83
------------------------------------------------------------
cagtgtgtcttgactcagcctcgctcagtgtccggatctcctggacaatcagtcaccatc
tcctgcactggaactcacaattatgtctcctggtgtcaacaccacccaggcaacgccccc
aaattattactttatgatttcgacaagcggccctcaggaatctctgatcgcttctctggc
tctaggtctggcaacacggcctccctgaccatctctggcctccagcctgaggatgaggcc
gattacttttgttgggcctttgaagcctttggcggagggaccaaggtgctcgtccttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 84 Sequence 5 N49P18
gcggacttggtgcagtctggggctgtgatgaagaagcctggggactcagtgagaatctcc
N49P18.2
tgtgaggctcgaggatacacattcactgactacgtcattcactggattcgacgggcccct
ggacaaggccttgaatggatggggtggattgatccaccttatggacaagtaaatattcca
tggaattttcagggcagggtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagaggtctaaagtctgacgacacgggcctctattattgcgtgagagatcgaagt
aatggatggggaaagcgattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgtggtcactgttcactcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 85
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagagccccc
aagttattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctaaccatcagtggactccaggatgacgatgacgcc
gaatatttttgttgggcatatgaagctttcggcggagggaccaagttgactgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 86 Sequence 6 N49P18.1
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagaatctcc
tgtgaggctcaaggatacacattcactgactacgtcattcactggattcgacgggcccct
ggacaaggccttgaatggatggggtggattaatccaggttatggacaagtaaatattcca
tggaactttcagggcagggtctccatgacccgagacacgtccatcgaaacagcatttctg
gacttaagaggtctaaagtctgacgacacgggcctctattattgcgtgagagatcgaagt
aatggatggggaaagcgattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgtggtcactgttcactcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtgatgcatgagg
ctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 87
------------------------------------------------------------
cagtctgccctgactcagcctcgctcaatgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcagtggactccaggatgacgatgacgcc
gaatacatttgttgggcatatgaagctttcggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 88 Sequence 7 N49P19
gcggacttggtgcagtctggggctgtggtgaaaaatgctggggcctcagtgagggtctcc
tgtgaggcttatggatacacattcgtggactacttcattcattgggtccgacaggcccct
ggacaaggctttgaatggatgggatacatggatcccttgaacgggcgcccaaacattgcg
cgaaaatttcagggcaggctctccctgagtcgagataggtccagcgaaacttcatttctg
gacttaagtggactgaggtctgacgactcggccgtctattattgtgtgagagacaagagt
aatggatcgggcagacggtttgactcgtctaattggtttctcgatctgtggggccgtgga
acccgggtcagtattttctcagcctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 89
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcaactcctggacagtcagtcaccatc
tcctgcactggaacccacaattatgtctcttggtgtcaacaacatccaggcagagccccc
aaattactaatttatgacttcaataagaggccctcaggggtcccggatcgcttctctggc
tccggatctggcggcacggcctccctaaccatcactggactccaggatgacgatgaagcg
gactatttttgttgggcctatgatgcttttggcggagggaccaagttgaccgtcctgcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 90 Sequence 8 N49P37
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagggtctcc
tgtgaggcttatggatacacattcagtgactacatcattcattggattcgacgggcccct
ggacgaggccttgaatggatgggatggatgaatccgatgggcggacaagtgaatattccg
tggaactttcaggggagagtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagaggactgaggtctgacgacacggccgtctattactgtgtgagagatcgcagc
aatggatcgggcaagcgatttgagtcctccaattggttcctcgatctgtggggccgcggg
accgcggtcactatttcctcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 91
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcagctcctggacagtccgtcaccatt
tcctgcactggaacccacaatttggtttcttggtgtcaacatcacccaggcagagccccc
aagttattaatttatgacttcaataagagaccctcaggtgtccctgatcgtttctctggc
tccgggtctggcggcacggcctccctaaccatcactggactccaggatgacgatgaggct
gaatatttttgttgggcgtatgaagtttttggcggagggaccaagttgaccgtgcttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 92 Sequence 9 N49P38
gcggacttggtgcagtctggggctgtggtgaagacgcctggggcctcagtgagggtctcc
N49P38.1
tgtgaggcttatggatacacattcattgactacatcattcattgggtccgacaggcccct
ggacaaggttttgaatggctgggatacatcgatcctatgaacgggcgcccaaacattgcg
cgaaaatttcagggcaggctctccctgagccgggatacgtccatcgaaacatcatttctg
gacttaagtggactgaggtctgacgactcggccgtctattattgtgtgagagacaagagt
aatggatcgggcaaacgatttgactcctctaattggtttctcgatctgtggggccgtgga
acgcgggtcagcatttcttcagcctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 93
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcagctcctggacagtcagtcaccatc
tcctgcactggaacccacaattatgtctcttggtgtcaacaacatccaggcagagccccc
aaattactaatttatgacttcaataagaggccctcaggggtcccggatcgcttctctggc
tccggatctggcggcacggcctccctaaccatcactagactccaggatgacgatgacgct
gactatttttgttgggcgtatgatgcttttggcggagggaccaagttgaccgtcctgcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 94 Sequence N49P55
gcggacttggtgcagtctggggctgtggtgaagaagcctggggcctcagtgagggtctcc 10
tgtgaggcttatggatacacattcactgactacatcattcattggattcgacaggcccct
ggacaaggccttgaatggatgggatggatgaatcctatgggcgggcgcacaaatattccg
tggaaatttcagggcagggtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagtggactaacgtctgacgacacggccgtctattattgcgtgagagacaagagt
aatggatcgggcaaacgatttgactcctctaattggttcctcgatctgtggggccgcgga
accccggtcactatttcctcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 95
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcagctcctggacagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacaacacccaggcagagccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctaagtatcactggactccaggatgacgatgaagct
gaatatttttgttgggcgtatgaagcttttggcggagggaccaagttgaccgtccttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 96 Sequence N49P56
gcggacttggtgcagtctggggctgtggtgaagaagcctggggcctcagtgcgggtctcc 11
tgtgaggcttatggatatacattcgttgactacctcattcattgggtccgacaggccccc
ggacaaggttttgaatggatgggatacatggatcctatgaacgggcgcccaaatattgcg
cgaaaatttcagggcaggctctccctgagccgagatacgtccatcgaaacatcatttctg
gacttaagtggactgaggtctgacgactcggccgtctattattgtgtgagagacaagagt
ggtggatcgggcaaactatttgactcctctaattggtttctcgatctgtggggccgtgga
acccgggtcagcatttcttcagcctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 97
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcagctcctggacagtcagtcaccatc
tcctgcaccggaactcacaattatgtctcttggtgtcaacaacatccaggcagagccccc
aaattactaatttatgacttcaataagaggccctcaggggtcccggatcgcttctctggc
tccggatctggcggcacggcctccctaaccatcactggactccaggatgacgatgacgct
gattatttttgttgggcgtatgatgcttttggcggagggaccaagttgaccgtcctgcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 98 Sequence N49P57
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagaatctcc 12
tgtgaggctcaaggatacacattcactgactacgtcattcactggattcgacgggcccct
ggacaaggccttgaatggatggggtggattaatccaggttatggacaagtaaatattcca
tggaactttcagggcagggtctccatgacccgagacacgtccatcgaaacagcttttctg
gagttaagaggtctaaagtctgacgacacgggcctctattattgcgtgagagatcgaagt
aatggatggggaaagcgattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgtgattactgttcactcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 99
------------------------------------------------------------
cagtctgccctgactcagcctcgctcaatgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcactggactccaggatgacgatgacgcc
gaatacatttgttgggcatatgaagctttcggcggagggaccaagttgaccatacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 100 Sequence N49P58
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagaatctcc 13
tgtgaggctcagggatatacattcaccgactacgtcattcattggattcgacgggcccct
ggacaaggccttgaatggatggggtggatggatccaagttatggacaagtcaatattcca
cggaactttcagggcagggtctccatgacccgggacacgttcagggaaacagcatatctg
gaattaagaggtctacagtctgacgacaagggcctctattattgtgtgagagatcgaagt
cacggatcgggaaggcaattcgagtcctccaactggttcctcgatctgtggggccgcggc
actgtggtcaatgttcagtcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 101
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacctccc
aaattattaatttatgacttcaataagagggcttcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccattagtggactccaggatgacgatgacgcc
gaatatttttgttgggcatatgaagctttcggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 102 Sequence N49P59
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcactgagaatctcc 14
tgtgaggctcaaggatacacattcactgactacgtcattcactggattcgacgggcccct
ggacaaggccttgaatggatgggatggatggatccaagttttggacaaatgaacattcca
cggaactttcagggcagggtctccatgacccgtgacatgtacatcgaaacagcatttctg
gacttaagaggtctaaagtctgacgacacgggcctctattattgcgtgagagatcgaagt
catggatcgggaaggctattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgtggtcactgttcagtcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 103
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacctccc
aaattattaatttatgacttcaataagagggcttcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccattagtggactccaggatgacgatgacgcc
gaatatttttgttgggcatatgaagctttcggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 104 Sequence N49P73
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagaatctcc 15
tgtgaggctcaaggatacagattcactgactacgtcattcattggattcgacgggcccct
ggacaaggccttgaatggatggggttgatggatccaagttttggacgaatgaatattcca
cggaaatttcagggcagggtctccatgacccgggacacgtccatggaaacagcatttctg
gacttcagaggtctaaattttgacgacacgggcctctattattgcgtgagagatcgaagt
catggatcgggaagactattcgagtcctccaattggttcctcgatctgtggggccgcggc
actgtggtcactgttcagtcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 105
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacctccc
aaattattaatttatgacttcaataagagggcatcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcagtggactccaagatgacgatgacgcc
gaatatttttgttgggcatatgaagctttcggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 106 Sequence N49P74
ccggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgagaatttcc 16
tgtgaggctcaaggatacacattcattgactacgtcattcactggattcgacgggcccct
ggacaaggccttgaatggatggggttgatggatccaacttatggacgaatgaatattcca
cggaagtttcagggcagggtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagaggtctaaaatctgacgacacgggcctctattattgcgtgagagatcgaagt
catggatcgggaaggctattcgagtcctccaactggttcctggatctgtggggccgcggc
actgtggtcactgttcagtcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacct
acatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccca
aatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggac
cgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctg
aggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggt
acgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
gcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagg
agtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcca
aagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgagc
tgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcg
ccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgc
tggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggc
agcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgc
agaagagcctctccctgtctccgggtaaa SEQ ID NO: 107
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagacctccc
aaattattaatttatgacttcaataagagggcttcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcagtggactccaagatgacgatgacgcc
gaatatttttgttgggcatatgaagctttcggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 108 Sequence N49P75
gcggacttggtgcagtctggggctgtggtgaagaagcctggggactcagtgaggatctcc 17
tgtgaggctcaaggatacagatttcttgactacatcattcactggattcgacgggcccct
ggacaaggccttgaatggatgggatggatgaatccaatgggcggacaagtaaacattcca
tggaactttcagggtagggtctccatgacccgggacacgtccatcgaaacagcatttctg
gacttaagaggactaaagtctgacgacacggccgtctattattgcgtgagagatcgcagt
aatggatcgggaaagcgattcgagtcctccaattggttcctcgatctgtggggccgcggg
actgcggtcactattcattcaccctccaccaagggcccatcggtcttccccctggcaccc
tcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttc
cccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttc
ccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctcc
agcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacacc
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagac
cctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaag
ccgcgggaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcac
caggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
ctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaa
ggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
tacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctc
accgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag
gctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 109
------------------------------------------------------------
cagtctgccctgactcagcctcgctcagtgtccgcatctcctgggcagtccgtcaccatt
tcctgcactggaacccacaatttggtctcttggtgtcaacatcacccaggcagagccccc
aaattattaatttatgacttcaataagaggccctcaggggtccctgatcgcttctctggc
tccgggtctggcggcacggcctccctgaccatcactggactccaggatgacgatgacgcc
gaatatttttgttgggcgtatgaagcttttggcggagggaccaagttgaccgtacttcgt
cagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggct
tggaaagcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaa
agcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcc
cacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctacagaatgttca SEQ ID NO: 110 Sequence N49P9
cacgtccaattggtgcagtctggaggtggggtgaagaagattggggccgctgtgaggatc 18
N49P9.1
tcctgcgaggtgactggatataaattcatggaccaactcataaactgggtgcggcaggcc
N49P9.2
cccggtcagggccttgagtggatgggatggatgaatccaacatatggacaagtaaattat
N49P9i7
tcatggagatttgaaggaagggtcaccatgaccagggacatggacaccgagacggccttc
atggagttgagaggactgagagtggacgacacggccgtctattattgcgcgagggggccc
tctggggaaaattatccttttcactattggggccagggtgtccgagtggtcgtctcgtca
ccctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 111
------------------------------------------------------------
gcatctgccctgactcagcctgcctccatgtctgcgtcccctggacagtcggtaaccatc
tcgtgctctggaaccagacacataatctctgcttggttccaacaatatccaggcaaacca
cccaaactcataatttttgacgacgataagcgtccctctggagttcctagtcgcttctct
gcctccaggcctggcgacacggcctccctgacaatctctaatgttcaacctgaggacgag
gcgacgtacatttgcaatacatatgaattctttggcggagggaccagattgaccgtccta
agtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaa
gccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtg
gcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaa
caaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaag
tcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtg
gcccctgcagaatgctct SEQ ID NO: 112 Sequence N49P22
cacattcagttgctacagtcggggcctcaagttaagaagtctggggacacagtgagaatc 19
tcctgtgagacctctggatataacttcgtcgactcccgtatccactgggtccgacagacc
ccggaaaaacgtctcagatggatgggctggatcaatcctctccaaggtggtgtgaattac
gcgccggaatttcagggcagaatcaggatgaccagggacacatttatagacacagtttac
gtggacctgagcggactgacaccggccgacacggcctattattactgcgcgcgagggatc
gatggcaagtcttacccctttcatttctggggccacggaacccgggtcaccgtcttctcg
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 113
------------------------------------------------------------
cgatttgccctgactcaacctgcctccgtgtctgggtctcctggacagacgatcaccata
acctgcgctggaggcagcgtctcctggtttcatttccctccaggcaaaacccccagactc
attatttatgagtcttctaagcgaccctctggggtctctcctcgattctctgggtcccag
tctggcagcacggcctcccttataatttctggcctccagtctgatgacgaagggacatac
ttctgttctattcttgaatttttcggcagagggactcttgtcaccgtcctgagtcagccc
aaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaag
gccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaag
gcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaac
aacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacaga
agctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgca
gaatgctct SEQ ID NO: 114 Sequence N49P23
caggtgcgcttggtgcagtctggggctggggcgaggaagactggggcctcaatgaaactt 20
tcctgctcgacctctggatacaccttcaccactcatcacggccacttcataaattgggtg
cgacaggcccgtggacaagggcttgagtggatggggtggatgaatcccatgactgggcag
atgaatattgaggggaaatttcagggcagagtcaccctcactcgagacatatacagtgac
acggcttacatggaaatgaccagactgacaactggcgacacgggcacttattactgtgcg
cgaggcgatttcggacagaattatccctttcattattggggccagggaagcctggtcatc
gtctcctcggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagc
acctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtg
acggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtccta
cagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggc
acccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaa
gttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactc
ctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcc
cggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag
ttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggag
cagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctg
aatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaa
accatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcc
cgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatccc
agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacg
cctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaag
agcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaac
cactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 115
------------------------------------------------------------
ctgtctgccctgactcagcctgcctccgtgtctgggtctcctgggcagtcggtcaccatc
tcctgctctggaacgaaccgttaccttgtctcctggtatcaacaacaccctgacaaagcc
cccaaactcatcatttatgacgacaataagcggccctcaggaatttctgatcgcttctca
gcctccaggcctgacgacacggcctccctgacaatctctggactccagactggggacgag
gctacttattggtgtgcctcatatgaacgttttggcggcgggacgaggctgaccgtcctt
agtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaa
gccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtg
gcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaa
caaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaag
tcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtg
gcccctgcagaatgctct SEQ ID NO: 116 Sequence N49P9.3
cacgtccaattggtgcagtctggaggtggggtgaagaagattggggccgctgtgaggatc 21
N49P9.4
tcctgcgaggtgtctggatacaacttcatggaccaattcataaattgggtgcgacaggcc
cccggtcagggccttgagtggatgggatggatgaacccaatatatggacaagtaaattat
tcatggagatttcaaggaagggtcaccatgaccagggacatgtacaccgacacggccttc
atggagttgagaggactgagagtggacgacacggccgtctattattgcgcgagggggccc
tctggggaaaattatccttttcactattggggccagggtgtccgagtggtcgtctcgtca
ccctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 117
------------------------------------------------------------
gcatctgccctgactcagcctgcctccatgtctgcgtcccctggacagtcggtaaccatc
tcgtgctctggaaccagacacataatctctgcttggttccaacaatatccaggcaaacca
cccaaactcataatttttgacgacgataagcgtccctctggagttcctagtcgcttctct
gcctccaggcctggcgacacggcctccctgacaatctctaatgttcaacctgaggacgag
gcgacatacatttgcaatacatatgaattctttggcggagggaccaaattgaccgtccta
agtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaa
gccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtg
gcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaa
caaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaag
tcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtg
gcccctgcagaatgctct SEQ ID NO: 118 Sequence N49P51
cacattcagttgctacagtcggggcctcaagttaagaagtctggggacacagtgagaatc 22
tcctgtgagacctctggatataacttcgtcgactcccgtatccactgggtccgacagacc
ccggaaaaacgtctcagatggatgggctggatcaatcctctccacggtggtgtgaattac
gcgccggaatttcagggcagaatcaggatgaccagggacacatttatagacacagtttac
gtggacctgagcggactgacaccggccgacacggcctattattactgcgcgcgagggatc
gatggcaagtcttacccctttcatttctggggccacggaacccgggtcaccgtcttctcg
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 119
------------------------------------------------------------
cgatttgccctgactcaacctgcctccgtgtctgggtctcctggacagacgatcaccata
acctgcgctggaggcagcgtctcctggtttcatttccctccaggcaaaacccccagactc
attatttatgagtcttctaagcgaccctctggggtctctcctcgattctctgggtcccag
tctggcagcacggcctccctcataatttctggcctccagtctgatgacgaagggacatac
ttctgttctattcttgaatttttcggcagagggactcttgtcaccgtcctgagtcagccc
aaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaag
gccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaag
gcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaac
aacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacaga
agctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgca
gaatgctct SEQ ID NO: 120 Sequence N49P52
cgtgttacattacaacaatctggggctatagtgaggcagcctggggcctcagtgaccgtc 23
tcctgcgagacttctggatatactttcaccaagtatttcatctactgggtgcgacaggcc
cctggacagggtcttgagtggctgggcagaatacacccccgaaccggtgccgtgaagtat
gcaccgagatttcagggtagactgtccatgaccagagactggtcactcgacacagcctac
ctcggattgaccggactgacactcggcgacacggctctatatttctgtgcgaggggggcc
tttgaggcagattcatatgggtcaagttatccctttcaccactggggccagggaacccta
gtcaccgtctccgcggcctccaccaagggcccatcggtcttccccctggcaccctcctcc
aagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaa
ccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggct
gtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagc
ttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggac
aagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacct
gaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatg
atctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgag
gtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgg
gaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggac
tggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatc
gagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc
ccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttc
tatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
accacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtg
gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctg
cacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 121
------------------------------------------------------------
tcctgggccctgactcaacccgcctccgtgtctgcgtctcctgggcagtcggtcaccatg
tcctgcactggattcggaaattataaccctgactcctggtaccaacaatacccaggcaaa
gcccccaaactcatcatttatgaagacaataaaagaccctcgggggtctctgatcgcttc
tctgcctccagacttggcagcacgtcttccctgacaatctctaacgtccaggctgcggac
gacgcccattatgtctgcgcctcctttgaatttttcggcggagggaccaagctgaccgtc
ctgagtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagctt
caagccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgaca
gtggcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctcc
aaacaaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtgg
aagtcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagaca
gtggcccctgcagaatgctct SEQ ID NO: 122 Sequence N49P53
cgtgtgacattacaacaatctggggctacagtgaagcagcctggggcctcagtgaccgtc 24
tcctgcgagacttctggatacactttcaccaagtataccattcactgggtgcgacaggcc
cctggacagggtcttcagtgggtgggcagaatacacccccgaaccggtgccgtgaagtat
gcaccgatatttcagggtaaagtgtccatgagtcgagacttgtcacgcgacacagcctac
ctcggattgaccagactgacgctcgccgacacggctctatttttctgtgcgaggggggcc
tttgaggcagatttaagtgggccaacttacccctttcaccactggggccaaggaacccta
gtcatcgtctccgcggcctccaccaagggcccatcggtcttccccctggcaccctcctcc
aagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaa
ccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggct
gtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagc
ttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggac
aagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacct
gaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatg
atctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgag
gtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgg
gaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggac
tggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatc
gagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc
ccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttc
tatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
accacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtg
gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctg
cacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 123
------------------------------------------------------------
tcctgggccctgactcaacccgcctccgtgtctgcgtctcctgggcagtcggtcaccatg
tcctgcactggattcggaaattataaccctgactcctggtaccaacaatacccaggcaaa
gcccccaaactcatcatttatgaggacaataaaagaccctcgggagtctctaatcgcttc
tctgcctccagacttggcagcacgtcttccctgacaatctctaacgtccaggccgctgac
gacgcccattatgtctgcgcctcctttgaatttttcggcggagggaccaagctgatcgtc
ctgagtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagctt
caagccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgaca
gtggcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctcc
aaacaaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtgg
aagtcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagaca
gtggcccctgcagaatgctct SEQ ID NO: 124 Sequence N49P54
aacgtgcagttgatgcagtctgggactgaggtgaagaagtctggggcctcggtgacaatc 25
tcttgtgagaccgctggattcaacttcatcgactccgtcatacactggctgcgccaggcc
cctggaggaggatttcagtggatggggtggatcaagcctcttagaggtgccgtcaattat
ccacagtttttgcagggcagggtctccatgacccgggacttgtccaccgacacggtgtac
atggtcttgaatggactgacacctgacgacacaggcctttattactgcgcgaaaggggcc
tttagagggggttctccctttggcttctggggccagggaactctgctcaccgtctcccca
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 125
------------------------------------------------------------
cagtctgccctgtctcagcctgtctccgtgtctgggtctcctggagagtcgatcaccatt
tcctgtactggagccaccacctggtatcaacaactcccaggcagaccccccaaactcatc
atttatgacgtcactaaccggccctcaggcatttctagtcgtttctctggctccacgtct
ggccacacggcctccctgacaatctccggtctccaggttgacgacgagggtctgtatcac
tgcgcctcacgtgaatttttcggcggagggaccaagctgaccgtcctgagtcagcccaag
gctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaaggcc
acactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaaggca
gatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaacaac
aagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacagaagc
tacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgcagaa tgctct
SEQ ID NO: 126 Sequence N49P60
caggtgcgactggtgcagtctgggcctcaggtgaagaagactggggcctcagtgagggtc 26
tcctgcgaaacctctggatacacgttcacctcctacttcatccattggttacgactgggc
cccggagaggggcttcagtggatggggtggatcaaccctttacatggtgccgtgaattat
gaaaacaaatttaggggcagggtcacaatcaccagggacacgtccacagacacagtgtat
ttggacatgagcagactgacccctgacgacacggccgtctatttctgcacaagaggaatc
gttgctgatgggtggccctatggccactggggccagggaacccaagtcaccgtctccccg
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 127
------------------------------------------------------------
tcctgggccctgactcagcctgcctccgtgtctgggtctcctggacagtcggtcgccatc
tcctgcgctggcggcagcgtctcctggtaccaggtgctcccaggcagagcccccaaactc
atcatttatgagggcgctaagcgaccctcaggggtttctgctcgcttctctggctcccag
tctggcaacacggcttacctgacaatttctgacctccagactgaggacgagggcatctac
ttctgctcttcacttcaattcttcggcggagggaccaaactgaccgtcctaagtcagccc
aaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaag
gccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaag
gcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaac
aacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacaga
agctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgca
gaatgctct SEQ ID NO: 128 Sequence N49P61
caggtgcgacttcagcagtctggtgtcgtggtgaggaagcctggggcctcagtgagaatt 27
tcctgcgagacttctggattcaccttcatcgaccacattgtccattgggtgcggcgggcc
cctggacgaggctttgaatggatgggttggatcaagcctcttaggggtgccgtagattat
gcaccccaacttcggggcaggatctccctgacgagggacatttacagtgaaaccgtcttt
atagacgtgagtcgactgacgtctggcgacacggcgatatacttttgttgtaaggccgcc
gcccctgaagaagcattcccccttcaatactggggccaggggacccaacttatcgtctcc
tcggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 129
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcctgcctttatgccaatgtagatatctgctggtatcaactacacccgggcagagccccc
aaacttctaattgttgacaataataagcggccctcaggagtctctcctcgcttctctggc
tccaagtctggcaccacggcctccctgacaatctctggacttcaggctgacgacgaggct
gaatatcactgctcttcaagaacattttttggcggggggaccaagttgaccgtcctgagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct SEQ ID NO: 130 Sequence N49P62
caggtgcgacttcagcagtctggtgtcgtggtgaggaagcctggggcctcagtgagactt 28
tcctgcgagacgtctggattcaaattcatcgaccacattgtcaactgggtgcggcgggcc
cctggacgaggctttgaatggatgggttggatcaagcctcttgggggtgtcgctgattat
gcaccccaacatcggggcaggatctcactgacgagggacatttacactgaaaccgtcttt
atagacctgagtcgactgacgtctggcgacacggcgatttatttctgttgtaaggccgcc
gcccctgatgaagcattcccccttgaatactggggccaggggacccaacttatcgtctcc
ccggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 131
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcctgcctttatgccaatgtagatatctgctggtatcaaatacagccgggcagattaccc
aaacttctgattgttgacaataataggcgaccctcaggagtctctcctcgcttctctggc
tccaagtctggcaccacggcctccctgacaatctctggacttcaggctgacgacgaggct
gaatatcactgctcttcaacaacattttttggcggggggaccaagttgaccgtcctcagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct SEQ ID NO: 132 Sequence N49P63
caggtgcgacttgtgcagtctggtcccgtgatgagaaagcctggggcctcagtgagaatt 29
tcttgcgagacatctggattcgccttcttggaccacattgtccactgggtgcggcgggcc
cctggacgcggctttgaatggatgggttgggttaagaccattgggggtgtcgttgattat
gcaccccaccttaggggcaggatctccgtgacgagagacgtctttagtgaaaccgtcttt
ctggacttgagtcgactgacgtctggcgacacggcgatgtatttttgttctaaggccgcc
gcccctgacgaagccttcccccttgaattttggggccaggggacccaagtcatcgtctcc
tcggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 133
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcttgcctttatgccaatgtggatatctgctggtatcaacttcacccgggcagagccccc
aaacttcttattcttgacaataataaacggccctcaggagtctctagtcgcttctccggt
tccaagtctggcaccacggcctccctaaccatctctgaccttcaggctgacgacgaggct
gaatatcactgctcttcaacaacattttttggcggggggaccaggttgaccgtcctgagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct SEQ ID NO: 134 Sequence N49P64
caggtgcgacttgtgcagtctggtcccgtggtgagaaagcctgggacctcagtgagaatt 30
tcttgcgagacatctggattcgccttcttggaccacattgtccactgggtgcggcgggcc
cctggacgcggctttgaatggatgggttgggttaagaccattgggggtgtcgttgattat
gcaccccaccttaggggcaggatctccgtgacgagggacgtatttagtgaaatcgtcttt
atggagttgagtcgactgacgtctggcgacacggcgatgtatttttgttctaaggccgcc
gcccctgacgaagccttcccccttgaattttggggccaggggacccaagtcatcgtctcc
tcggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 135
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcctgcctttatgccaatgtggatatctgctggtatcaacttcacccgggcagagccccc
aaacttctaattgttgacaataataagcggccctcaggagtctctagtcgcttctctggt
tccaagtctggcaccacggcctccctaacaatctctgatcttcaggctgacgacgaggct
gaatatcactgctcttcaacaacattttttggcggggggaccaggttgaccgtcctgagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct SEQ ID NO: 136 Sequence N49P65
caagtgcaactggtgcagtctggggctggggtgaagaagcctggggcctcagtgagggtc 31
tcctgcgagacatccggattcaagttcaccgagtactttatccactttttacgacaggcc
cctggacaagggcttgagtggatgggatggctcaaccctctcagaggtgccgtcaactat
ccacggaagtttcagggcagagtcactttgaccagggacatctacaccaccaccgtctac
atgcaacttaacggtctgacccctgacgacacggccgtctactactgtgccagagcggtc
tttaatgaagctttcccctttgactactggggccagggaagcctggtcaccgtctcctca
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 137
------------------------------------------------------------
tcctgggcccagactcagcctgcctccgtgtctgggtctcctggacagtcgatcaccatc
tcctgcgctggaatcgtcagtgatgcctggtaccagcaatacccaggcagaccccccaga
ctcatcctttatgacggcgataagcggccctcaggggtttctcctcgtttttctgcctcc
agggccggcaagacggcctccctgacaatttctgggctgcaggctgacgacgaggcttat
tatcactgcgcgtcaagggaattttttggaggcgtgaccaagttgaccgtcctaagtcag
cccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaac
aaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctgg
aaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagc
aacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccac
agaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccct
gcagaatgctct SEQ ID NO: 138 Sequence N49P66
caggtgcgacttcagcagtctggtgtcgtggtgaggaagcctggggcctcagtgagactt 32
tcctgcgagacgtctggcttcaaattcatcgaccacattgtcaactgggtgcggcgggcc
cctggacgaggctttgaatggatgggttggatcaagcctcttgggggtgtcgctgattat
gcaccccaacatcggggcaggatctcactgacgagggacatttacactgaaaccgtcttt
atagacctgagtcgactgacgtctggcgacacggcgatttatttttgttgtaaggccgcc
gcccctgatgaagcattcccccttgaatactggggccaggggacccaacttatcgtctcc
ccggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 139
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcctgcctttatgccaatgtagatatctgctggtatcaaatacagccgggcagattaccc
aaacttctgattgttgacaatgataggcgaccctcaggagtctctcctcgcttctctggc
tccaagtctggcaccacggcctccctgacaatctctggacttcaggctgacgacgaggct
gaatatcactgctcttcaacaacattttttggcggggggaccaagttgaccgtcctcagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct
SEQ ID NO: 140 Sequence N49P67
caggtgcgacttgtgcagtctggtcccgtgatgagaaagcctggggcctcagtgagaatt 33
tcttgcgagacatctggattcgccttcttggaccacattgtccactgggtgcggcgggcc
cctggacgcggctttgaatggatgggttgggttaagaccattgggggtgtcgttgattat
gcaccccaccttaggggcaggatctccgtgacgagagacgtctttagtgaaaccgtcttt
ctggacttgagtcgactgacgtctggcgacacggcgatgtatttttgttctaaggccgcc
gcccctgacgaagccttcccccttgaattttggggccaggggacccaagtcatcgtctcc
tcggcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtg
tcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
tcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccag
acctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgag
cccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggg
ggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacc
cctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaac
tggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtac
aacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatc
tccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggat
gagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgac
atcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctccc
gtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcagg
tggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactac
acgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 141
------------------------------------------------------------
caggctgccctgactcagcccgcctccgtgtccggctctcctggacagtcggtcaccatt
tcttgcctttatgccaatgtggatatctgctggtatcaacttcacccgggcagagccccc
aaacttctaattcttgacaataataaacggccctcaggagtctctagtcgcttctccggt
tccaagtctggcaccacggcctccctaaccatctctgaccttcaggctgacgacgaggct
gaatatcactgctcttcaacaactttttttggcggggggaccaggttgaccgtcctgagt
cagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagcc
aacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcc
tggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaa
agcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcc
cacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcc
cctgcagaatgctct SEQ ID NO: 142 Sequence N49P68
cacgtgcagttgaggcagtctgggactgaggcgaagaagtctggggcctcggtgacaatc 34
tcttgtgagaccgctggattcaacttcatcgactccgtcatacactggctgcgccaggcc
cctggtgggggatttcagtggatggggtggatcaagcctcttagaggtggcgtcaattat
ccacattatttgcagggcagaatctccatgacccgggacttgtccagtgacacggtttac
atggtcttaaatagactgacacctgccgacacaggcctttattactgcgcgaaaggggcc
tttggggggagttctccctttggcttctggggccagggaactctgctcaccgtctcccca
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 143
------------------------------------------------------------
cagtctgccctgtctcagcctgtctccgtgtctgggtctcctggagagtcgatcaccatt
tcctgtactgaagccaccacctggtatcaacaactcccaggcaaaccccccaaactcatc
atttatgacgtgaccaaccggccctcaggcatttcaagtcgtttctctggctccatgtct
ggtcgcacggcctccctgacaatctccggtctccaggttgacgacgagggtctctatcac
tgtgcctcacgtgaatttttcggcggggggaccaagctgaccgtcctgagtcagcccaag
gctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaaggcc
acactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaaggca
gatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaacaac
aagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacagaagc
tacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgcagaa tgctct
SEQ ID NO: 144 Sequence N49P69
cacgtgcaattgatgcagtctgggactcaggcgaagaagtctggggcctcggtgacaatt 35
tcttgtgagaccgctggattcaagttcatcgactccgtcatacactggctgcgccaggcc
cctggagggggatttcagtggatggggtggatcaagcctcttggaggtgccgtcaactat
ccaccctatttgcagggcaggatctccttgacccgtgacttgtccaccgacacaatttac
atggtcttgaatggactgacacctgccgacacaggcttttattactgcgccaaaggggcc
tttggggggggttctccctttggcttctggggccaggggactctgctcaccgtctcccca
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 145
------------------------------------------------------------
cagtctgccctgtctcagcctgtctccgtgtctgggtctcctggagactcgatcaccatt
tcttgttttggagccaccacctggtatcaacaactcccaggcagaccccccaaactcatc
atttatgacgtgactaaccggccctcaggcatttcaggtcgtttctctggctccatgtct
ggtcaaaaggcctccctgacaatctccggtctccaggttgacgacgagggtctctatcac
tgcgcctcacgtgaatttttcggcggggggaccaaactgaccgtcctgagtcagcccaag
gctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaaggcc
acactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaaggca
gatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaacaac
aagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacagaagc
tacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgcagaa tgctct
SEQ ID NO: 146 Sequence N49P70
cacgtgcagttgaggcagtctgggactgaggcgaagaagtctggggcctcggtgacaatc 36
tcttgtgagaccgctggattcaacttcatcgactccgtcatacactggctgcgccaggcc
cctggtgggggatttcagtggatggggtggatcaagcctcttagaggtggcgtcaattat
ccacattatttgcagggcagaatctccatgacccgggacttgtccagtgacacggtttac
atggtcttaaatagactgacacctgacgacacaggcctttactactgcgcgaaaggggcc
tttggggggagttctccctttggcttctggggccagggaactctgctcaccgtctcccca
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 147
------------------------------------------------------------
cagtctgccctgtctcagcctgtctccgtgtctgggtctcctggagagtcgatcaccatt
tcctgtactgaagccaccacctggtatcaacaactcccagggagatcccccaaactcatt
atttatgacgtgaccaaccggccctcaggcatttcaagtcgtttctctggctccatgtct
ggtcgcacggcctccctgacaatctccggtctccaggttgacgacgagggtctctatcac
tgtgcctcacgtgaatttttcggcggggggaccaagctgaccgtcctcagtcagcccaag
gctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaaggcc
acactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaaggca
gatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaacaac
aagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacagaagc
tacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgcagaa tgctct
SEQ ID NO: 148 Sequence N49P71
cgtgttacattacaacagtctggggctacagtgaggcagcctggggcctcagtcaccgtc 37
tcctgcgagacttctggattcaccttcatcaaatataccattcactgggtgcgacaggcc
cctggacagggtcttcagtgggtgggaagaatacacccccgaaccggtgccgtgaagttt
gcaccgatatttcagggtaaattttccatgagtcgagacttgtcacgcgacacagcctac
ctcggattgaccagactgacactcgccgacacggctctatttttctgtgcgaggggggcc
tttgaggcagatttatatgggccaacttacccctttcaccactggggccaaggaacccaa
gtcaccgtctccgcggcctccaccaagggcccatcggtcttccccctggcaccctcctcc
aagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaa
ccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggct
gtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagc
ttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggac
aagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacct
gaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatg
atctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgag
gtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgg
gaggagcagtacaacagcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggac
tggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatc
gagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc
ccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttc
tatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
accacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtg
gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctg
cacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 149
------------------------------------------------------------
tcctgggccctgactcaacccgcctccgtgtctgcgtctcctgggcagtcggtcaccatg
tcctgcactggattcggaagttataatcctgactcctggtaccagcaatacccaggcaaa
gcccccaaactcatcatttatgatgacaataaaagaccctcgggggtctctgatcgcttc
tctgcctccagacttggcagcacatcttcactgacaatctctaacgtccaggccgctgac
gacgcccattatgtctgcgcctcctttgagtttttcggcggggggaccaagctgaccgtc
ctgagtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagctt
caagccaacaaggccacactggtgtgtctcgtaagtgacttctacccgggagccgtgaca
gtggcctggaaggcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctcc
aaacaaagcaacaacaagtatgcggccagcagctacctgagcctgacgcccgagcagtgg
aagtcccacagaagctacagctgccgggtcacgcatgaagggagcaccgtggagaagaca
gtggcccctgcagaatgctct SEQ ID NO: 150 Sequence N49P72
cacattcagttgctacagtcggggcctcaagttaagaagtctggggacacagtgagaatc 38
tcctgtgagacctctggatataatttcgtcgactcccttatccactgggtccgacagacc
ccggaaaaacgtctcagatggatgggctggatcaatcctctccaaggtggtgtgaattac
gcgccggaatttcagggcagaatcaggatgaccagggacacgtttatagacacagtttac
gtggacttgagcggactgacaccggccgacacggcctattattactgcgcgcgagggatc
gatggcaattcttacccctttcatttctggggccacggaacccgggtcaccgtcttctcg
gcctccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcg
tggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctca
ggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc
tacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagccc
aaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgggggga
ccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccct
gaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactgg
tacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaac
agcacgtaccgggtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaag
gagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcc
aaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgag
ctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatc
gccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtg
ctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtgg
cagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacg
cagaagagcctctccctgtctccgggtaaa SEQ ID NO: 151
------------------------------------------------------------
cgatttgccctgactcaacctgcctccgtgtctgggtctcctggacagacgatcaccata
acctgcgctggaggcagcgtctcctggttccatttccctccaggcaaaacccccagactc
attatttatgagtcttctaagagaccctcaggggtctctcctcgattctctgggtcccag
tctggcagcacggcctccctaataatttctggcctccagtctgatgacgaagggacatac
ttctgttctattcttgaatttttcggcagagggactcttctcaccgtcctgagtcagccc
aaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaag
gccacactggtgtgtctcgtaagtgacttctacccgggagccgtgacagtggcctggaag
gcagatggcagccccgtcaaggtgggagtggagaccaccaaaccctccaaacaaagcaac
aacaagtatgcggccagcagctacctgagcctgacgcccgagcagtggaagtcccacaga
agctacagctgccgggtcacgcatgaagggagcaccgtggagaagacagtggcccctgca
gaatgctct SEQ ID NO: 152
TABLE-US-00004 TABLE 4 List of mAb variants and the corresponding
sequence and mutations. The amino acid sequence of the variants is
determined based on the reference antibody sequence (see table 2,
above for reference antibody sequences) and the mutations described
in the table. See below amino acid sequences and corresponding
oligonucleotide sequences. Related to Heavy chain Light chain mAb
sequence mutation mutations Swaps N49P6 1 CH1: 1.4A, 120R Constant:
1.5G LC7 swap CH3: 12 E, 14M N49P6.2 1 CH1: 120R CH3: 12 E, 14M
N49P7 2 CH1: 1.4A, 120R Constant: 1.5G CH3: 12 E, 14M N49P7.1 2
CH1: 120R CH3: 12 E, 14M N49P7A 2 CH1: 1.4A, 120R Variable: 42A
CH3: 12 E, 14M Constant: 1.5G N49P7F 2 CH1: 1.4A, 120R Variable:
42F CH3: 12 E, 14M Constant: 1.5G N49P7S 2 CH1: 1.4A, 120R
Variable: 42S CH3: 12 E, 14M Constant: 1.5G N49P7Y 2 CH1: 1.4A,
120R Variable: 42Y CH3: 12 E, 14M Constant: 1.5G N49P7-54TY 2
Variable: 59T/62Y Constant: 1.5G CH1: 1.4A, 120R CH3: 12 E, 14M
N49P7LS-1 2 CH1: 1.4A, 120R Constant: 1.5G CH3: 12 E, 14M, 107L,
114S N49P7LS-2 2 CH1: 1.4A, 120R Constant: 1.5G CH3: 107L, 114S
N49P7YTE 2 CH1: 1.4A, 120R Constant: 1.5G CH2: 15.1Y, 16T, 18E
N49P7L6 2.1 CH1: 1.4A, 120R Constant: 1.5G N49P7 heavy chain CH3:
12 E, 14M with N49P6 light chain N49P7L11 2.4 CH1: 1.4A, 120R N49P7
heavy chain CH3: 12 E, 14M with N49P11 light chain N49P7.1L9 2.18
CH1: 120R N49P7.1 heavy CH3: 12 E, 14M chain with N49P9 light chain
N49P7.1L19 2.7 CH1: 120R N49P7 heavy chain CH3: 12 E, 14M with
N49P19 light chain R49P7 2 CH1: 1.4A Constant: 1.5G Rhesus IgG1,
Rhesus LC3 N49P7.2 3 CH1: 120R CH3: 12 E, 14M N49P11 4 CH1: 120R
CH3: 12 E, 14M N49P18 5 CH1: 120R CH3: 12 E, 14M N49P18.2 5 CH1:
120R LC7 swap CH3: 12 E, 14M N49P18.1 6 CH1: 120R CH3: 12 E, 14M
N49P19 7 CH1: 120R CH3: 12 E, 14M N49P37 8 CH1: 1.4A, 120R
Constant: 1.5G CH3: 12 E, 14M N49P38 9 CH1: 120R Constant: 1.5G
CH3: 12 E, 14M N4938.1 9 CH1: 120R CH3: 12 E, 14M N49P55 10 CH1:
120R CH3: 12 E, 14M N49P56 11 CH1: 120R CH3: 12 E, 14M N49P57 12
CH1: 120R CH3: 12 E, 14M N49P58 13 CH1: 120R CH3: 12 E, 14M N49P59
14 CH1: 120R CH3: 12 E, 14M N49P73 15 CH1: 120R CH3: 12 E, 14M
N49P74 16 CH1: 120R CH3: 12 E, 14M N49P75 17 CH1: 120R CH3: 12 E,
14M N49P75.1 17 CH1: 1.4A, 120R Constant: 1.5G CH3: 12 E, 14M N49P9
18 CH1: 120R CH3: 12 E, 14M N49P9.1 18 CH1: 120R LC2 swap CH3: 12
E, 14M N49P9.2 18 CH1: 1.4A, 120R Constant: 1.5G CH3: 12 E, 14M
N49P9i7 18.2 CH1: 120R Part of CDRH3 of CH3: 12 E, 14M N49P7
swapped for entire CDRH3 of N49P9 N49P9i7H1 18.2 CH1: 120R CDRH3 of
N49P7 CH3: 12 E, 14M swapped for CDRH3 of N49P9 N49P9i7H2 18.2 CH1:
1.4S, 120R Constant: 1.5R CDRH3 and junction CH3: 12 E, 14M of
N49P7 swapped for CDRH3 of N49P9 N49P22 19 CH1: 120R CH3: 12 E, 14M
N49P23 20 CH1: 120R CH3: 12 E, 14M N49P9.3 21 CH1: 120R Constant:
1.5R CH3: 12 E, 14M N49P9.4 21 CH1: 120R CH3: 12 E, 14M N49P51 22
CH1: 120R CH3: 12 E, 14M N49P52 23 CH1: 120R CH3: 12 E, 14M N49P53
24 CH1: 120R CH3: 12 E, 14M N49P54 25 CH1: 120R CH3: 12 E, 14M
N49P60 26 CH1: 120R CH3: 12 E, 14M N49P61 27 CH1: 120R CH3: 12 E,
14M N49P62 28 CH1: 120R CH3: 12 E, 14M N49P63 29 CH1: 120R CH3: 12
E, 14M N49P64 30 CH1: 120R CH3: 12 E, 14M N49P65 31 CH1: 120R CH3:
12 E, 14M N49P66 32 CH1: 120R CH3: 12 E, 14M N49P67 33 CH1: 120R
CH3: 12 E, 14M N49P68 34 CH1: 120R CH3: 12 E, 14M N49P69 35 CH1:
120R CH3: 12 E, 14M
[0648] Amino acid and nucleotide sequences of additional anti-HIV
antibodies are shown below. Variable regions within the heavy and
light chain in the amino acid sequence are shaded and changes to
the amino acid sequence relative to a natural antibody sequence are
underlined. CDR residues are in bold.
TABLE-US-00005 >N49P6 HEAVY CHAIN SEQ ID NO: 153 ##STR00153##
##STR00154## ##STR00155##
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGK SEQ ID NO: 154
GCGGGACTGATGCAGTCTGGGGCTGTGATGAAGAATTCGGGGGCCTCAGTGAGGGTCTCTTGT
CAGGCTGATGGATACGACTTCATTGACTATGTCATTCACTGGTTTCGACAAAGACGTGGAGAA
GGTCTTGAGTGGCTGGGATGGATGAATCCCTCGGGAGGCGGCACAAACTATCCGCGACCATTT
CAGGGCAAAGTCACCATGACCAGGGACACGTCCACCGAGACAGCCTATTTAGATGTCAGAGG
ACTTACATATGACGACACGGCCGTCTATTATTGTGTGAGAGACAGGGCCAACGGTTCGGGAA
GAAGACGTTTTGAGTCGGTGAATTGGTTCCTGGATCTGTGGGGCCGCGGCACCCAAATAACAG
TCGTCTCGGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC
TGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC
GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG
ACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACAT
CTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTT
GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCT
TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCG
TGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG
GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGG
TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT
CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC
AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT
ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
ATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 155 ##STR00156## ##STR00157##
YPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVE
KTVAPAECS SEQ ID NO: 156
CAGTCTGCCCTAACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGTCAGTCAGTCACCATCTCCT
GCACTGGAACACACAATTATGTGTCCTGGTGTCAACAGAAACCGGGCCAAGCCCCCAAATTAT
TAATTTACGATTTCAATAAACGGCCCTCAGGGGTCTCTGATCGCTTCTCTGGCTCCACGTCTGG
CAACACGGCCTCCCTGACCATCTCTGGACTCCAGGCTGACGATGAGGGTCATTATTTTTGTTG
GGCGTTTGAAAATATCGGCGGAGGGACCAAGCTGACCGTCCTGGGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCC
GTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAG
CAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCA
CGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P6.2
HEAVY CHAIN SEQ ID NO: 157 ##STR00158## ##STR00159## ##STR00160##
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGK SEQ ID NO: 158
GCGGGACTGATGCAGTCTGGGGCTGTGATGAAGAATTCGGGGGCCTCAGTGAGGGTCTCTTGT
CAGGCTGATGGATACGACTTCATTGACTATGTCATTCACTGGTTTCGACAAAGACGTGGAGAA
GGTCTTGAGTGGCTGGGATGGATGAATCCCTCGGGAGGCGGCACAAACTATCCGCGACCATTT
CAGGGCAAAGTCACCATGACCAGGGACACGTCCACCGAGACAGCCTATTTAGATGTCAGAGG
ACTTACATATGACGACACGGCCGTCTATTATTGTGTGAGAGACAGGGCCAACGGTTCGGGAA
GAAGACGTTTTGAGTCGGTGAATTGGTTCCTGGATCTGTGGGGCCGCGGCACCCAAATAACAG
TCGTCTCGGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC
TGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC
GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG
ACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACAT
CTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTT
GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCT
TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCG
TGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG
GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGG
TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT
CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC
AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT
ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
ATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 159 ##STR00161## ##STR00162##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 160
CAGTCTGCCCTAACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGTCAGTCAGTCACCATCTCCT
GCACTGGAACACACAATTATGTGTCCTGGTGTCAACAGAAACCGGGCCAAGCCCCCAAATTAT
TAATTTACGATTTCAATAAACGGCCCTCAGGGGTCTCTGATCGCTTCTCTGGCTCCACGTCTGG
CAACACGGCCTCCCTGACCATCTCTGGACTCCAGGCTGACGATGAGGGTCATTATTTTTGTTG
GGCGTTTGAAAATATCGGCGGAGGGACCAAGCTGACCGTCCTGGGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7 HEAVY
CHAIN SEQ ID NO: 161 ##STR00163## ##STR00164##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 162
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 163 ##STR00165## ##STR00166##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 164
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7.1 HEAVY
CHAIN SEQ ID NO: 165 ##STR00167## ##STR00168##
SSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 166
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCATCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 167 ##STR00169## ##STR00170##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 168
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7A HEAVY
CHAIN SEQ ID NO: 169 ##STR00171## ##STR00172##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 170
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 171 ##STR00173## ##STR00174##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 172
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGGCTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7F HEAVY
CHAIN SEQ ID NO: 173 ##STR00175## ##STR00176##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 174
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 175 ##STR00177## ##STR00178##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 176
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTTTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7S HEAVY
CHAIN SEQ ID NO: 177 ##STR00179## ##STR00180##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 178
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 179 ##STR00181## ##STR00182##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 180
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTCTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7Y HEAVY
CHAIN SEQ ID NO: 181 ##STR00183## ##STR00184##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 182
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGT GTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 183 ##STR00185## ##STR00186##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 184
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTATCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7-54TY
HEAVY CHAIN SEQ ID NO: 185 ##STR00187## ##STR00188##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 186
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAACGTACGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 187 ##STR00189## ##STR00190##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 188
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7LS-1
HEAVY CHAIN SEQ ID NO: 189 ##STR00191## ##STR00192##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSP
GK SEQ ID NO: 190
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCT
GCATGAGGCTCTGCACAGCCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 191 ##STR00193## ##STR00194##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 192
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7LS-2
HEAVY CHAIN SEQ ID NO: 193 ##STR00195## ##STR00196##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSP
GK SEQ ID NO: 194
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGCT
GCATGAGGCTCTGCACAGCCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 195 ##STR00197## ##STR00198##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 196
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7YTE
HEAVY CHAIN SEQ ID NO: 197 ##STR00199## ##STR00200##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
YITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 198
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCTATATCACCCGGGAGCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 199 ##STR00201## ##STR00202##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 200
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7L6 HEAVY
CHAIN SEQ ID NO: 201 ##STR00203## ##STR00204##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 202
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 203 ##STR00205## ##STR00206##
YPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVE
KTVAPAECS SEQ ID NO: 204
CAGTCTGCCCTAACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGTCAGTCAGTCACCATCTCCT
GCACTGGAACACACAATTATGTGTCCTGGTGTCAACAGAAACCGGGCCAAGCCCCCAAATTAT
TAATTTACGATTTCAATAAACGGCCCTCAGGGGTCTCTGATCGCTTCTCTGGCTCCACGTCTGG
CAACACGGCCTCCCTGACCATCTCTGGACTCCAGGCTGACGATGAGGGTCATTATTTTTGTTG
GGCGTTTGAAAATATCGGCGGAGGGACCAAGCTGACCGTCCTGGGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCC
GTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAG
CAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCA
CGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P7L11
HEAVY CHAIN SEQ ID NO: 205 ##STR00207## ##STR00208##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK
SEQ ID NO: 206
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 207 ##STR00209## ##STR00210##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 208
CAGTGTGTCTTGACTCAGCCTCGCTCAGTGTCCGGATCTCCTGGACAATCAGTCACCATCTCCT
GCACTGGAACTCACAATTATGTCTCCTGGTGTCAACACCACCCAGGCAACGCCCCCAAATTAT
TACTTTATGATTTCGACAAGCGGCCCTCAGGAATCTCTGATCGCTTCTCTGGCTCTAGGTCTGG
CAACACGGCCTCCCTGACCATCTCTGGCCTCCAGCCTGAGGATGAGGCCGATTACTTTTGTTG
GGCCTTTGAAGCCTTTGGCGGAGGGACCAAGGTGCTCGTCCTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P7.1L9
HEAVY CHAIN SEQ ID NO: 209 ##STR00211## ##STR00212##
SSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 210
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCATCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 211 ##STR00213## ##STR00214##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 212
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P7.1L19
HEAVY CHAIN SEQ ID NO: 213 ##STR00215## ##STR00216##
SSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 214
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCATCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 215 ##STR00217## ##STR00218##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 216
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAACTCCTGGACAGTCAGTCACCATCTCCT
GCACTGGAACCCACAATTATGTCTCTTGGTGTCAACAACATCCAGGCAGAGCCCCCAAATTAC
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCGGATCGCTTCTCTGGCTCCGGATCTG
GCGGCACGGCCTCCCTAACCATCACTGGACTCCAGGATGACGATGAAGCGGACTATTTTTGTT
GGGCCTATGATGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTGCGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >R49P7 HEAVY
CHAIN SEQ ID NO: 217 ##STR00219## ##STR00220##
ASTKGPSVFPLAPSSRSTSESTAALGCLVKDYFPEPVTVSWNSGSLTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYVCNVNHKPSNTKVDKRVEIKTCGGGSKPPTCPPCPAPELLGGPSVFLFPPKPK
DTLMISRTPEVTCVVVDVSQEDPDVKFNWYVNGAEVHHAQTKPRETQYNSTYRVVSVLTVTHQD
WLNGKEYTCKVSNKALPAPIQKTISKDKGQPREPQVYTLPPSREELTKNQVSLTCLVKGFYPSDIV
VEWESSGQPENTYKTTPPVLDSDGSYFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSL
SPGK SEQ ID NO: 218
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATATAGATTTCCTGACTACATCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCCTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAATATTCCATGGAAATT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCACAATTC
AATCAGCCTCGACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTCCTCCAGGAGCACCTCCG
AGAGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCTGAACCCGTGACCGTGTCGT
GGAACTCAGGCTCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGGC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACGTCT
GCAACGTAAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGATAAAAACATG
TGGTGGTGGCAGCAAACCTCCCACGTGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC
GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGT
CACATGCGTGGTGGTAGACGTGAGCCAGGAAGACCCCGATGTCAAGTTCAACTGGTACGTAA
ATGGCGCGGAGGTGCATCATGCCCAGACGAAGCCACGGGAGACGCAGTACAACAGCACATAT
CGTGTGGTCAGCGTCCTCACCGTCACGCACCAGGACTGGCTGAACGGCAAGGAGTACACGTG
CAAGGTCTCCAACAAAGCCCTCCCGGCCCCCATCCAGAAAACCATCTCCAAAGACAAAGGGC
AGCCCCGAGAGCCTCAGGTGTACACCCTGCCCCCGTCCCGGGAGGAGCTGACCAAGAACCAG
GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGTGACATCGTCGTGGAGTGGGAGAGC
AGCGGGCAGCCGGAGAACACCTACAAGACCACCCCGCCCGTGCTGGACTCCGACGGCTCCTA
CTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATG
CTCCGTGCTGCATGAGGCTCTGCACAGCCACTACACGCAGAAGAGCCTCTCCCTGTCCCCGGG
TAAA LIGHT CHAIN SEQ ID NO: 219 ##STR00221## ##STR00222##
YPGAVEVAWKADGSAVNAGVETTKPSKQSNNKYAASSYLSLTSDQWKSHKSYSCQVTHEGSTV
EKTVAPAECS SEQ ID NO: 220
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCAGCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTTCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCGAGCGAGGAGCTTCAAGCCAACAAGGCCACACTAGTGTG
TCTGATCAGTGACTTCTACCCGGGAGCCGTGGAAGTGGCCTGGAAGGCAGATGGCAGCGCTG
TCAACGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGC
AGCTACCTGAGCCTGACGTCCGACCAGTGGAAGTCCCACAAGAGCTACAGCTGCCAGGTCAC
GCACGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGTTCA >N49P7.2 HEAVY
CHAIN SEQ ID NO: 221 ##STR00223## ##STR00224## ##STR00225##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 222
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATACAAATTTCCTGACTACATCATTCACTGGATTCGACGCGCCCCTGGACAA
GGCCTTGAGTGGATGGGGTGGATTAATCCAATGGGCGGACAAGTAAACATTCCATGGCAGTTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCCTCTATTATTGCGTGAGAGATCGAAGTAATGGATCGGGAA
GGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGCGGTCACTGTTC
ATTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 223 ##STR00226## ##STR00227##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 224
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCAGTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P11 HEAVY
CHAIN SEQ ID NO: 225 ##STR00228## ##STR00229## ##STR00230##
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGK SEQ ID NO: 226
TCGGCGGAATTGGTGCAATCTGGGGCTGTGGTGAAGAAGCCTGGGACCTCCGTGAAGGTCTCT
TGTCAGGCTTATGGATACACTTTTACCGACTACCTTATTCATTGGCTTCGACAGGCCCCTGGAC
AAGGACTTGAATGGATGGGATGGATGAATCCTGTTTATGGACAAGTAAATTATGCCCAAAACT
TTCAGGGCAGGGTCTCCATGACCAGGGACATTTACAGGGAAACAGCATTTCTAGAGGTGCGC
GACCTGAAGACTGACGACACAGGCACTTATTATTGTGTGAGAGACACAGGCGACGGTTCGCG
GAGACACTTTGACTCCATCAATTGGTTTCTCGATCTTTGGGGCCGCGGGACATGGATAAGGGT
CGCCCCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC
TGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC
GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG
ACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACAT
CTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTT
GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCT
TCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCG
TGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG
GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGG
TCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT
CCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCT
GACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGC
AGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT
ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
ATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 227 ##STR00231## ##STR00232##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 228
CAGTGTGTCTTGACTCAGCCTCGCTCAGTGTCCGGATCTCCTGGACAATCAGTCACCATCTCCT
GCACTGGAACTCACAATTATGTCTCCTGGTGTCAACACCACCCAGGCAACGCCCCCAAATTAT
TACTTTATGATTTCGACAAGCGGCCCTCAGGAATCTCTGATCGCTTCTCTGGCTCTAGGTCTGG
CAACACGGCCTCCCTGACCATCTCTGGCCTCCAGCCTGAGGATGAGGCCGATTACTTTTGTTG
GGCCTTTGAAGCCTTTGGCGGAGGGACCAAGGTGCTCGTCCTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P18 HEAVY
CHAIN SEQ ID NO: 229 ##STR00233## ##STR00234## ##STR00235##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 230
GCGGACTTGGTGCAGTCTGGGGCTGTGATGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCGAGGATACACATTCACTGACTACGTCATTCACTGGATTCGACGCGCCCCTGGACAA
GGCCTTGAATGGATGGGGTGGATTGATCCACCTTATGGACAAGTAAATATTCCATGGAATTTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
TCTAAAGTCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTAATGGATGGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTC
ACTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 231 ##STR00236## ##STR00237##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 232
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAGTTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTAACCATCAGTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACTGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P18.2
HEAVY CHAIN SEQ ID NO: 233 ##STR00238## ##STR00239## ##STR00240##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 234
GCGGACTTGGTGCAGTCTGGGGCTGTGATGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCGAGGATACACATTCACTGACTACGTCATTCACTGGATTCGACGCGCCCCTGGACAA
GGCCTTGAATGGATGGGGTGGATTGATCCACCTTATGGACAAGTAAATATTCCATGGAATTTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
TCTAAAGTCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTAATGGATGGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTC
ACTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 235 ##STR00241## ##STR00242##
FYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTV
EKTVAPAECS SEQ ID NO: 236
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAGTTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTAACCATCAGTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACTGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P18.1
HEAVY CHAIN SEQ ID NO: 237 ##STR00243## ##STR00244## ##STR00245##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 238
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCAAGGATACACATTCACTGACTACGTCATTCACTGGATTCGACGCGCCCCTGGACAA
GGCCTTGAATGGATGGGGTGGATTAATCCAGGTTATGGACAAGTAAATATTCCATGGAACTTT
CAGGGCAGGGTCTCCATGACCCGAGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
TCTAAAGTCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTAATGGATGGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTC
ACTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 239 ##STR00246## ##STR00247##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 240
CAGTCTGCCCTGACTCAGCCTCGCTCAATGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCAGTGGACTCCAGGATGACGATGACGCCGAATACATTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P19 HEAVY
CHAIN SEQ ID NO: 241 ##STR00248## ##STR00249##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 242
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAAAATGCTGGGGCCTCAGTGAGGGTCTCCTGT
GAGGCTTATGGATACACATTCGTGGACTACTTCATTCATTGGGTCCGACAGGCCCCTGGACAA
GGCTTTGAATGGATGGGATACATGGATCCCTTGAACGGGCGCCCAAACATTGCGCGAAAATTT
CAGGGCAGGCTCTCCCTGAGTCGAGATAGGTCCAGCGAAACTTCATTTCTGGACTTAAGTGGA
CTGAGGTCTGACGACTCGGCCGTCTATTATTGTGTGAGAGACAAGAGTAATGGATCGGGCAG
ACGGTTTGACTCGTCTAATTGGTTTCTCGATCTGTGGGGCCGTGGAACCCGGGTCAGTATTTTC
TCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 243 ##STR00250## ##STR00251##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 244
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAACTCCTGGACAGTCAGTCACCATCTCCT
GCACTGGAACCCACAATTATGTCTCTTGGTGTCAACAACATCCAGGCAGAGCCCCCAAATTAC
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCGGATCGCTTCTCTGGCTCCGGATCTG
GCGGCACGGCCTCCCTAACCATCACTGGACTCCAGGATGACGATGAAGCGGACTATTTTTGTT
GGGCCTATGATGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTGCGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P37
HEAVY CHAIN SEQ ID NO: 245 ##STR00252## ##STR00253## ##STR00254##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 246
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGGTCTCCTGT
GAGGCTTATGGATACACATTCAGTGACTACATCATTCATTGGATTCGACGGGCCCCTGGACGA
GGCCTTGAATGGATGGGATGGATGAATCCGATGGGCGGACAAGTGAATATTCCGTGGAACTT
TCAGGGGAGAGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAG
GACTGAGGTCTGACGACACGGCCGTCTATTACTGTGTGAGAGATCGCAGCAATGGATCGGGC
AAGCGATTTGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGGACCGCGGTCACTATT
TCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 247 ##STR00255## ##STR00256##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 248
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAGCTCCTGGACAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTTTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAGTTAT
TAATTTATGACTTCAATAAGAGACCCTCAGGTGTCCCTGATCGTTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTAACCATCACTGGACTCCAGGATGACGATGAGGCTGAATATTTTTGTTG
GGCGTATGAAGTTTTTGGCGGAGGGACCAAGTTGACCGTGCTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P38 HEAVY
CHAIN SEQ ID NO: 249 ##STR00257## ##STR00258##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 250
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGACGCCTGGGGCCTCAGTGAGGGTCTCCTGT
GAGGCTTATGGATACACATTCATTGACTACATCATTCATTGGGTCCGACAGGCCCCTGGACAA
GGTTTTGAATGGCTGGGATACATTGATCCTATGAACGGGCGCCCAAACATTGCGCGAAAATTT
CAGGGCAGGCTCTCCCTGAGCCGGGATACGTCCATCGAAACATCATTTCTGGACTTAAGTGGA
CTGAGGTCTGACGACTCGGCCGTCTATTATTGTGTGAGAGACAAGAGTAATGGATCGGGCAA
ACGATTTGACTCCTCTAATTGGTTTCTCGATCTGTGGGGCCGTGGAACGCGGGTCAGCATTTCT
TCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 251 ##STR00259## ##STR00260##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 252
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAGCTCCTGGACAGTCAGTCACCATCTCCT
GCACTGGAACCCACAATTATGTCTCTTGGTGTCAACAACATCCAGGCAGAGCCCCCAAATTAC
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCGGATCGCTTCTCTGGCTCCGGATCTG
GCGGCACGGCCTCCCTAACCATCACTAGACTCCAGGATGACGATGACGCTGACTATTTTTGTT
GGGCGTATGATGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTGGGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P38.1
HEAVY CHAIN SEQ ID NO: 253 ##STR00261## ##STR00262##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 254
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGACGCCTGGGGCCTCAGTGAGGGTCTCCTGT
GAGGCTTATGGATACACATTCATTGACTACATCATTCATTGGGTCCGACAGGCCCCTGGACAA
GGTTTTGAATGGCTGGGATACATTGATCCTATGAACGGGCGCCCAAACATTGCGCGAAAATTT
CAGGGCAGGCTCTCCCTGAGCCGGGATACGTCCATCGAAACATCATTTCTGGACTTAAGTGGA
CTGAGGTCTGACGACTCGGCCGTCTATTATTGTGTGAGAGACAAGAGTAATGGATCGGGCAA
ACGATTTGACTCCTCTAATTGGTTTCTCGATCTGTGGGGCCGTGGAACGCGGGTCAGCATTTCT
TCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 255 ##STR00263## ##STR00264##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 256
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAGCTCCTGGACAGTCAGTCACCATCTCCT
GCACTGGAACCCACAATTATGTCTCTTGGTGTCAACAACATCCAGGCAGAGCCCCCAAATTAC
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCGGATCGCTTCTCTGGCTCCGGATCTG
GCGGCACGGCCTCCCTAACCATCACTAGACTCCAGGATGACGATGACGCTGACTATTTTTGTT
GGGCGTATGATGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTGCGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P55
HEAVY CHAIN SEQ ID NO: 257 ##STR00265## ##STR00266##
PSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 258
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTCCTGT
GAGGCTTATGGATACACATTCACTGACTACATCATTCATTGGATTCGACAGGCCCCTGGACAA
GGCCTTGAATGGATGGGATGGATGAATCCTATGGGCGGGCGCACAAATATTCCGTGGAAATTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGTGG
ACTAACGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGACAAGAGTAATGGATCGGGCA
AACGATTTGACTCCTCTAATTGGTTCCTCGATCTGTGGGGCCGCGGAACCCCGGTCACTATTTC
CTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG
GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG
GAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT
CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG
CAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG
ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC
TCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG
TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAG
CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCA
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAA
CCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGAC
CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC
CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACA
GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG
CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 259 ##STR00267## ##STR00268##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 260
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAGCTCCTGGACAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACAACACCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTAAGTATCACTGGACTCCAGGATGACGATGAAGCTGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P56 HEAVY
CHAIN SEQ ID NO: 261 ##STR00269## ##STR00270##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 262
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGCCTCAGTGCGGGTCTCCTGT
GAGGCTTATGGATATACATTCGTTGACTACCTCATTCATTGGGTCCGACAGGCCCCCGGACAA
GGTTTTGAATGGATGGGATACATGGATCCTATGAACGGGCGCCCAAATATTGCGCGAAAATTT
CAGGGCAGGCTCTCCCTGAGCCGAGATACGTCCATCGAAACATCATTTCTGGACTTAAGTGGA
CTGAGGTCTGACGACTCGGCCGTCTATTATTGTGTGAGAGACAAGAGTGGTGGATCGGGCAA
ACTATTTGACTCCTCTAATTGGTTTCTCGATCTGTGGGGCCGTGGAACCCGGGTCAGCATTTCT
TCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 263 ##STR00271## ##STR00272##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 264
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCAGCTCCTGGACAGTCAGTCACCATCTCCT
GCACCGGAACTCACAATTATGTCTCTTGGTGTCAACAACATCCAGGCAGAGCCCCCAAATTAC
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCGGATCGCTTCTCTGGCTCCGGATCTG
GCGGCACGGCCTCCCTAACCATCACTGGACTCCAGGATGACGATGACGCTGATTATTTTTGTT
GGGCGTATGATGCTTTTGGCGGAGGGACCAAGTTGACCGTCCTGCGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P57
HEAVY CHAIN SEQ ID NO: 265 ##STR00273## ##STR00274## ##STR00275##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 266
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCAAGGATACACATTCACTGACTACGTCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCTTGAATGGATGGGGTGGATTAATCCAGGTTATGGACAAGTAAATATTCCATGGAACTTT
CAGGGCAGGGTCTCCATGACCCGAGACACGTCCATCGAAACAGCTTTTCTGGAGTTAAGAGGT
CTAAAGTCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTAATGGATGGGGAAA
GCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGATTACTGTTCAC
TCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 267 ##STR00276## ##STR00277##
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEK
TVAPTECS SEQ ID NO: 268
CAGTCTGCCCTGACTCAGCCTCGCTCAATGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATACATTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCATACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P58 HEAVY
CHAIN SEQ ID NO: 269 ##STR00278## ##STR00279##
##STR00280##
SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD
TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD
WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIA
VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS
LSPGK SEQ ID NO: 270
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCAGGGATATACATTCACCGACTACGTCATTCATTGGATTCGACGGGCCCCTGGACAA
GGCCTTGAATGGATGGGGTGGATGGATCCAAGTTATGGACAAGTCAATATTCCACGGAACTTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTTCAGGGAAACAGCATATCTGGAATTAAGAGG
TCTACAGTCTGACGACAAGGGCCTCTATTATTGTGTGAGAGATCGAAGTCACGGATCGGGAAG
GCAATTCGAGTCCTCCAACTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCAATGTTCA
GTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG
GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG
GAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT
CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG
CAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG
ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC
TCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG
TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAG
CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCA
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAA
CCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGAC
CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC
CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACA
GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG
CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 271 ##STR00281## ##STR00282##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 272
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCTCCCAAATTAT
TAATTTATGACTTCAATAAGAGGGCTTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATTAGTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P59 HEAVY
CHAIN SEQ ID NO: 273 ##STR00283## ##STR00284## ##STR00285##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 274
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCACTGAGAATCTCCTGT
GAGGCTCAAGGATACACATTCACTGACTACGTCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCTTGAATGGATGGGATGGATGGATCCAAGTTTTGGACAAATGAACATTCCACGGAACTTT
CAGGGCAGGGTCTCCATGACCCGTGACATGTACATCGAAACAGCATTTCTGGACTTAAGAGGT
CTAAAGTCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTCATGGATCGGGAAG
GCTATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTCAG
TCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 275 ##STR00286## ##STR00287##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 276
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCTCCCAAATTAT
TAATTTATGACTTCAATAAGAGGGCTTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATTAGTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P73 HEAVY
CHAIN SEQ ID NO: 277 ##STR00288## ##STR00289## ##STR00290##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 278
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGAATCTCCTGT
GAGGCTCAAGGATACAGATTCACTGACTACGTCATTCATTGGATTCGACGGGCCCCTGGACAA
GGCCTTGAATGGATGGGGTTGATGGATCCAAGTTTTGGACGAATGAATATTCCACGGAAATTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATGGAAACAGCATTTCTGGACTTCAGAGG
TCTAAATTTTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTCATGGATCGGGAAG
ACTATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTCAG
TCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG
AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC
AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA
CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT
CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT
GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGG
TGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAA
CAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAAC
CACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCC
GGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG
CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC
ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 279 ##STR00291##
##STR00292##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 280
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCTCCCAAATTAT
TAATTTATGACTTCAATAAGAGGGCATCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTG
GCGGCACGGCCTCCCTGACCATCAGTGGACTCCAAGATGACGATGACGCCGAATATTTTTGTT
GGGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCC
CCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGT
GTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P74
HEAVY CHAIN SEQ ID NO: 281 ##STR00293## ##STR00294##
STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 282
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGAATTTCCTGT
GAGGCTCAAGGATACACATTCATTGACTACGTCATTCACTGGATTCGACGGGCCCCTGGACAA
GGCCTTGAATGGATGGGGTTGATGGATCCAACTTATGGACGAATGAATATTCCACGGAAGTTT
CAGGGCAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
TCTAAAATCTGACGACACGGGCCTCTATTATTGCGTGAGAGATCGAAGTCATGGATCGGGAAG
GCTATTCGAGTCCTCCAACTGGTTCCTGGATCTGTGGGGCCGCGGCACTGTGGTCACTGTTCA
GTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG
GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTG
GAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACT
CTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTG
CAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG
ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC
TCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGG
TGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAG
CGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCA
ACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAA
CCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGAC
CTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC
CGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACA
GCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG
CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 283 ##STR00295## ##STR00296##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 284
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGACCTCCCAAATTAT
TAATTTATGACTTCAATAAGAGGGCTTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCAGTGGACTCCAAGATGACGATGACGCCGAATATTTTTGTTG
GGCATATGAAGCTTTCGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P75 HEAVY
CHAIN SEQ ID NO: 285 ##STR00297## ##STR00298## ##STR00299##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 286
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATACAGATTTCTTGACTACATCATTCACTGGATTCGACGAGCCCCTGGACAA
GGCCTTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAACATTCCATGGAACTT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGGACTGCGGTCACTATTC
ATTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 287 ##STR00300## ##STR00301##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 288
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTACTTCGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P75.1
HEAVY CHAIN SEQ ID NO: 289 ##STR00302## ##STR00303## ##STR00304##
SVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDT
LMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW
LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV
EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
SPGK SEQ ID NO: 290
GCGGACTTGGTGCAGTCTGGGGCTGTGGTGAAGAAGCCTGGGGACTCAGTGAGGATCTCCTGT
GAGGCTCAAGGATACAGATTTCTTGACTACATCATTCACTGGATTCGACGAGCCCCTGGACAA
GGCCTTGAATGGATGGGATGGATGAATCCAATGGGCGGACAAGTAAACATTCCATGGAACTT
TCAGGGTAGGGTCTCCATGACCCGGGACACGTCCATCGAAACAGCATTTCTGGACTTAAGAGG
ACTAAAGTCTGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGATCGGGAA
AGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGCGGGACTGCGGTCACTATTC
ATTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG
GGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT
GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGAC
TCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT
GCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGT
GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCA
GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
AACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA
ACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGA
CCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG
CCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC
AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGAT
GCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT
CHAIN SEQ ID NO: 291 ##STR00305## ##STR00306##
YPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVE
KTVAPTECS SEQ ID NO: 292
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGCATCTCCTGGGCAGTCCGTCACCATTTCCT
GCACTGGAACCCACAATTTGGTCTCTTGGTGTCAACATCACCCAGGCAGAGCCCCCAAATTAT
TAATTTATGACTTCAATAAGAGGCCCTCAGGGGTCCCTGATCGCTTCTCTGGCTCCGGGTCTGG
CGGCACGGCCTCCCTGACCATCACTGGACTCCAGGATGACGATGACGCCGAATATTTTTGTTG
GGCGTATGAAGCTTTTGGCGGAGGGACCAAGTTGACCGTACTTGGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCCCGT
CAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGC
AGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P9 HEAVY
CHAIN SEQ ID NO: 293 ##STR00307## ##STR00308##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 294
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGCGAGGGGACCCTCTGGGGAAA
ATTATCCTTTTCACTATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCACCCTCCACCAAGGG
CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGG
CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC
CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT
GGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCC
CAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCC
CACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA
AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG
AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA
AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCA
CCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC
CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG
CCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGA
CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACA
AGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC
CACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 295
##STR00309## ##STR00310##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 296
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9.1
HEAVY CHAIN SEQ ID NO: 297 ##STR00311## ##STR00312##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 298
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGCGAGGGGACCCTCTGGGGAAA
ATTATCCTTTTCACTATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCACCCTCCACCAAGGG
CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGG
CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC
CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT
GGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCC
CAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCC
CACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA
AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG
AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA
AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCA
CCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC
CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG
CCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGA
CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACA
AGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC
CACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 299
##STR00313## ##STR00314##
AVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV
APTECS SEQ ID NO: 300
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCTTGGAAAGCAGATAGCAGCCC
CGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCA
GCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTC
ACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCA >N49P9.2
HEAVY CHAIN SEQ ID NO: 301 ##STR00315## ##STR00316##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 302
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGCGAGGGGACCCTCTGGGGAAA
ATTATCCTTTTCACTATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCATCCTCCACCAAGGG
CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGG
CTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC
CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT
GGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCC
CAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCC
CACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCA
AGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG
AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA
AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCA
CCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCC
CCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTG
CCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT
CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGA
CCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACA
AGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC
CACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 303
##STR00317## ##STR00318##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 304
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAGGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9i7
HEAVY CHAIN SEQ ID NO: 305 ##STR00319## ##STR00320##
PSTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 306
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGAT
CGGGAAAGCGATTCGAGTCCTCCAATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCACCCT
CCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG
CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG
GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCC
TCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGA
ATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACT
CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC
CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC
GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAA
TGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCA
CCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGT
GTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG
TCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC
AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTC
ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGC
TCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ
ID NO: 307 ##STR00321## ##STR00322##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 308
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9i7H1
HEAVY CHAIN SEQ ID NO: 309 ##STR00323## ##STR00324## ##STR00325##
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTV
LHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY
PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT
QKSLSLSPGK SEQ ID NO: 310
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGAT
CGGGAAAGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCAGGGTGTCCGAGTGG
TCGTCTCGTCACCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC
CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGT
GTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC
AGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTA
CATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAAT
CTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAG
TCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACAT
GCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC
GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGG
TGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC
CCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCA
GCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATG
GGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCC
TCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCC
GTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA
LIGHT CHAIN SEQ ID NO: 311 ##STR00326## ##STR00327##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 312
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9i7H2
HEAVY CHAIN SEQ ID NO: 313 ##STR00328## ##STR00329## ##STR00330##
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK
PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH
QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS
DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
SLSLSPGK SEQ ID NO: 314
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGACTGGATATAAATTCATGGACCAACTCATAAACTGGGTGCGGCAGGCCCCCG
GTCAGGGCCTTGAGTGGATGGGATGGATGAATCCAACATATGGACAAGTAAATTATTCATGG
AGATTTGAAGGAAGGGTCACCATGACCAGGGACATGGACACCGAGACGGCCTTCATGGAGTT
GAGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGTGAGAGATCGCAGTAATGGAT
CGGGAAAGCGATTCGAGTCCTCCAATTGGTTCCTCGATCTGTGGGGCCGTGGGACTGCGGTCA
CAATTCAATCATCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA
CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG
TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCT
CAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCT
ACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAA
TCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA
TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGG
CGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGG
GTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAA
GGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC
CCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTC
AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT
GGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
CTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTC
CGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA A
LIGHT CHAIN SEQ ID NO: 315 ##STR00331## ##STR00332##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 316
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACGTACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAGATTGACCGTCCTACGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P22
HEAVY CHAIN SEQ ID NO: 317 ##STR00333## ##STR00334##
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 318
CACATTCAGTTGCTACAGTCGGGGCCTCAAGTTAAGAAGTCTGGGGACACAGTGAGAATCTCC
TGTGAGACCTCTGGATATAACTTCGTCGACTCCCGTATCCACTGGGTCCGACAGACCCCGGAA
AAACGTCTCAGATGGATGGGCTGGATCAATCCTCTCCAAGGTGGTGTGAATTACGCGCCGGAA
TTTCAGGGCAGAATCAGGATGACCAGGGACACATTTATAGACACAGTTTACGTGGACCTGAG
CGGACTGACACCGGCCGACACGGCCTATTATTACTGCGCGCGAGGGATCGATGGCAAGTCTTA
CCCCTTTCATTTCTGGGGCCACGGAACCCGGGTCACCGTCTTCTCGGCCTCCACCAAGGGCCC
ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG
CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG
CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT
GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAG
CAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC
CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG
ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
CCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCA
GGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA
TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC
CCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA
TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 319
##STR00335## ##STR00336##
VAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPA
ECS SEQ ID NO: 320
CGATTTGCCCTGACTCAACCTGCCTCCGTGTCTGGGTCTCCTGGACAGACGATCACCATAACCT
GCGCTGGAGGCAGCGTCTCCTGGTTTCATTTCCCTCCAGGCAAAACCCCCAGACTCATTATTTA
TGAGTCTTCTAAGCGACCCTCTGGGGTCTCTCCTCGATTCTCTGGGTCCCAGTCTGGCAGCACG
GCCTCCCTTATAATTTCTGGCCTCCAGTCTGATGACGAAGGGACATACTTCTGTTCTATTCTTG
AATTTTTCGGCAGAGGGACTCTTGTCACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGTCA
CTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAA
GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTG
GGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCT
GAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAG
GGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P23 HEAVY CHAIN
SEQ ID NO: 321 ##STR00337## ##STR00338##
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWL
NGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE
WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO: 322
CAGGTGCGCTTGGTGCAGTCTGGGGCTGGGGCGAGGAAGACTGGGGCCTCAATGAAACTTTC
CTGCTCGACCTCTGGATACACCTTCACCACTCATCACGGCCACTTCATAAATTGGGTGCGACA
GGCCCGTGGACAAGGGCTTGAGTGGATGGGGTGGATGAATCCCATGACTGGGCAGATGAATA
TTGAGGGGAAATTTCAGGGCAGAGTCACCCTCACTCGAGACATATACAGTGACACGGCTTAC
ATGGAAATGACCAGACTGACAACTGGCGACACGGGCACTTATTACTGTGCGCGAGGCGATTT
CGGACAGAATTATCCCTTTCATTATTGGGGCCAGGGAAGCCTGGTCATCGTCTCCTCGGCCTC
CACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC
GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGG
CGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC
AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAAT
CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCA
CACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCC
AAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT
GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG
CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACC
GTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCT
CCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT
ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC
AAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAA
CTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCAC
CGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTC
TGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID
NO: 323 ##STR00339## ##STR00340##
YPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVE
KTVAPAECS SEQ ID NO: 324
CTGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGGCAGTCGGTCACCATCTCCT
GCTCTGGAACGAACCGTTACCTTGTCTCCTGGTATCAACAACACCCTGACAAAGCCCCCAAAC
TCATCATTTATGACGACAATAAGCGGCCCTCAGGAATTTCTGATCGCTTCTCAGCCTCCAGGC
CTGACGACACGGCCTCCCTGACAATCTCTGGACTCCAGACTGGGGACGAGGCTACTTATTGGT
GTGCCTCATATGAACGTTTTGGCGGCGGGACGAGGCTGACCGTCCTTAGTCAGCCCAAGGCTG
CCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGG
TGTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9.3
HEAVY CHAIN SEQ ID NO: 325 ##STR00341## ##STR00342##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 326
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGTCTGGATACAACTTCATGGACCAATTCATAAATTGGGTGCGACAGGCCCCCGG
TCAGGGCCTTGAGTGGATGGGATGGATGAACCCAATATATGGACAAGTAAATTATTCATGGA
GATTTCAAGGAAGGGTCACCATGACCAGGGACATGTACACCGACACGGCCTTCATGGAGTTG
AGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGCGAGGGGACCCTCTGGGGAAAA
TTATCCTTTTCACTATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCACCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 327
##STR00343## ##STR00344##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 328
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACATACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAAATTGACCGTCCTACGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P9.4
HEAVY CHAIN SEQ ID NO: 329 ##STR00345## ##STR00346##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 330
CACGTCCAATTGGTGCAGTCTGGAGGTGGGGTGAAGAAGATTGGGGCCGCTGTGAGGATCTC
CTGCGAGGTGTCTGGATACAACTTCATGGACCAATTCATAAATTGGGTGCGACAGGCCCCCGG
TCAGGGCCTTGAGTGGATGGGATGGATGAACCCAATATATGGACAAGTAAATTATTCATGGA
GATTTCAAGGAAGGGTCACCATGACCAGGGACATGTACACCGACACGGCCTTCATGGAGTTG
AGAGGACTGAGAGTGGACGACACGGCCGTCTATTATTGCGCGAGGGGACCCTCTGGGGAAAA
TTATCCTTTTCACTATTGGGGCCAGGGTGTCCGAGTGGTCGTCTCGTCACCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 331
##STR00347## ##STR00348##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 332
GCATCTGCCCTGACTCAGCCTGCCTCCATGTCTGCGTCCCCTGGACAGTCGGTAACCATCTCGT
GCTCTGGAACCAGACACATAATCTCTGCTTGGTTCCAACAATATCCAGGCAAACCACCCAAAC
TCATAATTTTTGACGACGATAAGCGTCCCTCTGGAGTTCCTAGTCGCTTCTCTGCCTCCAGGCC
TGGCGACACGGCCTCCCTGACAATCTCTAATGTTCAACCTGAGGACGAGGCGACATACATTTG
CAATACATATGAATTCTTTGGCGGAGGGACCAAATTGACCGTCCTAAGTCAGCCCAAGGCTGC
CCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGT
GTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCC
CCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCC
AGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGT
CACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P51
HEAVY CHAIN SEQ ID NO: 333 ##STR00349##
##STR00350##
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 334
CACATTCAGTTGCTACAGTCGGGGCCTCAAGTTAAGAAGTCTGGGGACACAGTGAGAATCTCC
TGTGAGACCTCTGGATATAACTTCGTCGACTCCCGTATCCACTGGGTCCGACAGACCCCGGAA
AAACGTCTCAGATGGATGGGCTGGATCAATCCTCTCCACGGTGGTGTGAATTACGCGCCGGAA
TTTCAGGGCAGAATCAGGATGACCAGGGACACATTTATAGACACAGTTTACGTGGACCTGAG
CGGACTGACACCGGCCGACACGGCCTATTATTACTGCGCGCGAGGGATCGATGGCAAGTCTTA
CCCCTTTCATTTCTGGGGCCACGGAACCCGGGTCACCGTCTTCTCGGCCTCCACCAAGGGCCC
ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG
CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG
CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT
GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAG
CAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC
CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG
ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
CCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCA
GGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA
TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC
CCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA
TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 335
##STR00351## ##STR00352##
VAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPA
ECS SEQ ID NO: 336
CGATTTGCCCTGACTCAACCTGCCTCCGTGTCTGGGTCTCCTGGACAGACGATCACCATAACCT
GCGCTGGAGGCAGCGTCTCCTGGTTTCATTTCCCTCCAGGCAAAACCCCCAGACTCATTATTTA
TGAGTCTTCTAAGCGACCCTCTGGGGTCTCTCCTCGATTCTCTGGGTCCCAGTCTGGCAGCACG
GCCTCCCTCATAATTTCTGGCCTCCAGTCTGATGACGAAGGGACATACTTCTGTTCTATTCTTG
AATTTTTCGGCAGAGGGACTCTTGTCACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGTCA
CTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAA
GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTG
GGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCT
GAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAG
GGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P52 HEAVY CHAIN
SEQ ID NO: 337 ##STR00353## ##STR00354##
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV
VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 338
CGTGTTACATTACAACAATCTGGGGCTATAGTGAGGCAGCCTGGGGCCTCAGTGACCGTCTCC
TGCGAGACTTCTGGATATACTTTCACCAAGTATTTCATCTACTGGGTGCGACAGGCCCCTGGA
CAGGGTCTTGAGTGGCTGGGCAGAATACACCCCCGAACCGGTGCCGTGAAGTATGCACCGAG
ATTTCAGGGTAGACTGTCCATGACCAGAGACTGGTCACTCGACACAGCCTACCTCGGATTGAC
CGGACTGACACTCGGCGACACGGCTCTATATTTCTGTGCGAGGGGGGCCTTTGAGGCAGATTC
ATATGGGTCAAGTTATCCCTTTCACCACTGGGGCCAGGGAACCCTAGTCACCGTCTCCGCGGC
CTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC
AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC
AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC
CCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT
GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAA
CTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC
CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG
ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT
AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCT
CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG
CCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG
GTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCT
GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGA
ACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAG
GCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ
ID NO: 339 ##STR00355## ##STR00356##
SDFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGS
TVEKTVAPAECS SEQ ID NO: 340
TCCTGGGCCCTGACTCAACCCGCCTCCGTGTCTGCGTCTCCTGGGCAGTCGGTCACCATGTCCT
GCACTGGATTCGGAAATTATAACCCTGACTCCTGGTACCAACAATACCCAGGCAAAGCCCCCA
AACTCATCATTTATGAAGACAATAAAAGACCCTCGGGGGTCTCTGATCGCTTCTCTGCCTCCA
GACTTGGCAGCACGTCTTCCCTGACAATCTCTAACGTCCAGGCTGCGGACGACGCCCATTATG
TCTGCGCCTCCTTTGAATTTTTCGGCGGAGGGACCAAGCTGACCGTCCTGAGTCAGCCCAAGG
CTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACAC
TGGTGTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCA
GCCCCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCG
GCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCG
GGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P53
HEAVY CHAIN SEQ ID NO: 341 ##STR00357## ##STR00358##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 342
CGTGTGACATTACAACAATCTGGGGCTACAGTGAAGCAGCCTGGGGCCTCAGTGACCGTCTCC
TGCGAGACTTCTGGATACACTTTCACCAAGTATACCATTCACTGGGTGCGACAGGCCCCTGGA
CAGGGTCTTCAGTGGGTGGGCAGAATACACCCCCGAACCGGTGCCGTGAAGTATGCACCGAT
ATTTCAGGGTAAAGTGTCCATGAGTCGAGACTTGTCACGCGACACAGCCTACCTCGGATTGAC
CAGACTGACGCTCGCCGACACGGCTCTATTTTTCTGTGCGAGGGGGGCCTTTGAGGCAGATTT
AAGTGGGCCAACTTACCCCTTTCACCACTGGGGCCAAGGAACCCTAGTCATCGTCTCCGCGGC
CTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC
AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC
AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC
CCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT
GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAA
CTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC
CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG
ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT
AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCT
CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG
CCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG
GTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCT
GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGA
ACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAG
GCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ
ID NO: 343 ##STR00359## ##STR00360##
DFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGST
VEKTVAPAECS SEQ ID NO: 344
TCCTGGGCCCTGACTCAACCCGCCTCCGTGTCTGCGTCTCCTGGGCAGTCGGTCACCATGTCCT
GCACTGGATTCGGAAATTATAACCCTGACTCCTGGTACCAACAATACCCAGGCAAAGCCCCCA
AACTCATCATTTATGAGGACAATAAAAGACCCTCGGGAGTCTCTAATCGCTTCTCTGCCTCCA
GACTTGGCAGCACGTCTTCCCTGACAATCTCTAACGTCCAGGCCGCTGACGACGCCCATTATG
TCTGCGCCTCCTTTGAATTTTTCGGCGGAGGGACCAAGCTGATCGTCCTGAGTCAGCCCAAGG
CTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACAC
TGGTGTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCA
GCCCCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCG
GCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCG
GGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P54
HEAVY CHAIN SEQ ID NO: 345 ##STR00361## ##STR00362##
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE
VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ
ID NO: 346
AACGTGCAGTTGATGCAGTCTGGGACTGAGGTGAAGAAGTCTGGGGCCTCGGTGACAATCTCT
TGTGAGACCGCTGGATTCAACTTCATCGACTCCGTCATACACTGGCTGCGCCAGGCCCCTGGA
GGAGGATTTCAGTGGATGGGGTGGATCAAGCCTCTTAGAGGTGCCGTCAATTATCCACAGTTT
TTGCAGGGCAGGGTCTCCATGACCCGGGACTTGTCCACCGACACGGTGTACATGGTCTTGAAT
GGACTGACACCTGACGACACAGGCCTTTATTACTGCGCGAAAGGGGCCTTTAGAGGGGGTTCT
CCCTTTGGCTTCTGGGGCCAGGGAACTCTGCTCACCGTCTCCCCAGCCTCCACCAAGGGCCCA
TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGC
CTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC
GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTG
ACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGC
AACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACC
GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA
CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA
CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAG
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT
CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC
CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT
CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 347
##STR00363## ##STR00364##
VAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPA
ECS SEQ ID NO: 348
CAGTCTGCCCTGTCTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGAGAGTCGATCACCATTTCCT
GTACTGGAGCCACCACCTGGTATCAACAACTCCCAGGCAGACCCCCCAAACTCATCATTTATG
ACGTCACTAACCGGCCCTCAGGCATTTCTAGTCGTTTCTCTGGCTCCACGTCTGGCCACACGGC
CTCCCTGACAATCTCCGGTCTCCAGGTTGACGACGAGGGTCTGTATCACTGCGCCTCACGTGA
ATTTTTCGGCGGAGGGACCAAGCTGACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGTCAC
TCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAAG
TGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTGG
GAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCTG
AGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAGG
GAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P60 HEAVY CHAIN SEQ
ID NO: 349 ##STR00365## ##STR00366##
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE
VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ
ID NO: 350
CAGGTGCGACTGGTGCAGTCTGGGCCTCAGGTGAAGAAGACTGGGGCCTCAGTGAGGGTCTC
CTGCGAAACCTCTGGATACACGTTCACCTCCTACTTCATCCATTGGTTACGACTGGGCCCCGG
AGAGGGGCTTCAGTGGATGGGGTGGATCAACCCTTTACATGGTGCCGTGAATTATGAAAACA
AATTTAGGGGCAGGGTCACAATCACCAGGGACACGTCCACAGACACAGTGTATTTGGACATG
AGCAGACTGACCCCTGACGACACGGCCGTCTATTTCTGCACAAGAGGAATCGTTGCTGATGGG
TGGCCCTATGGCCACTGGGGCCAGGGAACCCAAGTCACCGTCTCCCCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 351
##STR00367## ##STR00368##
AVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTV
APAECS SEQ ID NO: 352
TCCTGGGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGGTCGCCATCTCCT
GCGCTGGCGGCAGCGTCTCCTGGTACCAGGTGCTCCCAGGCAGAGCCCCCAAACTCATCATTT
ATGAGGGCGCTAAGCGACCCTCAGGGGTTTCTGCTCGCTTCTCTGGCTCCCAGTCTGGCAACA
CGGCTTACCTGACAATTTCTGACCTCCAGACTGAGGACGAGGGCATCTACTTCTGCTCTTCACT
TCAATTCTTCGGCGGAGGGACCAAACTGACCGTCCTAAGTCAGCCCAAGGCTGCCCCCTCGGT
CACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGT
AAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGG
TGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTAC
CTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGA
AGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P61 HEAVY CHAIN
SEQ ID NO: 353 ##STR00369## ##STR00370##
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 354
CAGGTGCGACTTCAGCAGTCTGGTGTCGTGGTGAGGAAGCCTGGGGCCTCAGTGAGAATTTCC
TGCGAGACTTCTGGATTCACCTTCATCGACCACATTGTCCATTGGGTGCGGCGGGCCCCTGGA
CGAGGCTTTGAATGGATGGGTTGGATCAAGCCTCTTAGGGGTGCCGTAGATTATGCACCCCAA
CTTCGGGGCAGGATCTCCCTGACGAGGGACATTTACAGTGAAACCGTCTTTATAGACGTGAGC
CGACTGACGTCTGGCGACACGGCGATATACTTTTGTTGTAAGGCCGCCGCCCCTGAAGAAGCA
TTCCCCCTTCAATACTGGGGCCAGGGGACCCAACTTATCGTCTCCTCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 355
##STR00371## ##STR00372##
PGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEK
TVAPAECS SEQ ID NO: 356
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCCT
GCCTTTATGCCAATGTAGATATCTGCTGGTATCAACTACACCCGGGCAGAGCCCCCAAACTTC
TAATTGTTGACAATAATAAGCGGCCCTCAGGAGTCTCTCCTCGCTTCTCTGGCTCCAAGTCTGG
CACCACGGCCTCCCTGACAATCTCTGGACTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAAGAACATTTTTTGGCGGGGGGACCAAGTTGACCGTCCTGAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P62 HEAVY
CHAIN SEQ ID NO: 357 ##STR00373## ##STR00374##
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 358
CAGGTGCGACTTCAGCAGTCTGGTGTCGTGGTGAGGAAGCCTGGGGCCTCAGTGAGACTTTCC
TGCGAGACGTCTGGATTCAAATTCATCGACCACATTGTCAACTGGGTGCGGCGGGCCCCTGGA
CGAGGCTTTGAATGGATGGGTTGGATCAAGCCTCTTGGGGGTGTCGCTGATTATGCACCCCAA
CATCGGGGCAGGATCTCACTGACGAGGGACATTTACACTGAAACCGTCTTTATAGACCTGAGT
CGACTGACGTCTGGCGACACGGCGATTTATTTCTGTTGTAAGGCCGCCGCCCCTGATGAAGCA
TTCCCCCTTGAATACTGGGGCCAGGGGACCCAACTTATCGTCTCCCCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 359
##STR00375## ##STR00376##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 360
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCCT
GCCTTTATGCCAATGTAGATATCTGCTGGTATCAAATACAGCCGGGCAGATTACCCAAACTTC
TGATTGTTGACAATAATAGGCGACCCTCAGGAGTCTCTCCTCGCTTCTCTGGCTCCAAGTCTGG
CACCACGGCCTCCCTGACAATCTCTGGACTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAACAACATTTTTTGGCGGGGGGACCAAGTTGACCGTCCTCAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P63 HEAVY
CHAIN SEQ ID NO: 361 ##STR00377## ##STR00378##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 362
CAGGTGCGACTTGTGCAGTCTGGTCCCGTGATGAGAAAGCCTGGGGCCTCAGTGAGAATTTCT
TGCGAGACATCTGGATTCGCCTTCTTGGACCACATTGTCCACTGGGTGCGGCGGGCCCCTGGA
CGCGGCTTTGAATGGATGGGTTGGGTTAAGACCATTGGGGGTGTCGTTGATTATGCACCCCAC
CTTAGGGGCAGGATCTCCGTGACGAGAGACGTCTTTAGTGAAACCGTCTTTCTGGACTTGAGC
CGACTGACGTCTGGCGACACGGCGATGTATTTTTGTTCTAAGGCCGCCGCCCCTGACGAAGCC
TTCCCCCTTGAATTTTGGGGCCAGGGGACCCAAGTCATCGTCTCCTCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 363
##STR00379## ##STR00380##
PGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEK
TVAPAECS SEQ ID NO: 364
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCTT
GCCTTTATGCCAATGTGGATATCTGCTGGTATCAACTTCACCCGGGCAGAGCCCCCAAACTTC
TTATTCTTGACAATAATAAACGGCCCTCAGGAGTCTCTAGTCGCTTCTCCGGTTCCAAGTCTGG
CACCACGGCCTCCCTAACCATCTCTGACCTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAACAACATTTTTTGGCGGGGGGACCAGGTTGACCGTCCTGAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P64 HEAVY
CHAIN SEQ ID NO: 365 ##STR00381## ##STR00382##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 366
CAGGTGCGACTTGTGCAGTCTGGTCCCGTGGTGAGAAAGCCTGGGACCTCAGTGAGAATTTCT
TGCGAGACATCTGGATTCGCCTTCTTGGACCACATTGTCCACTGGGTGCGGCGGGCCCCTGGA
CGCGGCTTTGAATGGATGGGTTGGGTTAAGACCATTGGGGGTGTCGTTGATTATGCACCCCAC
CTTAGGGGCAGGATCTCCGTGACGAGGGACGTATTTAGTGAAATCGTCTTTATGGAGTTGAGT
CGACTGACGTCTGGCGACACGGCGATGTATTTTTGTTCTAAGGCCGCCGCCCCTGACGAAGCC
TTCCCCCTTGAATTTTGGGGCCAGGGGACCCAAGTCATCGTCTCCTCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 367
##STR00383## ##STR00384##
PGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEK
TVAPAECS SEQ ID NO: 368
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCCT
GCCTTTATGCCAATGTGGATATCTGCTGGTATCAACTTCACCCGGGCAGAGCCCCCAAACTTC
TAATTGTTGACAATAATAAGCGGCCCTCAGGAGTCTCTAGTCGCTTCTCTGGTTCCAAGTCTGG
CACCACGGCCTCCCTAACAATCTCTGATCTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAACAACATTTTTTGGCGGGGGGACCAGGTTGACCGTCCTGAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P65 HEAVY
CHAIN SEQ ID NO: 369 ##STR00385## ##STR00386##
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE
VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ
PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ
ID NO: 370
CAAGTGCAACTGGTGCAGTCTGGGGCTGGGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTCTC
CTGCGAGACATCCGGATTCAAGTTCACCGAGTACTTTATCCACTTTTTACGACAGGCCCCTGG
ACAAGGGCTTGAGTGGATGGGATGGCTCAACCCTCTCAGAGGTGCCGTCAACTATCCACGGA
AGTTTCAGGGCAGAGTCACTTTGACCAGGGACATCTACACCACCACCGTCTACATGCAACTTA
ACGGTCTGACCCCTGACGACACGGCCGTCTACTACTGTGCCAGAGCGGTCTTTAATGAAGCTT
TCCCCTTTGACTACTGGGGCCAGGGAAGCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCC
CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT
GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA
GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGG
TGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA
GCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCA
CCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
GACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAA
GACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAA
GCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACC
AGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC
ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC
CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT
ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAG
AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC
TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 371
##STR00387## ##STR00388##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 372
TCCTGGGCCCAGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCT
GCGCTGGAATCGTCAGTGATGCCTGGTACCAGCAATACCCAGGCAGACCCCCCAGACTCATCC
TTTATGACGGCGATAAGCGGCCCTCAGGGGTTTCTCCTCGTTTTTCTGCCTCCAGGGCCGGCAA
GACGGCCTCCCTGACAATTTCTGGGCTGCAGGCTGACGACGAGGCTTATTATCACTGCGCGTC
AAGGGAATTTTTTGGAGGCGTGACCAAGTTGACCGTCCTAAGTCAGCCCAAGGCTGCCCCCTC
GGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCT
CGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCA
AGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAG
CTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGC
ATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P66 HEAVY
CHAIN SEQ ID NO: 373 ##STR00389## ##STR00390##
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 374
CAGGTGCGACTTCAGCAGTCTGGTGTCGTGGTGAGGAAGCCTGGGGCCTCAGTGAGACTTTCC
TGCGAGACGTCTGGCTTCAAATTCATCGACCACATTGTCAACTGGGTGCGGCGGGCCCCTGGA
CGAGGCTTTGAATGGATGGGTTGGATCAAGCCTCTTGGGGGTGTCGCTGATTATGCACCCCAA
CATCGGGGCAGGATCTCACTGACGAGGGACATTTACACTGAAACCGTCTTTATAGACCTGAGT
CGACTGACGTCTGGCGACACGGCGATTTATTTTTGTTGTAAGGCCGCCGCCCCTGATGAAGCA
TTCCCCCTTGAATACTGGGGCCAGGGGACCCAACTTATCGTCTCCCCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 375
##STR00391## ##STR00392##
GAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKT
VAPAECS SEQ ID NO: 376
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCCT
GCCTTTATGCCAATGTAGATATCTGCTGGTATCAAATACAGCCGGGCAGATTACCCAAACTTC
TGATTGTTGACAATGATAGGCGACCCTCAGGAGTCTCTCCTCGCTTCTCTGGCTCCAAGTCTGG
CACCACGGCCTCCCTGACAATCTCTGGACTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAACAACATTTTTTGGCGGGGGGACCAAGTTGACCGTCCTCAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P67 HEAVY
CHAIN SEQ ID NO: 377 ##STR00393## ##STR00394##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 378
CAGGTGCGACTTGTGCAGTCTGGTCCCGTGATGAGAAAGCCTGGGGCCTCAGTGAGAATTTCT
TGCGAGACATCTGGATTCGCCTTCTTGGACCACATTGTCCACTGGGTGCGGCGGGCCCCTGGA
CGCGGCTTTGAATGGATGGGTTGGGTTAAGACCATTGGGGGTGTCGTTGATTATGCACCCCAC
CTTAGGGGCAGGATCTCCGTGACGAGAGACGTCTTTAGTGAAACCGTCTTTCTGGACTTGAGT
CGACTGACGTCTGGCGACACGGCGATGTATTTTTGTTCTAAGGCCGCCGCCCCTGACGAAGCC
TTCCCCCTTGAATTTTGGGGCCAGGGGACCCAAGTCATCGTCTCCTCGGCCTCCACCAAGGGC
CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC
AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC
ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA
AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAA
AGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCAC
CAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCC
CATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC
CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAA
GAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 379
##STR00395## ##STR00396##
PGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEK
TVAPAECS SEQ ID NO: 380
CAGGCTGCCCTGACTCAGCCCGCCTCCGTGTCCGGCTCTCCTGGACAGTCGGTCACCATTTCTT
GCCTTTATGCCAATGTGGATATCTGCTGGTATCAACTTCACCCGGGCAGAGCCCCCAAACTTC
TAATTCTTGACAATAATAAACGGCCCTCAGGAGTCTCTAGTCGCTTCTCCGGTTCCAAGTCTGG
CACCACGGCCTCCCTAACCATCTCTGACCTTCAGGCTGACGACGAGGCTGAATATCACTGCTC
TTCAACAACTTTTTTTGGCGGGGGGACCAGGTTGACCGTCCTGAGTCAGCCCAAGGCTGCCCC
CTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTG
TCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGT
CAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGC
AGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCAC
GCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P68 HEAVY
CHAIN SEQ ID NO: 381 ##STR00397## ##STR00398##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 382
TTGTGAGACCGCTGGATTCAACTTCATCGACTCCGTCATACACTGGCTGCGCCAGGCCCCTGG
TGGGGGATTTCAGTGGATGGGGTGGATCAAGCCTCTTAGAGGTGGCGTCAATTATCCACATTA
TTTGCAGGGCAGAATCTCCATGACCCGGGACTTGTCCAGTGACACGGTTTACATGGTCTTAAA
TAGACTGACACCTGCCGACACAGGCCTTTATTACTGCGCGAAAGGGGCCTTTGGGGGGAGTTC
TCCCTTTGGCTTCTGGGGCCAGGGAACTCTGCTCACCGTCTCCCCAGCCTCCACCAAGGGCCC
ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG
CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG
CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT
GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAG
CAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC
CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG
ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
CCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCA
GGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA
TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC
CCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA
TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 383
##STR00399## ##STR00400##
TVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP
AECS SEQ ID NO: 384
CAGTCTGCCCTGTCTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGAGAGTCGATCACCATTTCCT
GTACTGAAGCCACCACCTGGTATCAACAACTCCCAGGCAAACCCCCCAAACTCATCATTTATG
ACGTGACCAACCGGCCCTCAGGCATTTCAAGTCGTTTCTCTGGCTCCATGTCTGGTCGCACGG
CCTCCCTGACAATCTCCGGTCTCCAGGTTGACGACGAGGGTCTCTATCACTGTGCCTCACGTG
AATTTTTCGGCGGGGGGACCAAGCTGACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGTCA
CTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAA
GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTG
GGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCT
GAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAG
GGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P69 HEAVY CHAIN
SEQ ID NO: 385 ##STR00401## ##STR00402##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 386
CACGTGCAATTGATGCAGTCTGGGACTCAGGCGAAGAAGTCTGGGGCCTCGGTGACAATTTCT
TGTGAGACCGCTGGATTCAAGTTCATCGACTCCGTCATACACTGGCTGCGCCAGGCCCCTGGA
GGGGGATTTCAGTGGATGGGGTGGATCAAGCCTCTTGGAGGTGCCGTCAACTATCCACCCTAT
TTGCAGGGCAGGATCTCCTTGACCCGTGACTTGTCCACCGACACAATTTACATGGTCTTGAAT
GGACTGACACCTGCCGACACAGGCTTTTATTACTGCGCCAAAGGGGCCTTTGGGGGGGGTTCT
CCCTTTGGCTTCTGGGGCCAGGGGACTCTGCTCACCGTCTCCCCAGCCTCCACCAAGGGCCCA
TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGC
CTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC
GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTG
ACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGC
AACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACC
GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA
CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA
CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAG
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT
CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC
CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT
CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 387
##STR00403## ##STR00404##
TVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP
AECS SEQ ID NO: 388
CAGTCTGCCCTGTCTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGAGACTCGATCACCATTTCTT
GTTTTGGAGCCACCACCTGGTATCAACAACTCCCAGGCAGACCCCCCAAACTCATCATTTATG
ACGTGACTAACCGGCCCTCAGGCATTTCAGGTCGTTTCTCTGGCTCCATGTCTGGTCAAAAGG
CCTCCCTGACAATCTCCGGTCTCCAGGTTGACGACGAGGGTCTCTATCACTGCGCCTCACGTG
AATTTTTCGGCGGGGGGACCAAACTGACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGTCA
CTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAA
GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTG
GGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCT
GAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAG
GGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P70 HEAVY CHAIN
SEQ ID NO: 389 ##STR00405## ##STR00406##
FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
LGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP
ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 390
CACGTGCAGTTGAGGCAGTCTGGGACTGAGGCGAAGAAGTCTGGGGCCTCGGTGACAATCTC
TTGTGAGACCGCTGGATTCAACTTCATCGACTCCGTCATACACTGGCTGCGCCAGGCCCCTGG
TGGGGGATTTCAGTGGATGGGGTGGATCAAGCCTCTTAGAGGTGGCGTCAATTATCCACATTA
TTTGCAGGGCAGAATCTCCATGACCCGGGACTTGTCCAGTGACACGGTTTACATGGTCTTAAA
TAGACTGACACCTGACGACACAGGCCTTTACTACTGCGCGAAAGGGGCCTTTGGGGGGAGTTC
TCCCTTTGGCTTCTGGGGCCAGGGAACTCTGCTCACCGTCTCCCCAGCCTCCACCAAGGGCCC
ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG
CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAG
CGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT
GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAG
CAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCAC
CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG
ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAG
ACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAG
CCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCA
GGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA
TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCC
CCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA
TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 391
##STR00407## ##STR00408##
TVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAP
AECS SEQ ID NO: 392
CAGTCTGCCCTGTCTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGAGAGTCGATCACCATTTCCT
GTACTGAAGCCACCACCTGGTATCAACAACTCCCAGGGAGATCCCCCAAACTCATTATTTATG
ACGTGACCAACCGGCCCTCAGGCATTTCAAGTCGTTTCTCTGGCTCCATGTCTGGTCGCACGG
CCTCCCTGACAATCTCCGGTCTCCAGGTTGACGACGAGGGTCTCTATCACTGTGCCTCACGTG
AATTTTTCGGCGGGGGGACCAAGCTGACCGTCCTCAGTCAGCCCAAGGCTGCCCCCTCGGTCA
CTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGTAA
GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGTG
GGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTACCT
GAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGAAG
GGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P71 HEAVY CHAIN
SEQ ID NO: 393 ##STR00409## ##STR00410##
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV
TVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI
SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWE
SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO: 394
CGTGTTACATTACAACAGTCTGGGGCTACAGTGAGGCAGCCTGGGGCCTCAGTCACCGTCTCC
TGCGAGACTTCTGGATTCACCTTCATCAAATATACCATTCACTGGGTGCGACAGGCCCCTGGA
CAGGGTCTTCAGTGGGTGGGAAGAATACACCCCCGAACCGGTGCCGTGAAGTTTGCACCGAT
ATTTCAGGGTAAATTTTCCATGAGTCGAGACTTGTCACGCGACACAGCCTACCTCGGATTGAC
CAGACTGACACTCGCCGACACGGCTCTATTTTTCTGTGCGAGGGGGGCCTTTGAGGCAGATTT
ATATGGGCCAACTTACCCCTTTCACCACTGGGGCCAAGGAACCCAAGTCACCGTCTCCGCGGC
CTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC
AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC
AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTC
CCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT
GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAA
CTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCC
CCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG
ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCAT
AATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCT
CACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAG
CCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG
GTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCT
GGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGA
ACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC
TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAG
GCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ
ID NO: 395 ##STR00411## ##STR00412##
SDFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGS
TVEKTVAPAECS SEQ ID NO: 396
TCCTGGGCCCTGACTCAACCCGCCTCCGTGTCTGCGTCTCCTGGGCAGTCGGTCACCATGTCCT
GCACTGGATTCGGAAGTTATAATCCTGACTCCTGGTACCAGCAATACCCAGGCAAAGCCCCCA
AACTCATCATTTATGATGACAATAAAAGACCCTCGGGGGTCTCTGATCGCTTCTCTGCCTCCA
GACTTGGCAGCACATCTTCACTGACAATCTCTAACGTCCAGGCCGCTGACGACGCCCATTATG
TCTGCGCCTCCTTTGAGTTTTTCGGCGGGGGGACCAAGCTGACCGTCCTGAGTCAGCCCAAGG
CTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACAC
TGGTGTGTCTCGTAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCA
GCCCCGTCAAGGTGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCG
GCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCG
GGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT >N49P72
HEAVY CHAIN SEQ ID NO: 397 ##STR00413## ##STR00414##
PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID
NO: 398
CACATTCAGTTGCTACAGTCGGGGCCTCAAGTTAAGAAGTCTGGGGACACAGTGAGAATCTCC
TGTGAGACCTCTGGATATAATTTCGTCGACTCCCTTATCCACTGGGTCCGACAGACCCCGGAA
AAACGTCTCAGATGGATGGGCTGGATCAATCCTCTCCAAGGTGGTGTGAATTACGCGCCGGAA
TTTCAGGGCAGAATCAGGATGACCAGGGACACGTTTATAGACACAGTTTACGTGGACTTGAGC
GGACTGACACCGGCCGACACGGCCTATTATTACTGCGCGCGAGGGATCGATGGCAATTCTTAC
CCCTTTCATTTCTGGGGCCACGGAACCCGGGTCACCGTCTTCTCGGCCTCCACCAAGGGCCCA
TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGC
CTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC
GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTG
ACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGC
AACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACC
GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGA
CACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGA
CCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGC
CGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAG
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCAT
CGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC
CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT
CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCA
CGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGA
GCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT
ACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA LIGHT CHAIN SEQ ID NO: 399
##STR00415## ##STR00416##
AWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAE CS
SEQ ID NO: 400
CGATTTGCCCTGACTCAACCTGCCTCCGTGTCTGGGTCTCCTGGACAGACGATCACCATAACCT
GCGCTGGAGGCAGCGTCTCCTGGTTCCATTTCCCTCCAGGCAAAACCCCCAGACTCATTATTT
ATGAGTCTTCTAAGAGACCCTCAGGGGTCTCTCCTCGATTCTCTGGGTCCCAGTCTGGCAGCA
CGGCCTCCCTAATAATTTCTGGCCTCCAGTCTGATGACGAAGGGACATACTTCTGTTCTATTCT
TGAATTTTTCGGCAGAGGGACTCTTCTCACCGTCCTGAGTCAGCCCAAGGCTGCCCCCTCGGT
CACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCGT
AAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGG
TGGGAGTGGAGACCACCAAACCCTCCAAACAAAGCAACAACAAGTATGCGGCCAGCAGCTAC
CTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCGGGTCACGCATGA
AGGGAGCACCGTGGAGAAGACAGTGGCCCCTGCAGAATGCTCT
Polypeptides
[0649] In some embodiments, the invention provides isolated
polypeptides comprising an individual light chain or heavy chain
described herein as well as antigen binding fragments thereof.
Polypeptides (e.g., intact antibodies) comprising both a light
chain and a heavy chain are also provided.
[0650] Also provided are polypeptides that comprise: a polypeptide
comprising SEQ ID NOS:1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,
25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57,
59, 61, 63, 65, 67, 69, 71, 73, 75, 153, 157, 161, 165, 169, 173,
177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225,
229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277,
281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329,
333, 337, 341, 345, 349, 353, 357, 361, 365, 369, 373, 377, 381,
385, 389, 393 or 397 or an antigen binding fragment thereof.
[0651] Also provided are polypeptides that comprise: a polypeptide
comprising SEQ ID NOS:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,
26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58,
60, 62, 64, 66, 68, 70, 72, 74, 76, 155, 159, 163, 167, 171, 175,
179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227,
231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279,
283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331,
335, 339, 343, 347, 351, 355, 359, 363, 367, 371, 375, 379, 383,
387, 391, 395 or 399 or an antigen binding fragment thereof.
[0652] Also provided are polypeptides that comprise: a polypeptide
having at least about 90% sequence identity to SEQ ID NOS:1, 3, 5,
7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39,
41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73,
75, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197,
201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249,
253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301,
305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, 353,
357, 361, 365, 369, 373, 377, 381, 385, 389, 393 or 397.
[0653] In some embodiments, the polypeptide comprises a polypeptide
having at least about 95%, at least about 96%, at least about 97%,
at least about 98%, or at least about 99% sequence identity to SEQ
ID NOS: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,
33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65,
67, 69, 71, 73, 75, 153, 157, 161, 165, 169, 173, 177, 181, 185,
189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237,
241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289,
293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341,
345, 349, 353, 357, 361, 365, 369, 373, 377, 381, 385, 389, 393 or
397.
[0654] Also provided are polypeptides that comprise: a polypeptide
having at least about 90% sequence identity to SEQ ID NOS:2, 4, 6,
8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,
42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74,
76, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199,
203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251,
255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303,
307, 311, 315, 319, 323, 327, 331, 335, 339, 343, 347, 351, 355,
359, 363, 367, 371, 375, 379, 383, 387, 391, 395 or 399.
[0655] In some embodiments, the polypeptide comprises a polypeptide
having at least about 95%, at least about 96%, at least about 97%,
at least about 98%, or at least about 99% sequence identity to SEQ
ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,
34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66,
68, 70, 72, 74, 76, 155, 159, 163, 167, 171, 175, 179, 183, 187,
191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239,
243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291,
295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339, 343,
347, 351, 355, 359, 363, 367, 371, 375, 379, 383, 387, 391, 395 or
399.
Polynucleotides
[0656] In some embodiments, the invention encompasses
polynucleotides comprising polynucleotides that encode a
polypeptide as described herein, such as a heavy chain or light
chain sequence of an HIV antibody or a fragment of such a
polypeptide. For example, the invention provides a polynucleotide
comprising a nucleic acid sequence that encodes an antibody to
gp120 or encodes a fragment of such an antibody. The
polynucleotides of the invention can be in the form of RNA or in
the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA;
and can be double-stranded or single-stranded, and if single
stranded can be the coding strand or non-coding (anti-sense)
strand.
[0657] In some embodiments, the polynucleotides are isolated. In
certain embodiments, the polynucleotides are substantially
pure.
[0658] In some embodiments, the invention provides a polynucleotide
comprising a polynucleotide encoding a polypeptide comprising a
sequence selected from the group consisting of SEQ ID NOS:1-76,
153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177,
179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203,
205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227,229,
231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255,
257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281,
283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307,
309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333,
335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359,
361, 363. 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385,
387, 389, 391, 393, 395 and 397.
[0659] In some embodiments, the invention provides a polynucleotide
comprising a polynucleotide encoding a polypeptide comprising the
heavy or light chain variable region found within a sequence
selected from the group consisting of SEQ ID NOS:1-76, 153, 155,
157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181,
183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207,
209, 211, 213, 215, 217, 219, 221, 223, 225, 227,229, 231, 233,
235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259,
261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285,
287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311,
313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337,
339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363.
365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389,
391, 393, 395 and 397.
[0660] Also provided is a polynucleotide encoding a polypeptide
having at least about 95%, at least about 96%, at least about 97%,
at least about 98%, or at least about 99% sequence identity to SEQ
ID NOS:1-76, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173,
175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199,
201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225,
227,229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251,
253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277,
279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303,
305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329,
331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355,
357, 359, 361, 363. 365, 367, 369, 371, 373, 375, 377, 379, 381,
383, 385, 387, 389, 391, 393, 395 or 397.
[0661] The invention further provides a polynucleotide comprising a
sequence selected from the group consisting of SEQ ID NOS:77-152,
154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178,
180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200 202, 204,
206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230,
232, 234, 236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256,
258, 260, 262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282,
284, 286, 288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308,
310, 312, 314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334,
336, 338, 340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360,
362, 364, 366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386,
388, 390, 392, 394, 396, 398 and 400.
[0662] Also provided is a polynucleotide having at least 70%, 75%,
80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,
97%, 98%, or 99% sequence identity to SEQ ID NOS:77-152, 154, 156,
158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182,
184, 186, 188, 190, 192, 194, 196, 198, 200 202, 204, 206, 208,
210, 212, 214, 216, 218, 220, 222, 224, 226, 228, 230, 232, 234,
236, 238, 240, 242, 244, 246, 248, 250, 252, 254, 256, 258, 260,
262, 264, 266, 268, 270, 272, 274, 276, 278, 280, 282, 284, 286,
288, 290, 292, 294, 296, 298, 300, 302, 304, 306, 308, 310, 312,
314, 316, 318, 320, 322, 324, 326, 328, 330, 332, 334, 336, 338,
340, 342, 344, 346, 348, 350, 352, 354, 356, 358, 360, 362, 364,
366, 368, 370, 372, 374, 376, 378, 380, 382, 384, 386, 388, 390,
392, 394, 396, 398, or 400.
[0663] In some embodiments the polynucleotides comprise the coding
sequence for the mature polypeptide fused in the same reading frame
to a polynucleotide which aids, for example, in expression and
secretion of a polypeptide from a host cell (e.g. a leader sequence
which functions as a secretory sequence for controlling transport
of a polypeptide from the cell). The polypeptide having a leader
sequence is a preprotein and can have the leader sequence cleaved
by the host cell to form the mature form of the polypeptide. The
polynucleotides can also encode for a proprotein which is the
mature protein plus additional 5' amino acid residues. A mature
protein having a prosequence is a proprotein and is an inactive
form of the protein. Once the prosequence is cleaved an active
mature protein remains.
[0664] In certain embodiments the polynucleotides comprise the
coding sequence for the mature polypeptide fused in the same
reading frame to a marker sequence that allows, for example, for
purification of the encoded polypeptide. For example, the marker
sequence can be a hexa-histidine tag supplied by a pQE-9 vector to
provide for purification of the mature polypeptide fused to the
marker in the case of a bacterial host, or the marker sequence can
be a hemagglutinin (HA) tag derived from the influenza
hemagglutinin protein when a mammalian host (e.g. COS-7 cells) is
used.
[0665] The present invention further relates to variants of the
hereinabove described polynucleotides encoding, for example,
fragments, analogs, and derivatives.
[0666] The polynucleotide variants can contain alterations in the
coding regions, non-coding regions, or both. In some embodiments
the polynucleotide variants contain alterations which produce
silent substitutions, additions, or deletions, but do not alter the
properties or activities of the encoded polypeptide. In some
embodiments, nucleotide variants are produced by silent
substitutions due to the degeneracy of the genetic code.
Polynucleotide variants can be produced for a variety of reasons,
e.g., to optimize codon expression for a particular host (change
codons in the human mRNA to those preferred by a bacterial host
such as E. coli).
[0667] Vectors and cells comprising the polynucleotides described
herein are also provided. The term "vector" means a construct,
which is capable of delivering, and expressing, one or more gene(s)
or sequence(s) of interest in a host cell. Examples of vectors
include, but are not limited to, viral vectors, naked DNA or RNA
expression vectors, plasmid, cosmid or phage vectors, DNA or RNA
expression vectors associated with cationic condensing agents, DNA
or RNA expression vectors encapsulated in liposomes, and certain
eukaryotic cells, such as producer cells. "Vector" also includes
shuttle and expression vectors. In some embodiments, the vector is
a plasmid construct and also includes an origin of replication
(e.g., the Co1E1 origin of replication) and a selectable marker
(e.g., ampicillin or tetracycline resistance), for replication and
selection, respectively. An "expression vector" refers to a vector
that contains the necessary control sequences or regulatory
elements for expression of the antibodies including antibody
fragments of the invention, in bacterial or eukaryotic cells.
Methods
[0668] The anti-HIV antibodies of the invention are useful in a
variety of applications including, but not limited to, therapeutic
treatment methods, such as the treatment, cure, functional cure, or
prevention of HIV infection. The methods of use may be in vitro, ex
vivo, or in vivo methods.
[0669] In some embodiments, the antibodies disclosed herein may be
used as neutralizing antibodies, passively administered or given
via gene therapies.
[0670] In one aspect, the anti-HIV antibodies are useful for
detecting the presence of HIV in a biological sample. The term
"detecting" as used herein encompasses quantitative or qualitative
detection. In certain embodiments, a biological sample comprises a
cell or tissue.
[0671] Certain other methods can be used to detect binding of
anti-HIV antibodies to antigens such as gp120. Such methods
include, but are not limited to, antigen-binding assays that are
well known in the art, such as western blots, radioimmunoassays,
ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays,
immunoprecipitation assays, fluorescent immunoassays, protein A
immunoassays, and immunohistochemistry (IHC).
[0672] In certain embodiments, the antibodies are labeled. Labels
include, but are not limited to, labels or moieties that are
detected directly (such as fluorescent, chromophoric,
electron-dense, chemiluminescent, and radioactive labels), as well
as moieties, such as enzymes or ligands, that are detected
indirectly, e.g., through an enzymatic reaction or molecular
interaction.
[0673] In certain embodiments, the antibodies are immobilized on an
insoluble matrix. Immobilization entails separating the antibody
from any antigen that remains free in solution. This conventionally
is accomplished by either insolubilizing the antibody before the
assay procedure, as by adsorption to a water-insoluble matrix or
surface (Bennich et al., U.S. Pat. No. 3,720,760), or by covalent
coupling (for example, using glutaraldehyde cross-linking), or by
insolubilizing the antibody after formation of a complex between
the antibody and antigen, e.g., by immunoprecipitation.
[0674] The present invention provides for methods of treating or
preventing HIV infection comprising administering a therapeutically
effective amount of an antibody as described herein to a subject
(e.g., a subject in need of treatment). In some embodiments, the
subject is a human.
[0675] Subjects at risk for HIV-related diseases or disorders
include patients who have come into contact with an infected person
or who have been exposed to HIV-1 in some other way. Administration
of a prophylactic agent can occur prior to the manifestation of
symptoms characteristic of HIV-1-related disease or disorder, such
that a disease or disorder is prevented or, alternatively, delayed
in its progression.
[0676] In some embodiments of the present invention, the subject is
administered effective amounts of more than one anti-HIV antibody
of the invention. In some embodiments, the subject is administered
a pharmaceutical composition comprising a combination of antibodies
of the invention, in order to treat or prevent HIV infection. In
some embodiments, a combination of antibodies are administered,
which can include a combination comprising any one or more of N49P6
or an antigen binding fragment thereof, N49P7 or an antigen binding
fragment thereof, N49P7.1 or an antigen binding fragment thereof,
N49P9 or an antigen binding fragment thereof, or N49P11 or an
antigen binding fragment thereof. In some embodiments, the antibody
comprises the VH and VL regions of N49P6, N49P7, N49P7.1, N49P9, or
N49P11 as described herein. In some embodiments, the antibody
comprises the CDRs of the VH and V.sub.L regions of N49P6, N49P7,
N49P7.1, N49P9, or N49P11 as described herein. In some embodiments,
the combination comprises i) N49P6 or an antigen binding fragment
thereof, ii) N49P7 or an antigen binding fragment thereof and iii)
N49P11 or an antigen binding fragment thereof. In some embodiments,
the subject is administered a polyclonal composition of antibodies
comprising any one of i) N49P6 or an antigen binding fragment
thereof, ii) N49P7 or an antigen binding fragment thereof and/or
iii) N49P11 or an antigen binding fragment thereof in combination
with one or more natural or variant antibodies as described herein.
Such combinations can be selected according to the desired
immunity. The composition can further include one or more other
broadly neutralizing antibodies.
[0677] Methods for preventing an increase in HIV-1 virus titer,
virus replication, virus proliferation or an amount of an HIV-1
viral protein in a subject are further provided. In one embodiment,
a method includes administering to the subject an amount of an
anti-HIV antibody effective to prevent an increase in HIV-1 titer,
virus replication or an amount of an HIV-1 protein of one or more
HIV strains or isolates in the subject.
[0678] For in vivo treatment of human patients, the patient is
usually administered or provided a pharmaceutical formulation
including an anti-HIV antibody of the invention. When used for in
vivo therapy, the antibodies of the invention are administered to
the patient in therapeutically effective amounts (i.e., amounts
that eliminate or reduce the patient's viral burden). The
antibodies can be administered to a human patient, in accord with
known methods, such as intravenous administration, e.g., as a bolus
or by continuous infusion over a period of time, by intramuscular,
intraperitoneal, intracerobrospinal, subcutaneous, intra-articular,
intrasynovial, intrathecal, oral, topical, or inhalation routes.
The antibodies may be administered parenterally, when possible, at
the target cell site, or intravenously. Intravenous or subcutaneous
administration of the antibody is preferred in certain embodiments.
Therapeutic compositions of the invention are administered to a
patient or subject systemically, parenterally, or locally.
[0679] For parenteral administration, the antibodies can be
formulated in a unit dosage injectable form (solution, suspension,
emulsion) in association with a pharmaceutically acceptable,
parenteral vehicle. Examples of such vehicles are water, saline,
Ringer's solution, dextrose solution, and 5% human serum albumin.
Nonaqueous vehicles such as fixed oils and ethyl oleate are also
used. Liposomes are used as carriers. The vehicle contains minor
amounts of additives such as substances that enhance isotonicity
and chemical stability, e.g., buffers and preservatives. The
antibodies are typically formulated in such vehicles at
concentrations of about 1 mg/ml to 10 mg/ml.
[0680] The dose and dosage regimen depends upon a variety of
factors readily determined by a physician, such as the nature of
the infection and the characteristics of the particular cytotoxic
agent or growth inhibitory agent conjugated to the antibody (when
used), e.g., its therapeutic index, the patient, and the patient's
history. Generally, a therapeutically effective amount of an
antibody is administered to a patient. In particular embodiments,
the amount of antibody administered is in the range of about 0.1
mg/kg to about 20 mg/kg of patient body weight. Depending on the
type and severity of the infection, about 0.1 mg/kg to about 20
mg/kg body weight (e.g., about 0.1-15 mg/kg/dose) of antibody is an
initial candidate dosage for administration to the patient,
whether, for example, by one or more separate administrations, or
by continuous infusion. The progress of this therapy is readily
monitored by conventional methods and assays and based on criteria
known to the physician or other persons of skill in the art.
[0681] Antibodies of the invention can be coupled to a drug for
delivery to a treatment site or coupled to a detectable label to
facilitate imaging of a site comprising cells of interest, such as
cells infected with HIV. Methods for coupling antibodies to drugs
and detectable labels are well known in the art, as are methods for
imaging using detectable labels. Labeled antibodies may be employed
in a wide variety of assays, employing a wide variety of labels.
Detection of the formation of an antibody-antigen complex between
an antibody of the invention and an epitope of interest (an HIV
epitope) can be facilitated by attaching a detectable substance to
the antibody. Suitable detection means include the use of labels
such as radionucleotides, enzymes, coenzymes, fluorescers,
chemiluminescers, chromogens, enzyme substrates or co-factors,
enzyme inhibitors, prosthetic group complexes, free radicals,
particles, dyes, and the like. Examples of suitable enzymes include
horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase,
or acetylcholinesterase; examples of suitable prosthetic group
complexes include streptavidin/biotin and avidin/biotin; examples
of suitable fluorescent materials include umbelliferone,
fluorescein, fluorescein isothiocyanate, rhodamine,
dichlorotriazinylamine fluorescein, dansyl chloride or
phycoerythrin; an example of a luminescent material is luminol;
examples of bioluminescent materials include luciferase, luciferin,
and aequorin; and examples of suitable radioactive material include
.sup.125I, .sup.131I, .sup.35S, or .sup.3H. Such labeled reagents
may be used in a variety of well-known assays, such as
radioimmunoassays, enzyme immunoassays, e.g., ELISA, fluorescent
immunoassays, and the like.
[0682] The antibodies can be tagged with such labels by known
methods. For instance, coupling agents such as aldehydes,
carbodiimides, dimaleimide, imidates, succinimides, bid-diazotized
benzadine and the like are used to tag the antibodies with the
above-described fluorescent, chemiluminescent, and enzyme labels.
An enzyme is typically combined with an antibody using bridging
molecules such as carbodiimides, periodate, diisocyanates,
glutaraldehyde and the like. Various labeling techniques are
described in Morrison, Methods in Enzymology 32b, 103 (1974),
Syvanen et al., J. Biol. Chem. 284, 3762 (1973) and Bolton and
Hunter, Biochem J. 133, 529(1973).
[0683] In one embodiment, the antibodies can be administered as
immunoconjugates, conjugated to a second molecule. For example, the
second molecule can be a toxin, a label, a radioisotope, a drug, or
a chemical compound.
[0684] An antibody according to the invention may be conjugated to
a therapeutic moiety such as a cytotoxin, a therapeutic agent, or a
radioactive metal ion or radioisotope. Examples of radioisotopes
include, but are not limited to, I-131, I-123, I-125, Y-90, Re-188,
Re-186, At-211, Cu-67, Bi-212, Bi-213, Pd-109, Tc-99, In-111, and
the like. Such antibody conjugates can be used for modifying a
given biological response; the drug moiety is not to be construed
as limited to classical chemical therapeutic agents. For example,
the drug moiety may be a protein or polypeptide possessing a
desired biological activity. Such proteins may include, for
example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or
diphtheria toxin, TLR agonists (such as TLR7 agonist), or
monomethylauristatin E.
[0685] Other therapeutic regimens can be combined with the
administration of the anti-HIV antibody of the present invention.
The combined administration includes co-administration, using
separate formulations or a single pharmaceutical formulation, and
consecutive administration in either order, wherein preferably
there is a time period while both (or all) active agents
simultaneously exert their biological activities. Preferably such
combined therapy results in a synergistic therapeutic effect.
[0686] For any application, the antibody, antigen binding fragment,
or nucleic acid encoding the antibody or antigen binding fragment
can be combined with anti-retroviral therapy. Antiretroviral drugs
are broadly classified by the phase of the retrovirus life-cycle
that the drug inhibits. The disclosed antibodies can be
administered in conjunction with nucleoside analog
reverse-transcriptase inhibitors (such as zidovudine, didanosine,
zalcitabine, stavudine, lamivudine, abacavir, emtricitabine,
entecavir, and apricitabine), nucleotide reverse transcriptase
inhibitors (such as tenofovir and adefovir), non-nucleoside reverse
transcriptase inhibitors (such as efavirenz, nevirapine,
delavirdine, etravirine, and rilpivirine), protease inhibitors
(such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir,
lopinavir, fosamprenavir, atazanavir, tipranavir, and darunavir),
entry or fusion inhibitors (such as maraviroc and enfuvirtide),
maturation inhibitors, (such as bevirimat and vivecon), or a broad
spectrum inhibitors, such as natural antivirals. In some examples,
a disclosed antibody or active fragment thereof or nucleic acids
encoding such is administered in conjunction with IL-15, or
conjugated to IL-15.
[0687] Single or multiple administrations of the compositions
including the antibody, antigen binding fragment, or nucleic acid
encoding the antibody or antigen binding fragment, that are
disclosed herein, are administered depending on the dosage and
frequency as required and tolerated by the patient. In any event,
the composition should provide a sufficient quantity of at least
one of the antibodies disclosed herein to effectively treat the
patient. The dosage can be administered once, but may be applied
periodically until either a therapeutic result is achieved or until
side effects warrant discontinuation of therapy.
[0688] One approach to administration of nucleic acids is direct
administration with plasmid DNA, such as with a mammalian
expression plasmid. The nucleotide sequence encoding the disclosed
antibody, or antibody binding fragments thereof, can be placed
under the control of a promoter to increase expression. Another
approach is to administer the nucleic acids in the form of
mRNA.
[0689] In some embodiments, the subject is administered cells that
are engineered to express the anti-HIV antibody. In some
embodiments, the cells are engineered immune cells, such as B
cells. In some embodiments, the cells are engineered, autologous
cells.
[0690] In another approach to using nucleic acids, an anti-HIV
antibody, or antibody binding fragment thereof can also be
expressed by attenuated viral hosts or vectors or bacterial
vectors. Recombinant vaccinia virus, adeno-associated virus (AAV),
herpes virus, retrovirus, cytomegalovirus or other viral vectors
can be used to express the antibody. For example, vaccinia vectors
and methods useful protocols are described in U.S. Pat. No.
4,722,848. BCG (Bacillus Calmette Guerin) provides another vector
for expression of the disclosed antibodies (see Stover, Nature
351:456-460, 1991).
Compositions
[0691] The present invention also encompasses compositions
comprising one or more antibodies of the invention. In certain
embodiments, the compositions are pharmaceutical compositions. In
some embodiments, formulations are prepared for storage and use by
combining an antibody with a pharmaceutically acceptable vehicle
(e.g. carrier, excipient) (Remington, The Science and Practice of
Pharmacy 20th Edition Mack Publishing, 2000). Suitable
pharmaceutically acceptable vehicles include, but are not limited
to, nontoxic buffers such as phosphate, citrate, and other organic
acids; salts such as sodium chloride; antioxidants including
ascorbic acid and methionine; preservatives (e.g.
octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;
benzalkonium chloride; benzethonium chloride; phenol, butyl or
benzyl alcohol; alkyl parabens, such as methyl or propyl paraben;
catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low
molecular weight polypeptides (e.g. less than about 10 amino acid
residues); proteins such as serum albumin, gelatin, or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;
amino acids such as glycine, glutamine, asparagine, histidine,
arginine, or lysine; carbohydrates such as monosacchandes,
disaccharides, glucose, mannose, or dextrins; chelating agents such
as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol;
salt-forming counter-ions such as sodium; metal complexes (e.g.
Zn-protein complexes); and non-ionic surfactants such as TWEEN or
polyethylene glycol (PEG).
[0692] For the treatment or prevention of HIV, the appropriate
dosage of an antibody or combination of antibodies of the present
invention can depend on a variety of factors, such as the severity
and course of the disease, the responsiveness of the disease,
whether the antibody or agent is administered for therapeutic or
preventative purposes, previous therapy, patient's clinical
history, and so on all at the discretion of the treating physician.
The antibody or agent can be administered one time or over a series
of treatments lasting from several days to several months, or until
a cure is effected or a diminution of the disease state is
achieved. The administering physician can easily determine optimum
dosages, dosing methodologies and repetition rates. In certain
embodiments, dosage is from 0.01 .mu.g to 100 mg per kg of body
weight, and can be given once or more daily, weekly, monthly or
yearly. In certain embodiments, the antibody or combination of
antibodies is given once every two weeks or once every three weeks.
In certain embodiments, the dosage of the antibody is from about
0.1 mg to about 20 mg per kg of body weight. The treating physician
can estimate repetition rates for dosing based on measured
residence times and concentrations of the drug in bodily fluids or
tissues.
[0693] Effective dosages and schedules for administering
embodiments of the present invention can be determined empirically.
In some embodiments, and effective amount of one or more antibodies
are administered to neutralize, treat, prevent or eradicate HIV
infection. In some embodiments, compositions comprising one or more
nucleic acid molecules of the invention are administered to the
subject. In some embodiments, genetic constructs capable of
inducing production of antibodies of the present invention may be
administered to a patient in need thereof.
[0694] Controlled-release parenteral formulations can be made as
implants, oily injections, or as particulate systems. For a broad
overview of protein delivery systems see, Banga, A. J., Therapeutic
Peptides and Proteins: Formulation, Processing, and Delivery
Systems, Technomic Publishing Company, Inc., Lancaster, Pa.,
(1995). Particulate systems include microspheres, microparticles,
microcapsules, nanocapsules, nanospheres, and nanoparticles.
Microcapsules contain the therapeutic protein, such as a cytotoxin
or a drug, as a central core. In microspheres the therapeutic is
dispersed throughout the particle. Particles, microspheres, and
microcapsules smaller than about 1 .mu.m are generally referred to
as nanoparticles, nanospheres, and nanocapsules, respectively.
Capillaries have a diameter of approximately 5 .mu.m so that only
nanoparticles are administered intravenously. Microparticles are
typically around 100 .mu.m in diameter and are administered
subcutaneously or intramuscularly. See, for example, Kreuter, J.,
Colloidal Drug Delivery Systems, J. Kreuter, ed., Marcel Dekker,
Inc., New York, N.Y., pp. 219-342 (1994); and Tice & Tabibi,
Treatise on Controlled Drug Delivery, A. Kydonieus, ed., Marcel
Dekker, Inc. New York, N.Y., pp. 315-339, (1992).
[0695] Polymers can be used for ion-controlled release of the
antibody compositions disclosed herein. Various degradable and
nondegradable polymeric matrices for use in controlled drug
delivery are known in the art (Langer, Accounts Chem. Res.
26:537-542, 1993). For example, the block copolymer, polaxamer 407,
exists as a viscous yet mobile liquid at low temperatures but forms
a semisolid gel at body temperature. It has been shown to be an
effective vehicle for formulation and sustained delivery of
recombinant interleukin-2 and urease (Johnston et al., Pharm. Res.
9:425-434, 1992; and Pec et al., J. Parent. Sci. Tech. 44(2):58-65,
1990). Alternatively, hydroxyapatite has been used as a
microcarrier for controlled release of proteins (Ijntema et al.,
Int. J. Pharm. 112:215-224, 1994). In yet another aspect, liposomes
are used for controlled release as well as drug targeting of the
lipid-capsulated drug (Betageri et al., Liposome Drug Delivery
Systems, Technomic Publishing Co., Inc., Lancaster, Pa. (1993)).
Numerous additional systems for controlled delivery of therapeutic
proteins are known (see U.S. Pat. Nos. 5,055,303; 5,188,837;
4,235,871; 4,501,728; 4,837,028; 4,957,735; 5,019,369; 5,055,303;
5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206;
5,271,961; 5,254,342 and 5,534,496).
[0696] In some embodiments, the compositions of the invention may
be injectable suspensions, solutions, sprays, lyophilized powders,
syrups, elixirs and the like. Any suitable form of composition may
be used. To prepare such a composition, a nucleic acid or vector of
the invention, having the desired degree of purity, is mixed with
one or more pharmaceutically acceptable carriers and/or excipients.
The carriers and excipients must be "acceptable" in the sense of
being compatible with the other ingredients of the composition.
Acceptable carriers, excipients, or stabilizers are nontoxic to
recipients at the dosages and concentrations employed, and include,
but are not limited to, water, saline, phosphate buffered saline,
dextrose, glycerol, ethanol, or combinations thereof, buffers such
as phosphate, citrate, and other organic acids; antioxidants
including ascorbic acid and methionine; preservatives (such as
octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;
benzalkonium chloride, benzethonium chloride; phenol, butyl or
benzyl alcohol; alkyl parabens such as methyl or propyl paraben;
catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low
molecular weight (less than about 10 residues) polypeptide;
proteins, such as serum albumin, gelatin, or immunoglobulins;
hydrophilic polymers such as polyvinylpyrrolidone; amino acids such
as glycine, glutamine, asparagine, histidine, arginine, or lysine;
monosaccharides, disaccharides, and other carbohydrates including
glucose, mannose, or dextrins; chelating agents such as EDTA;
sugars such as sucrose, mannitol, trehalose or sorbitol;
salt-forming counter-ions such as sodium; metal complexes (e.g.,
Zn-protein complexes); and/or non-ionic surfactants such as
TWEEN.TM. PLURONICS.TM. or polyethylene glycol (PEG).
[0697] The compositions can be designed to introduce the
antibodies, nucleic acids or expression vectors to a desired site
of action and release it at an appropriate and controllable rate.
Methods of preparing controlled-release formulations are known in
the art. For example, controlled release preparations can be
produced by the use of polymers to complex or absorb the immunogen
and/or immunogenic composition. A controlled-release formulations
can be prepared using appropriate macromolecules (for example,
polyesters, polyamino acids, polyvinyl, pyrrolidone,
ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or
protamine sulfate) known to provide the desired controlled release
characteristics or release profile. Another possible method to
control the duration of action by a controlled-release preparation
is to incorporate the active ingredients into particles of a
polymeric material such as, for example, polyesters, polyamino
acids, hydrogels, polylactic acid, polyglycolic acid, copolymers of
these acids, or ethylene vinylacetate copolymers. Alternatively,
instead of incorporating these active ingredients into polymeric
particles, it is possible to entrap these materials into
microcapsules prepared, for example, by coacervation techniques or
by interfacial polymerization, for example, hydroxymethylcellulose
or gelatin-microcapsule and poly-(methylmethacrylate) microcapsule,
respectively, in colloidal drug delivery systems (for example,
liposomes, albumin microspheres, microemulsions, nano-particles and
nanocapsules) or in macroemulsions. Such techniques are disclosed
in New Trends and Developments in Vaccines, Voller et al. (eds.),
University Park Press, Baltimore, Md., 1978 and Remington's
Pharmaceutical Sciences, 16th edition.
[0698] The compositions can be administered using any suitable
delivery method including, but not limited to, intramuscular,
intravenous, intradermal, mucosal, and topical delivery. Such
techniques are well known to those of skill in the art. More
specific examples of delivery methods are intramuscular injection,
intradermal injection, and subcutaneous injection. However,
delivery need not be limited to injection methods. Further,
delivery of DNA to animal tissue has been achieved by cationic
liposomes (Watanabe et al., (1994) Mol. Reprod. Dev. 38:268-274;
and WO 96/20013), direct injection of naked DNA into animal muscle
tissue (Robinson et al., (1993) Vaccine 11:957-960; Hoffman et al.,
(1994) Vaccine 12: 1529-1533; Xiang et al., (1994) Virology 199:
132-140; Webster et al., (1994) Vaccine 12: 1495-1498; Davis et
al., (1994) Vaccine 12: 1503-1509; and Davis et al., (1993) Hum.
Mol. Gen. 2: 1847-1851), or intradermal injection of DNA using
"gene gun" technology (Johnston et al., (1994) Meth. Cell Biol.
43:353-365). Alternatively, delivery routes can be oral, intranasal
or by any other suitable route. Delivery also be accomplished via a
mucosal surface such as the anal, vaginal or oral mucosa.
[0699] Dosing schedules (or regimens) can be readily determined for
the particular subject and composition. Hence, the composition can
be administered one or more times to the subject. Preferably, there
is a set time interval between separate administrations of the
composition. While this interval varies for every subject,
typically it can range from 10 days to several weeks, and is often
2, 4, 6 or 8 weeks. In some embodiments, the interval can be
typically from 2 to 6 weeks.
[0700] The compositions of the invention can be administered alone,
or can be co-administered, or sequentially administered, with other
HIV immunogens and/or HIV immunogenic compositions, e.g., with
"other" immunological, antigenic or vaccine or therapeutic
compositions thereby providing multivalent or "cocktail" or
combination compositions of the invention and methods of employing
them. Again, the ingredients and manner (sequential or
co-administration) of administration, as well as dosages can be
determined taking into consideration such factors as the age, sex,
weight, species and condition of the particular subject, and the
route of administration.
Kits
[0701] The present invention also includes kits useful in
performing diagnostic and prognostic assays using the antibodies of
the present invention. Kits of the invention include a suitable
container comprising an HIV-1 antibody of the invention in either
labeled or unlabeled form. In addition, when the antibody is
supplied in a labeled form suitable for an indirect binding assay,
the kit further includes reagents for performing the appropriate
indirect assay. For example, the kit includes one or more suitable
containers including enzyme substrates or derivatizing agents,
depending on the nature of the label. Control samples and/or
instructions are also included.
Sample Embodiments
[0702] This section describes exemplary compositions and methods of
the invention, presented without limitation, as a series of
paragraphs, some or all of which may be alphanumerically designated
for clarity and efficiency. Each of these paragraphs can be
combined with one or more other paragraphs, and/or with disclosure
from elsewhere in this application, including the materials
incorporated by reference, in any suitable manner. Some of the
paragraphs below expressly refer to and further limit other
paragraphs, providing without limitation examples of some of the
suitable combinations. [0703] 1. An isolated anti-HIV antibody that
is capable of neutralizing at least 95% of the HIV pseudoviruses
listed in Table 1 with an IC50 value of less than 50 .mu.g/mL.
[0704] 2. An isolated anti-HIV antibody that is capable of
neutralizing at least 99% of the HIV pseudoviruses listed in Table
1 with an IC50 value of less than 50 .mu.g/mL. [0705] 3. An
isolated anti-HIV antibody that is capable of neutralizing 100% of
the HIV pseudoviruses listed in Table 1 with an IC50 value of less
than 50 .mu.g/mL. [0706] 4. An isolated anti-HIV antibody that
neutralizes 100% of the HIV clade B, G and D viruses listed in
Table 1 with an IC50 value of less than 50 .mu.g/mL. [0707] 5. The
isolated anti-HIV antibody of any of paragraphs 1-4, wherein the
anti-HIV antibody binds to a HIV gp120 epitope comprising outer
domain loop D (which comprises 275-283), the CD4 binding loop
(which comprises 354-371), the bridging sheet (which comprises
427-439) and loop V5 (which comprises 455-463) and gp120 inner
domain: helix alpha-1 of Layer 2 (comprising positions 96-106) and
469-480 (loop prior and helix alpha-5 of Layer 3). [0708] 6. The
isolated anti-HIV antibody of any of paragraphs 1-5, wherein the
anti-HIV antibody binds to a HIV gp120 Layer 2 residues W96, K97,
E102, G124, Loop D residues E275, N276, T278, N279, N280, A281,
K282, CD4 binding loop residues P364, 5365, G366, G367, D368, 1371,
bridging sheet residues W427, Q428, G429, Loop V5 residues T455,
R456, D457, G458, G459, A460, N461, T463, and Layer 3 residues
R469, P470, G471, G472, G473, N474, K476, D477, R480. [0709] 7. The
isolated anti-HIV antibody of any of paragraphs 1-6, wherein the
antibody has a Kd for BaL-gp120 of at least about
2.456.times.10.sup.-8M as determined by surface plasmon resonance.
[0710] 8. The isolated anti-HIV antibody of any of paragraphs 1-7,
wherein the antibody has a Kd for BaL-gp120 of at least about
1.59.times.10.sup.-8M as determined by surface plasmon resonance.
[0711] 9. The isolated anti-HIV antibody of any of paragraphs 1-8,
wherein the antibody has a Kd for BaL-gp120 of at least about
1.562.times.10.sup.-8M as determined by surface plasmon resonance.
[0712] 10. The isolated anti-HIV antibody of any of paragraphs 1-9,
wherein the antibody has a Kd for BaL-gp120 of at least about
1.143.times.10.sup.-9M as determined by surface plasmon resonance.
[0713] 11. The isolated anti-HIV antibody of any of paragraphs
1-10, wherein the antibody has Kd for BaL-gp120 of at least about
8.602.times.10.sup.-10 M as determined by surface plasmon
resonance. [0714] 12. The isolated anti-HIV antibody of any of
paragraphs 1-11, wherein the anti-HIV antibody further neutralizes
strain CNE5 (clade CRF01_AE) with an IC50 value of less than 50
.mu.g/mL. [0715] 13. The isolated anti-HIV antibody of any of
paragraphs 1-12, wherein the antibody is capable of neutralizing
HIV pseudoviruses listed in Table 1 with a median IC50 value of
less than 0.5 .mu.g/mL. [0716] 14. The isolated anti-HIV antibody
of any of paragraphs 1-13, wherein the anti-HIV antibody
neutralizes at least 50%, at least 55%, at least 60%, at least 65%,
at least 70%, at least 75%, at least 80%, at least 85%, at least
90%, at least 95%, or at least 99% of the HIV pseudoviruses listed
in Table 1 with an IC50 value of less than about 1 .mu.g/ml,
between about 1-5 .mu.g/ml or greater than about 5 .mu.g/ml. [0717]
15. The isolated anti-HIV antibody of any of paragraphs 1-14,
wherein the anti-HIV antibody neutralizes at least about 86.4% of
the HIV pseudoviruses listed in Table 1 with an IC50 value of less
than 1 .mu.g/mL. [0718] 16. The isolated anti-HIV antibody of
paragraph 15, wherein the antibody is N49P7 or an antigen binding
fragment thereof. [0719] 17. The isolated anti-HIV antibody of
paragraph 16, wherein the antibody comprises the VH and VL regions
of N49P7 as described herein. [0720] 18. The isolated anti-HIV
antibody of paragraph 17, wherein the antibody comprises the CDRs
of the VH and VL regions of N49P7 as described herein. [0721] 19.
The isolated anti-HIV antibody of any of paragraphs 1-14, wherein
the anti-HIV antibody neutralizes at least 88.7% of the HIV
pseudoviruses listed in Table 1 with an IC50 value of less than 1
.mu.g/mL. [0722] 20. The isolated anti-HIV antibody of paragraph
19, wherein the antibody is N49P7.1 or an antigen binding fragment
thereof [0723] 21. The isolated anti-HIV antibody of paragraph 20,
wherein the antibody comprises the VH and VL regions of N49P7.1 as
described herein. [0724] 22. The isolated anti-HIV antibody of
paragraph 21, wherein the antibody comprises the CDRs of the VH and
VL regions of N49P7.1 as described herein. [0725] 23. The isolated
anti-HIV antibody of any of paragraphs 1-22, wherein the anti-HIV
antibody neutralizes at least 84.5% of the HIV pseudoviruses listed
in Table 1 with an IC50 value of less than 1 .mu.g/mL. [0726] 24.
The isolated anti-HIV antibody of paragraph 23, wherein the
antibody is N49P7.2 or an antigen binding fragment thereof [0727]
25. The isolated anti-HIV antibody of any of paragraph 24, wherein
the antibody comprises the VH and VL regions of N49P7.2 as
described herein. [0728] 26. The isolated anti-HIV antibody of any
of paragraph 25, wherein the antibody comprises the CDRs of the VH
and VL regions of N49P7.2 as described herein. [0729] 27. The
isolated anti-HIV antibody of any of paragraphs 1-14, wherein the
anti-HIV antibody neutralizes at least 71.8% of the HIV
pseudoviruses listed in Table 1 with an IC50 value of less than 1
.mu.g/mL. [0730] 28. The isolated anti-HIV antibody of paragraph
27, wherein the antibody is N49P6 or an antigen binding fragment
thereof. [0731] 29. The isolated anti-HIV antibody of paragraph 28,
wherein the antibody comprises the VH and VL regions of N49P6 as
described herein. [0732] 30. The isolated anti-HIV antibody of
paragraph 29, wherein the antibody comprises the CDRs of the VH and
VL regions of N49P6 as described herein. [0733] 31. The isolated
anti-HIV antibody of any of paragraphs 1-14, wherein the anti-HIV
antibody neutralizes at least 93.3% of the HIV pseudoviruses listed
in Table 1 with an IC50 value of less than 1 .mu.g/mL. [0734] 32.
The isolated anti-HIV antibody of paragraph 31, wherein the
antibody is N49P9 or an antigen binding fragment thereof. [0735]
33. The isolated anti-HIV antibody of paragraph 32, wherein the
antibody comprises the VH and VL regions of N49P9 as described
herein. [0736] 34. The isolated anti-HIV antibody of paragraph 33,
wherein the antibody comprises the CDRs of the VH and VL regions of
N49P9 as described herein. [0737] 35. The isolated anti-HIV
antibody of any of paragraphs 1-14, wherein the anti-HIV antibody
neutralizes at least 91.1% of the HIV pseudoviruses listed in Table
1 with an IC50 value of less than 1 .mu.g/mL. [0738] 36. The
isolated anti-HIV antibody of paragraph 35, wherein the antibody is
N49P9.1 or an antigen binding fragment thereof [0739] 37. The
isolated anti-HIV antibody of paragraph 36, wherein the antibody
comprises VH and VL regions of N49P9.1 as described herein. [0740]
38. The isolated anti-HIV antibody of paragraph 37, wherein the
antibody comprises the CDRs of the VH and VL regions of N49P9.1 as
described herein. [0741] 39. The isolated anti-HIV antibody of any
of paragraphs 1-14, wherein the anti-HIV antibody neutralizes at
least 41.9% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. [0742] 40. The isolated anti-HIV
antibody of paragraph 39, wherein the anti-HIV antibody is N49P11
or an antigen binding fragment thereof. [0743] 41. The isolated
anti-HIV antibody of paragraph 40, wherein the anti-HIV antibody
comprises the VH and VL regions of N49P11 as described herein.
[0744] 42. The isolated anti-HIV antibody of paragraph 41, wherein
the anti-HIV antibody comprises the CDRs of the VH and VL regions
of N49P11 as described herein. [0745] 43. The isolated anti-HIV
antibody of any of paragraphs 1-14, wherein the anti-HIV antibody
neutralizes at least 2.1% of the HIV pseudoviruses listed in Table
1 with an IC50 value of less than 1 .mu.g/mL. [0746] 44. The
isolated anti-HIV antibody of paragraph 43, wherein the anti-HIV
antibody is N49P18.1 or an antigen binding fragment thereof [0747]
45. The isolated anti-HIV antibody of paragraph 44, wherein the
anti-HIV antibody comprises the VH and VL regions of N49P18.1 as
described herein. [0748] 46. The isolated anti-HIV antibody of
paragraph 45, wherein the anti-HIV antibody comprises the CDRs of
the VH and VL regions of N49P18.1 as described herein. [0749] 47.
The isolated anti-HIV antibody of any of paragraphs 1-14, wherein
the anti-HIV antibody neutralizes at least 60% of the HIV
pseudoviruses listed in Table 1 with an IC50 value of less than 1
.mu.g/mL. [0750] 48. The isolated anti-HIV antibody of paragraph
47, wherein the anti-HIV antibody is N49P19 or an antigen binding
fragment thereof. [0751] 49. The isolated anti-HIV antibody of
paragraph 48, wherein the anti-HIV antibody comprises the VH and VL
regions of N49P19 as described herein. [0752] 50. The isolated
anti-HIV antibody of paragraph 49, wherein the anti-HIV antibody
comprises the CDRs of the VH and VL regions of N49P19 as described
herein. [0753] 51. The isolated anti-HIV antibody of any of
paragraphs 1-14, wherein the anti-HIV antibody neutralizes at least
58.3% of the HIV pseudoviruses listed in Table 1 with an IC50 value
of less than 1 .mu.g/mL. [0754] 52. The isolated anti-HIV antibody
of paragraph 51, wherein the anti-HIV antibody is N49P22 or an
antigen binding fragment thereof. [0755] 53. The isolated anti-HIV
antibody of paragraph 52, wherein the anti-HIV antibody comprises
the VH and VL regions of N49P22 as described herein. [0756] 54. The
isolated anti-HIV antibody of paragraph 53, wherein the anti-HIV
antibody comprises the CDRs of the VH and VL regions of N49P22 as
described herein. [0757] 55. The isolated anti-HIV antibody of any
of paragraphs 1-14, wherein the anti-HIV antibody neutralizes at
least 88.6% of the HIV pseudoviruses listed in Table 1 with an IC50
value of less than 1 .mu.g/mL. [0758] 56. The isolated anti-HIV
antibody of paragraph 55, wherein the anti-HIV antibody is N49P23
or an antigen binding fragment thereof. [0759] 57. The isolated
anti-HIV antibody of paragraph 56, wherein the anti-HIV antibody
comprises the VH and VL regions of N49P23 as described herein.
[0760] 58. The isolated anti-HIV antibody of paragraph 57, wherein
the anti-HIV antibody comprises the CDRs of the VH and VL regions
of N49P23 as described herein. [0761] 59. The isolated anti-HIV
antibody of any of paragraphs 1-58, wherein anti-HIV antibody is
selected from the group consisting of: [0762] a. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYDFIDYV (SEQ ID NO:401), CDR H2 comprises MNPSGGGT (SEQ ID NO:402)
and CDR H3 comprises VRDRANGSGRRRFESVNWFLDL (SEQ ID NO:403); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAFEN (SEQ ID NO:404); [0763] b.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYKFPDYI (SEQ ID NO:405), CDR H2 comprises INPMGGQV
(SEQ ID NO:406) and CDR H3 comprises VRDRSNGSGRRFESSN (SEQ ID
NO:407); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0764] c. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFTDYL (SEQ ID NO:409), CDR H2
comprises MNPVYGQV (SEQ ID NO:410) and CDR H3 comprises
VRDTGDGSRRHFDSINWFLDL (SEQ ID NO:411); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFD and CDR
L3 comprises WAFEA (SEQ ID NO:412); [0765] d. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYV (SEQ ID NO:413), CDR H2 comprises IDPPYGQV (SEQ ID NO:414)
and CDR H3 comprises VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0766] e.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFVDYF (SEQ ID NO:416), CDR H2 comprises MDPLNGRP
(SEQ ID NO:417) and CDR H3 comprises VRDKSNGSGRRFDSSNWFLDL (SEQ ID
NO:418); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAYDA (SEQ
ID NO:419); [0767] f. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFSDYI (SEQ ID NO:420), CDR H2
comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEV (SEQ ID NO:422); [0768] g. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFIDYI (SEQ ID NO:423), CDR H2 comprises IDPMNGRP (SEQ ID NO:424)
and CDR H3 comprises VRDKSNGSGKRFDSSNWFLDL (SEQ ID NO:425); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAYDA (SEQ ID NO:419); [0769] h.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFTDYI (SEQ ID NO:426), CDR H2 comprises MNPMGGRT
(SEQ ID NO:427) and CDR H3 comprises VRDKSNGSGKRFDSSNWFLDL (SEQ ID
NO:425); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0770] i. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYTFVDYL (SEQ ID NO:428), CDR H2
comprises MDPMNGRP (SEQ ID NO:429) and CDR H3 comprises
VRDKSGGSGKLFDSSNWFLDL (SEQ ID NO:430); and a light chain variable
region, wherein CDR L1 comprises HNY, CDR L2 comprises DFN and CDR
L3 comprises WAYDA (SEQ ID NO:419); [0771] j. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTDYV (SEQ ID NO:413), CDR H2 comprises INPGYGQV (SEQ ID NO:431)
and CDR H3 comprises VRDRSNGWGKRFESSNWFLDL (SEQ ID NO:415); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0772] k.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYTFTDYV (SEQ ID NO:413), CDR H2 comprises MDPSYGQV
(SEQ ID NO:432) and CDR H3 comprises VRDRSHGSGRQFESSNWFLDL (SEQ ID
NO:433); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408);
[0773] l. an antibody comprising a heavy chain variable region,
wherein CDR comprises GYTFTDYV (SEQ ID NO:413), CDR H2 comprises
MDPSFGQM (SEQ ID NO:434) and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL
(SEQ ID NO:435); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0774] m. an antibody comprising a heavy chain variable
region, wherein CDR comprises GYRFTDYV (SEQ ID NO:436), CDR H2
comprises MDPSFGRM (SEQ ID NO:437) and CDR H3 comprises
VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0775] n. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFIDYV (SEQ ID NO:438), CDR H2 comprises MDPTYGRM (SEQ ID NO:439)
and CDR H3 comprises VRDRSHGSGRLFESSNWFLDL (SEQ ID NO:435); and a
light chain variable region, wherein CDR L1 comprises HNL, CDR L2
comprises DFN and CDR L3 comprises WAYEA (SEQ ID NO:408); [0776] o.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GYRFLDYI (SEQ ID NO:440), CDR H2 comprises MNPMGGQV
(SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID
NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408); [0777] p. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2
comprises MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD
and CDR L3 comprises NTYEF (SEQ ID NO:446); [0778] q. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYNFVDSR (SEQ ID NO:447), CDR H2 comprises INPLQGGV (SEQ ID NO:448)
and CDR H3 comprises ARGIDGKSYPFHF (SEQ ID NO:449); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
ESS and CDR L3 comprises SILEF (SEQ ID NO:450); [0779] r. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYTFTTHHGHF (SEQ ID NO:500), CDR H2 comprises MNPMTGQM
(SEQ ID NO:462) and CDR H3 comprises ARGDFGQNYPFHY (SEQ ID NO:463);
and a light chain variable region, wherein CDR L1 comprises NRYL
(SEQ ID NO:464), CDR L2 comprises DDN and CDR L3 comprises ASYER
(SEQ ID NO:465); [0780] s. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYNFMDQF (SEQ ID NO:466),
CDR H2 comprises MNPIYGQV (SEQ ID NO:467) and CDR H3 comprises
ARGPSGENYPFHY (SEQ ID NO:444); and a light chain variable region,
wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2 comprises DDD
and CDR L3 comprises NTYEF (SEQ ID NO:446); [0781] t. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYNFVDSR (SEQ ID NO:447), CDR H2 comprises INPLHGGV (SEQ ID NO:468)
and CDR H3 comprises ARGIDGKSYPFHF (SEQ ID NO:449); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
ESS and CDR L3 comprises SILEF (SEQ ID NO:450); [0782] u. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GYTFTKYF (SEQ ID NO:451), CDR H2 comprises IHPRTGAV (SEQ
ID NO:452) and CDR H3 comprises ARGAFEADSYGSSYPFHH (SEQ ID NO:453);
and a light chain variable region, wherein CDR L1 comprises GNYNP
(SEQ ID NO:454), CDR L2 comprises EDN and CDR L3 comprises ASFEF
(SEQ ID NO:455); [0783] v. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYTFTKYT (SEQ ID NO:456),
CDR H2 comprises IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises
ARGAFEADLSGPTYPFHH (SEQ ID NO:457); and a light chain variable
region, wherein CDR L1 comprises GNYNP (SEQ ID NO:454), CDR L2
comprises EDN and CDR L3 comprises ASFEF (SEQ ID NO:455); [0784] w.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GFNFIDSV (SEQ ID NO:458), CDR H2 comprises IKPLRGAV
(SEQ ID NO:459) and CDR H3 comprises AKGAFRGGSPFGF (SEQ ID NO:460);
and a light chain variable region, wherein CDR L1 comprises DVT and
CDR L2 comprises ASREF (SEQ ID NO:461); [0785] x. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYTFTSYF (SEQ ID NO:469), CDR H2 comprises INPLHGAV (SEQ ID NO:470)
and CDR H3 comprises TRGIVADGWPYGH (SEQ ID NO:471); and a light
chain variable region, wherein CDR L1 comprises S, CDR L2 comprises
EGA and CDR L3 comprises SSLQF (SEQ ID NO:472); [0786] y. an
antibody comprising a heavy chain variable region, wherein CDR H1
comprises GFTFIDHI (SEQ ID NO:473), CDR H2 comprises IKPLRGAV (SEQ
ID NO:459) and CDR H3 comprises CKAAAPEEAFPLQY (SEQ ID NO:474); and
a light chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DNN and CDR L3 comprises SSRTF (SEQ ID NO:475); [0787] z.
an antibody comprising a heavy chain variable region, wherein CDR
H1 comprises GFKFIDHI (SEQ ID NO:476), CDR H2 comprises IKPLGGVA
(SEQ ID NO:477) and CDR H3 comprises CKAAAPDEAFPLEY (SEQ ID
NO:478); and a light chain variable region, wherein CDR L1
comprises NVD, CDR L2 comprises DNN and CDR L3 comprises SSTTF (SEQ
ID NO:479); [0788] aa. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GFAFLDH (SEQ ID NO:480),
CDR H2 comprises VKTIGGVV (SEQ ID NO:481) and CDR H3 comprises
SKAAAPDEAFPLEF (SEQ ID NO:482); and a light chain variable region,
wherein CDR L1 comprises NVD, CDR L2 comprises DNN and CDR L3
comprises SSTTF (SEQ ID NO:479); [0789] bb. an antibody comprising
a heavy chain variable region, wherein CDR H1 comprises GFKFTEYF
(SEQ ID NO:483), CDR H2 comprises LNPLRGAV (SEQ ID NO:484) and CDR
H3 comprises ARAVFNEAFPFDY (SEQ ID NO:485); and a light chain
variable region, wherein CDR L1 comprises VS, CDR L2 comprises DGD
and CDR L3 comprises ASREF (SEQ ID NO:461); [0790] cc. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GFKFIDHI (SEQ ID NO:476), CDR H2 comprises IKPLGGVA (SEQ ID NO:477)
and CDR H3 comprises CKAAAPDEAFPLEY (SEQ ID NO:478); and a light
chain variable region, wherein CDR L1 comprises NVD, CDR L2
comprises DND and CDR L3 comprises SSTTF (SEQ ID NO:479); [0791]
dd. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GFAFLDHI (SEQ ID NO:486), CDR H2 comprises
VKTIGGVV (SEQ ID NO:481) and CDR H3 comprises SKAAAPDEAFPLEF (SEQ
ID NO:482); and a light chain variable region, wherein CDR L1
comprises NVD, CDR L2 comprises DNN and CDR L3 comprises SSTTF (SEQ
ID NO:479); [0792] ee. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GFKFIDSV (SEQ ID NO:487),
CDR H2 comprises IKPLGGAV (SEQ ID NO:488) and CDR H3 comprises
AKGAFGGGSPFGF (SEQ ID NO:489); and a light chain variable region,
wherein CDR L1 comprises DVT and CDR L2 comprises ASREF (SEQ ID
NO:461); [0793] ff. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GFNFIDSV (SEQ ID NO:458), CDR H2
comprises IKPLRGGV (SEQ ID NO:490) and CDR H3 comprises
AKGAFGGSSPFGF (SEQ ID NO:491); and a light chain variable region,
wherein CDR L1 comprises DVT and CDR L2 comprises ASREF (SEQ ID
NO:461); [0794] gg. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GFTFIKYT (SEQ ID NO:492), CDR H2
comprises IHPRTGAV (SEQ ID NO:452) and CDR H3 comprises
ARGAFEADLYGPTYPFHH (SEQ ID NO:493); and a light chain variable
region, wherein CDR L1 comprises GSYNP (SEQ ID NO:494), CDR L2
comprises DDN and CDR L3 comprises ASFEF (SEQ ID NO:455); [0795]
hh. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYNFVDSL (SEQ ID NO:495), CDR H2 comprises
INPLQGGV (SEQ ID NO:448) and CDR H3 comprises ARGIDGNSYPFHF (SEQ ID
NO:496); and a light chain variable region, wherein CDR L1
comprises S, CDR L2 comprises ESS and CDR L3 comprises SILEF (SEQ
ID NO:450); [0796] ii. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPTYGQV (SEQ ID NO:443) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0797] jj. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYRFPDYI (SEQ ID NO:497), CDR H2 comprises MNPMGGQV (SEQ ID NO:421)
and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a
light chain variable region, wherein CDR L1 comprises HNY, CDR L2
comprises DFN and CDR L3 comprises WAFEN (SEQ ID NO:404); [0798]
kk. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFD and CDR L3 comprises WAFEA (SEQ
ID NO:412); [0799] ll. an antibody comprising a heavy chain
variable region, wherein CDR comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2
comprises DDD and CDR L3 comprises NTYEF (SEQ ID NO:446); [0800]
mm. an antibody comprising a heavy chain variable region, wherein
CDR H1 comprises GYRFPDYI (SEQ ID NO:497), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNY, CDR L2 comprises DFN and CDR L3 comprises WAYDA (SEQ
ID NO:419); [0801] nn. an antibody comprising a heavy chain
variable region, wherein CDR H1 comprises GYRFPDYI (SEQ ID NO:497),
CDR H2 comprises MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises HNL, CDR L2 comprises DFN and CDR
L3 comprises WAYEA (SEQ ID NO:408); [0802] oo. an antibody
comprising a heavy chain variable region, wherein CDR H1 comprises
GYKFMDQL (SEQ ID NO:442), CDR H2 comprises MNPTYGQV (SEQ ID NO:443)
and CDR H3 comprises VRDRSNGSGKRFESSN (SEQ ID NO:498); and a light
chain variable region, wherein CDR L1 comprises RHII (SEQ ID
NO:445), CDR L2 comprises DDD and CDR L3 comprises NTYEF (SEQ ID
NO:446); [0803] pp. an antibody comprising a heavy chain variable
region, wherein CDR H1 comprises GYKFMDQL (SEQ ID NO:442), CDR H2
comprises (SEQ ID NO:443) and CDR H3 comprises
VRDRSNGSGKRFESSNWFLDL (SEQ ID NO:441); and a light chain variable
region, wherein CDR L1 comprises RHII (SEQ ID NO:445), CDR L2
comprises DDD and CDR L3 comprises NTYEF (SEQ ID NO:446); and
[0804] qq. an antibody comprising a heavy chain variable region,
wherein CDR H1 comprises GYRFLDYI (SEQ ID NO:440), CDR H2 comprises
MNPMGGQV (SEQ ID NO:421) and CDR H3 comprises VRDRSNGSGKRFESSNWFLDL
(SEQ ID NO:441); and a light chain variable region, wherein CDR L1
comprises HNL, CDR L2 comprises DFN and CDR L3 comprises WAYEA (SEQ
ID NO:408). [0805] 60. The isolated anti-HIV antibody of any of
claims 1-59, wherein the anti-HIV antibody comprises a heavy chain
or an antigen binding fragment thereof and a light chain or an
antigen binding fragment thereof, wherein the heavy chain or
antigen binding fragment thereof comprises a heavy chain variable
(V.sub.H) region and the light chain or antigen binding fragment
thereof comprises a light chain variable (V.sub.L) region; wherein
the anti-HIV antibody is selected from the group consisting of an
antibody: [0806] a. wherein the VH region comprises amino acids
1-128 of SEQ ID NO:1 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:2 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0807] b. wherein the VH region comprises amino acids 1-127 of SEQ
ID NO:3 or a variant thereof comprising 1, 2, 3, or 4 conservative
amino acid substitutions; wherein the VL region comprises amino
acids 1-99 of SEQ ID NO:4 or a variant thereof comprising 1, 2, 3,
or 4 conservative amino acid substitutions; [0808] c. wherein the
VH region comprises amino acids 1-127 of SEQ ID NO:5 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:6 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0809] d. wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:7 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:8 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0810] e. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:9 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:10 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0811] f. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:11 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:12 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0812] g. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:13 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:14 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0813] h. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:15 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:16 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0814] i. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:17 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:18 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0815] j. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:19 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:20 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0816] k. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:21 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:22 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0817] l. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:23 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:24 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions;
[0818] m. wherein the VH region comprises amino acids 1-127 of SEQ
ID NO:25 or a variant thereof comprising 1, 2, 3, or 4 conservative
amino acid substitutions; wherein the VL region comprises amino
acids 1-99 of SEQ ID NO:26 or a variant thereof comprising 1, 2, 3,
or 4 conservative amino acid substitutions; [0819] n. wherein the
VH region comprises amino acids 1-127 of SEQ ID NO:27 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:28 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0820] o. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:29 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:30 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0821] p. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:31 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:32 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0822] q. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:33 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:34 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0823] r. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:35 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:36 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0824] s. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:37 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:38 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0825] t. wherein the VH
region comprises amino acids 1-123 of SEQ ID NO:39 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:40 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0826] u. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:41 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:42 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0827] v. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:43 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:44 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0828] w. wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:45 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:46 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0829] x. wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:47 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:48 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0830] y. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:49 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:50 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0831] z. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:51 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:52 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0832] aa. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:53 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:54 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0833] bb. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:55 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:56 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0834] cc. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:57 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:58 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0835] dd. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:59 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:60 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0836] ee. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:61 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-98 of
SEQ ID NO:62 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0837] ff. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:63 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:64 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0838] gg. wherein the VH
region comprises amino acids 1-121 of SEQ ID NO:65 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:66 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0839] hh. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:67 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:68 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0840] ii. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:69 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:70 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0841] jj. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:71 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-96 of
SEQ ID NO:72 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0842] kk. wherein the VH
region comprises amino acids 1-125 of SEQ ID NO:73 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-101 of
SEQ ID NO:74 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0843] ll. wherein the VH
region comprises amino acids 1-120 of SEQ ID NO:75 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-97 of
SEQ ID NO:76 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0844] mm. wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:153 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:155 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0845] nn. wherein the VH
region comprises amino acids 1-128 of SEQ ID NO:157 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:159 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0846] oo. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:161 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:163 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0847] pp. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:165 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:167 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0848] qq. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:169 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:171 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0849] rr. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:173 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:175 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0850] ss. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:177 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:179 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0851] tt. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:181 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:183 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0852] uu. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:185 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:187 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0853] vv. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:189 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:191 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0854] ww. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:193 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:195 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0855] xx. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:197 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:199 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0856] yy. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:201 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:203 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0857] zz. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:205 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:207 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0858] aaa. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:209 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-100 of
SEQ ID NO:211 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; [0859] bbb. wherein the VH
region comprises amino acids 1-127 of SEQ ID NO:213 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; wherein the VL region comprises amino acids 1-99 of
SEQ ID NO:215 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VH region
comprises amino acids 1-127 of SEQ ID NO:217 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
wherein the VL region comprises amino acids 1-99 of SEQ ID NO:219
or a variant thereof comprising 1, 2, 3, or 4 conservative amino
acid substitutions; [0860] ccc. wherein the VH region comprises
amino acids 1-127 of SEQ ID NO:221 or a variant thereof comprising
1, 2, 3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:223 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; [0861] ddd. wherein the VH region comprises amino
acids 1-128 of SEQ ID NO:225 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:227 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; [0862] eee. wherein the VH region comprises amino
acids 1-127 of SEQ ID NO:229 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:231 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; [0863] fff. wherein the VH region comprises amino
acids 1-127 of SEQ ID NO:233 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:235 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions; [0864] ggg. wherein the VH region comprises amino
acids 1-127 of SEQ ID NO:237 or a variant thereof comprising 1, 2,
3, or 4 conservative amino acid substitutions; wherein the VL
region comprises amino acids 1-99 of SEQ ID NO:239 or a variant
thereof comprising 1, 2, 3, or 4 conservative amino acid
substitutions;
[0865] hhh. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:241 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:243 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0866] iii. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:245 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:247 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0867] jjj. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:249 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:251 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0868] kkk. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:253 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:255 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0869] lll. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:257 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:259 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0870] mmm. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:261 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:263 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0871] nnn. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:265 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:267 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0872] ooo. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:269 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:271 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0873] ppp. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:273 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:275 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0874] qqq. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:277 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:279 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0875] rrr. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:281 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:283 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0876] sss. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:285 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:287 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0877] ttt. wherein the VH region comprises amino acids 1-127 of
SEQ ID NO:289 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:291 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0878] uuu. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:293 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:295 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0879] vvv. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:297 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:299 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0880] www. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:301 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:303 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0881] xxx. wherein the VH region comprises amino acids 1-123 of
SEQ ID NO:305 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:307 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0882] yyy. wherein the VH region comprises amino acids 1-128 of
SEQ ID NO:309 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:311 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0883] zzz. wherein the VH region comprises amino acids 1-128 of
SEQ ID NO:313 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:315 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0884] aaaa. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:317 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-97 of SEQ ID NO:319 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0885] bbbb. wherein the VH region comprises amino acids 1-123 of
SEQ ID NO:321 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:323 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0886] cccc. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:325 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:327 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0887] dddd. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:329 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-100 of SEQ ID NO:331 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0888] eeee. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:333 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-97 of SEQ ID NO:335 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0889] ffff. wherein the VH region comprises amino acids 1-125 of
SEQ ID NO:337 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-101 of SEQ ID NO:339 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0890] gggg. wherein the VH region comprises amino acids 1-125 of
SEQ ID NO:341 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-101 of SEQ ID NO:343 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0891] hhhh. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:345 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:347 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0892] iiii. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:349 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-97 of SEQ ID NO:351 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0893] jjjj. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:353 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:355 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0894] kkkk. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:357 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:359 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0895] llll. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:361 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:363 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0896] mmmm. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:365 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:367 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0897] nnnn. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:369 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-98 of SEQ ID NO:371 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0898] oooo. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:373 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:375 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0899] pppp. wherein the VH region comprises amino acids 1-121 of
SEQ ID NO:377 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-99 of SEQ ID NO:379 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0900] qqqq. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:381 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:383 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0901] rrrr. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:385 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:387 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0902] ssss. wherein the VH region comprises amino acids 1-120 of
SEQ ID NO:389 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-96 of SEQ ID NO:391 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0903] tttt. wherein the VH region comprises amino acids 1-125 of
SEQ ID NO:393 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; wherein the VL region
comprises amino acids 1-101 of SEQ ID NO:395 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions;
[0904] uuuu. wherein the VH region comprises and amino acids 1-120
of SEQ ID NO:397 or a variant thereof comprising 1, 2, 3, or 4
conservative amino acid substitutions; and wherein the VL region
comprises amino acids 1-97 of SEQ ID NO:399 or a variant thereof
comprising 1, 2, 3, or 4 conservative amino acid substitutions.
[0905] 61. The anti-HIV antibody of any of paragraphs 1-60, wherein
the anti-HIV antibody is selected from the group consisting of:
[0906] a. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:1 or an antigen binding fragment thereof and a
light chain amino acid sequence comprising SEQ ID NO:2 or an
antigen binding fragment thereof; [0907] b. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:3 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:4 or an antigen binding fragment
thereof; [0908] c. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:5 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:6 or an antigen binding fragment thereof; [0909] d. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID NO:7
or an antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:8 or an antigen binding fragment
thereof; [0910] e. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:9 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:10 or an antigen binding fragment thereof; [0911] f. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:11 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:12 or an antigen binding
fragment thereof; [0912] g. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:13 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:14 or an antigen binding fragment thereof; [0913] h. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:15 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:16 or an antigen
binding fragment thereof; [0914] i. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:17 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:18 or an antigen binding fragment thereof;
[0915] j. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:19 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:20 or an
antigen binding fragment thereof;
[0916] k. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:21 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:22 or an
antigen binding fragment thereof; [0917] l. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:23 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:24 or an antigen binding fragment
thereof; [0918] m. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:25 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:26 or an antigen binding fragment thereof; [0919] n. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:27 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:28 or an antigen binding
fragment thereof; [0920] o. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:29 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:30 or an antigen binding fragment thereof; [0921] p. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:31 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:32 or an antigen
binding fragment thereof; [0922] q. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:33 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:34 or an antigen binding fragment thereof;
[0923] r. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:35 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:36 or an
antigen binding fragment thereof; [0924] s. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:37 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:38 or an antigen binding fragment
thereof; [0925] t. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:39 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:40 or an antigen binding fragment thereof; [0926] u. an antibody
comprising a heavy chain amino acid sequence comprising SEQ ID
NO:41 or an antigen binding fragment thereof and a light chain
amino acid sequence comprising SEQ ID NO:42 or an antigen binding
fragment thereof; [0927] v. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:43 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:44 or an antigen binding fragment thereof; [0928] w. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:45 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:46 or an antigen
binding fragment thereof; [0929] x. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:47 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:48 or an antigen binding fragment thereof;
[0930] y. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:49 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:50 or an
antigen binding fragment thereof; [0931] z. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:51 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:52 or an antigen binding fragment
thereof; [0932] aa. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:53 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:54 or an antigen binding fragment thereof; [0933] bb. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:55 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:56 or an antigen
binding fragment thereof; [0934] cc. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:57 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:58 or an antigen binding fragment thereof;
[0935] dd. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:59 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:60 or an
antigen binding fragment thereof; [0936] ee. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:61 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:62 or an antigen binding fragment
thereof; [0937] ff. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:63 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:64 or an antigen binding fragment thereof; [0938] gg. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:65 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:66 or an antigen
binding fragment thereof; [0939] hh. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:67 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:68 or an antigen binding fragment thereof;
[0940] ii. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:69 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:70 or an
antigen binding fragment thereof; [0941] jj. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:71 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:72 or an antigen binding fragment
thereof; [0942] kk. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:73 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:74 or an antigen binding fragment thereof; [0943] ll. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:75 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:76 or an antigen
binding fragment thereof; [0944] mm. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:153 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:155 or an antigen binding fragment thereof;
[0945] nn. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:157 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:159 or an
antigen binding fragment thereof; [0946] oo. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:161 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:163 or an antigen binding fragment
thereof; [0947] pp. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:165 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:167 or an antigen binding fragment thereof; [0948] qq. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:169 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:171 or an antigen
binding fragment thereof; [0949] rr. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:173 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:175 or an antigen binding fragment thereof;
[0950] ss. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:177 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:179 or an
antigen binding fragment thereof; [0951] tt. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:181 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:183 or an antigen binding fragment
thereof; [0952] uu. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:185 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:187 or an antigen binding fragment thereof; [0953] vv. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:189 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:191 or an antigen
binding fragment thereof; [0954] ww. an antibody comprising a heavy
chain amino acid sequence comprising SEQ ID NO:193 or an antigen
binding fragment thereof and a light chain amino acid sequence
comprising SEQ ID NO:195 or an antigen binding fragment thereof;
[0955] xx. an antibody comprising a heavy chain amino acid sequence
comprising SEQ ID NO:197 or an antigen binding fragment thereof and
a light chain amino acid sequence comprising SEQ ID NO:199 or an
antigen binding fragment thereof; [0956] yy. an antibody comprising
a heavy chain amino acid sequence comprising SEQ ID NO:201 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:203 or an antigen binding fragment
thereof; [0957] zz. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:205 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:207 or an antigen binding fragment thereof; [0958] aaa. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:209 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:211 or an antigen
binding fragment thereof; [0959] bbb. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:213 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:215 or an antigen binding fragment
thereof; [0960] ccc. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:217 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:219 or an antigen binding fragment thereof; [0961] ddd.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:221 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:223 or an antigen
binding fragment thereof; [0962] eee. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:225 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:227 or an antigen binding fragment
thereof; [0963] fff. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:229 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:231 or an antigen binding fragment thereof; [0964] ggg.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:233 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:235 or an antigen
binding fragment thereof; [0965] hhh. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:237 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:239 or an antigen binding fragment
thereof; [0966] iii. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:241 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:243 or an antigen binding fragment thereof; [0967] jjj.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:245 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:247 or an antigen
binding fragment thereof; [0968] kkk. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:249 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:251 or an antigen binding fragment
thereof; [0969] lll. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:253 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:255 or an antigen binding fragment thereof; [0970] mmm.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:257 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:259 or an antigen
binding fragment thereof; [0971] nnn. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:261 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:263 or an antigen binding fragment
thereof; [0972] ooo. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:265 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:267 or an antigen binding fragment thereof; [0973] ppp.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:269 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:271 or an antigen
binding fragment thereof; [0974] qqq. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:273 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:275 or an antigen binding fragment
thereof; [0975] rrr. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:277 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:279 or an antigen binding fragment thereof; [0976] sss.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:281 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:283 or an antigen
binding fragment thereof; [0977] ttt. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:285 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:287 or an antigen binding fragment
thereof; [0978] uuu. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:289 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:291 or an antigen binding fragment thereof; [0979] vvv.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:293 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:295 or an antigen
binding fragment thereof; [0980] www. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:297 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:299 or an antigen binding fragment
thereof;
[0981] xxx. an antibody comprising a heavy chain amino acid
sequence comprising SEQ ID NO:301 or an antigen binding fragment
thereof and a light chain amino acid sequence comprising SEQ ID
NO:303 or an antigen binding fragment thereof; [0982] yyy. an
antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:305 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:307 or an antigen
binding fragment thereof; [0983] zzz. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:309 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:311 or an antigen binding fragment
thereof; [0984] aaaa. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:313 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:315 or an antigen binding fragment thereof; [0985] bbbb.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:317 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:319 or an antigen
binding fragment thereof; [0986] cccc. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:321 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:323 or an antigen binding fragment
thereof; [0987] dddd. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:325 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:327 or an antigen binding fragment thereof; [0988] eeee.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:329 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:331 or an antigen
binding fragment thereof; [0989] ffff. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:333 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:335 or an antigen binding fragment
thereof; [0990] gggg. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:337 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:339 or an antigen binding fragment thereof; [0991] hhhh.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:341 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:343 or an antigen
binding fragment thereof; [0992] iiii. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:345 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:347 or an antigen binding fragment
thereof; [0993] jjjj. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:349 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:351 or an antigen binding fragment thereof; [0994] kkkk.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:353 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:355 or an antigen
binding fragment thereof; [0995] llll. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:357 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:359 or an antigen binding fragment
thereof; [0996] mmmm. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:361 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:363 or an antigen binding fragment thereof; [0997] nnnn.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:365 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:367 or an antigen
binding fragment thereof; [0998] oooo. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:369 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:371 or an antigen binding fragment
thereof; [0999] pppp. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:373 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:375 or an antigen binding fragment thereof; [1000] qqqq.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:377 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:379 or an antigen
binding fragment thereof; [1001] rrrr. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:381 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:383 or an antigen binding fragment
thereof; [1002] ssss. an antibody comprising a heavy chain amino
acid sequence comprising SEQ ID NO:385 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:387 or an antigen binding fragment thereof; [1003] tttt.
an antibody comprising a heavy chain amino acid sequence comprising
SEQ ID NO:389 or an antigen binding fragment thereof and a light
chain amino acid sequence comprising SEQ ID NO:391 or an antigen
binding fragment thereof; [1004] uuuu. an antibody comprising a
heavy chain amino acid sequence comprising SEQ ID NO:393 or an
antigen binding fragment thereof and a light chain amino acid
sequence comprising SEQ ID NO:395 or an antigen binding fragment
thereof; and [1005] vvvv. an antibody comprising a heavy chain
amino acid sequence comprising SEQ ID NO:397 or an antigen binding
fragment thereof and a light chain amino acid sequence comprising
SEQ ID NO:399 or an antigen binding fragment thereof. [1006] 62. An
isolated host cell expressing the antibody of any of paragraphs
1-61. [1007] 63. One or more vectors comprising a nucleic acid
encoding the antibody of any of paragraphs 1-62. [1008] 64. The one
or more vectors of paragraph 63, wherein one vector encodes a light
chain sequence and another vector encodes a heavy chain sequence.
[1009] 65. The one or more vectors of paragraph 64, wherein one
vector encodes a light chain sequence and a heavy chain sequence.
[1010] 66. A cell comprising the one or more vectors of any of
paragraphs 62-65. [1011] 67. An engineered cell that expresses the
antibody of any of paragraphs 1-66. [1012] 68. The cell of
paragraph 67, wherein the cell is an immune cell. [1013] 69. The
cell of paragraph 68, wherein the immune cell is a B cell. [1014]
70. A pharmaceutical composition comprising one or more antibodies
of any of paragraphs 1-61 and/or cells of any of paragraphs 66-69
and a pharmaceutically acceptable carrier. [1015] 71. A method for
treating or preventing HIV infection in a subject, comprising
administering to the subject an effective amount of the composition
of paragraph 70. [1016] 72. A method of functionally curing HIV
comprising administering to the subject an effective amount of the
composition of paragraph 70. [1017] 73. The method of any of
paragraphs 71-72, wherein the composition is administered in
combination with another therapy. [1018] 74. The method of
paragraph 73, wherein the therapy is an anti-retroviral
therapy.
[1019] Application of the teachings of the present invention to a
specific problem is within the capabilities of one having ordinary
skill in the art in light of the teaching contained herein.
Examples of the compositions and methods of the invention appear in
the following non-limiting Examples.
EXAMPLES
Example 1. Deconvoluting an HIV Super-Neutralizing Plasma
Response
[1020] Anti-HIV-I envelope monoclonal antibodies isolated from
memory B-cells have yielded broadly neutralizing antibodies
(bNAbs), though none were pan-neutralizing. Here we identify a
pan-neutralizing antibody lineage against a novel epitope by
coupling proteomics of plasma antibodies with lineage analysis of
bone marrow plasma cells from two HIV-1 "elite neutralizers." In
both, a single lineage of anti-CD4 binding site antibodies matched
circulating bNAbs sequences. Members of a single plasma cell
lineage potently neutralized 100% of a validated multi-tier 117
pseudovirus panel, matching the sequence, specificity, and
neutralization breadth of the circulating bNAbs. X-ray
crystallography analysis of pan-neutralizing monoclonal, N49P7,
identified its unique ability to bypass the CD4-binding site Phe43
cavity while reaching deep into the highly conserved residues of
Layer 3 of the gp120 inner domain, likely accounting for its
pan-neutralization. Conjoint analysis of plasma antibodies by
proteomics and bone marrow derived lineages will improve
understanding the evolution of anti-HIV-I bNAb responses.
[1021] Here we employed a matched genomic and proteomic approach to
deconvolute a very broadly neutralizing response directed against
gp120. The primary test subject, N60 (referred to as Subject 1 in a
previous publication (Sajadi et al., J Virol 86, 5014-5025 (2012))
belongs to a previously reported Natural Viral Suppressor (NVS)
cohort of subtype B-infected patients who exhibit persistent titers
of very broad and potent neutralizing antibodies (Sajadi et al., J
Infect Dis 213, 156-164 (2016); Sajadi et al., J Virol 86,
5014-5025 (2012).
[1022] We have previously found that multiple HIV-infected subjects
harbor broad and potent neutralizing activities with highly shared
biochemical determinants, such as basic isoelectric points (pI) and
specificities for binding epitopes on free monomeric gp120 (Sajadi
et al., J Acquir Immune Defic Syndr 57, 9-15 (2011); Sajadi et al.,
J Infect Dis 213, 156-164 (2016); Sajadi et al., J Virol 86,
5014-5025 (2012)). Serum antibodies from N60 were able to
neutralize 90% of 118 multi-clade Tier 2/3 panel of viruses (Table
5). The duration of such neutralization potency and breadth over a
5-year period was confirmed by sequential testing of N60 plasma
against a cross-clade, multi-tier panel of viruses (Table 6).
TABLE-US-00006 TABLE 5 Neutralization of N60 parent and affinity
purified samples. Titer in TZM.bl cells (ug/ml) N60 Pro N60 N60
Virus ID Clade* Tier IC50 IC50 IC50 6535.3 B 1B 23.629 2.337 1.399
QH0692.42 B 2 73.193 10.496 5.384 SC422661.8 B 2 30.877 3.333 2.194
PVO.4 B 3 23.164 1.478 1.005 TRO.11 B 2 35.183 7.264 5.693
AC10.0.29 B 2 27.920 4.144 3.550 RHPA4259.7 B 2 14.971 3.373 2.257
THRO4156.18 B 2 42.864 17.930 6.848 REJO4541.67 B 2 21.061 4.071
3.186 TRJO4551.58 B 3 72.808 16.072 13.344 WITO4160.33 B 2 151.278
46.052 23.311 CAAN5342.A2 B 2 30.870 4.007 3.148 WEAU d15 410 787 B
(T/F) 2 32.622 4.254 2.479 1006 11 C3 1601 B (T/F) 2 31.461 5.019
3.047 1054 07 TC4 1499 B (T/F) 2 104.772 27.878 10.870 1056 10 TA11
1826 B (T/F) 1B 209.754 22.420 12.264 1012 11 TC21 3257 B (T/F) 1B
39.521 3.783 2.738 6240 08 TA5 4622 B (T/F) 2 216.472 45.439 38.068
6244 13 B5 4576 B (T/F) 2 58.906 4.678 4.487 62357 14 D3 4589 B
(T/F) 2 60.360 11.454 8.697 SC05 8C11 2344 B (T/F) 2 28.437 4.712
3.912 Du156.12 C 2 37.524 6.824 5.405 Du172.17 C 2 119.944 >50
38.171 Du422.1 C 2 46.145 17.533 14.580 ZM197M.PB7 C 2 28.614
14.055 4.300 ZM214M.PL15 C 2 485.829 >50 >50 ZM233M.PB6 C 2
169.452 21.342 20.248 ZM249M.PL1 C 2 102.326 15.919 12.597
ZM53M.PB12 C 2 25.867 10.571 6.323 ZM109F.PB4 C 1B 210.029 >50
30.049 ZM135M.PL10a C 2 260.838 32.686 21.300 CAP45.2.00.G3 C 2
350.560 >50 >50 CAP210.2.00.E8 C 2 367.728 >50 >50
HIV-001428-2.42 C 2 25.972 2.701 2.187 HIV-0013095-2.11 C 2 211.157
22.522 18.247 HIV-16055-2.3 C 2 92.761 12.576 10.268 HIV-16845-2.22
C 2 426.772 >50 49.375 Ce1086_B2 C (T/F) NC 11.192 >50 1.641
Ce0393_C3 C (T/F) NC 142.594 30.286 15.431 Ce1176_A3 C (T/F) NC
192.528 45.344 28.479 Ce2010_F5 C (T/F) NC 70.275 19.463 12.692
Ce0682 E4 C (T/F) NC 64.759 17.431 10.243 Ce1172 H1 C (T/F) NC
>528 >50 >50 Ce2060 G9 C (T/F) NC >528 >50 >50
Ce703010054_2A2 C (T/F) NC 188.873 31.683 19.604 BF1266.431a C
(T/F) NC 154.369 46.996 27.310 246F C1G C (T/F) NC 352.889 >50
48.226 249M B10 C (T/F) NC 183.182 21.542 19.517 ZM247v1(Rev-) C
(T/F) NC 190.864 >50 >50 7030102001E5(Rev-) C (T/F) NC 33.817
3.270 3.724 1394C9G1(Rev-) C (T/F) NC 59.578 16.555 5.566
Ce704809221_1B3 C (T/F) NC 65.767 35.580 10.697 CNE19 BC NC 16.594
2.854 1.520 CNE20 BC NC 15.633 4.173 1.565 CNE21 BC NC 91.501
22.960 14.653 CNE17 BC NC 139.056 21.438 13.846 CNE30 BC NC 221.349
>50 40.694 CNE52 BC NC 56.900 7.694 5.036 CNE53 BC NC 20.570
3.483 2.635 CNE58 BC NC 22.749 4.549 2.858 MS208.A1 A NC 211.293
>50 32.229 Q23.17 A 1B 17.575 2.938 1.794 Q461.e2 A 2 >528
>50 >50 Q769.d22 A 2 35.201 6.293 3.506 Q259.d2.17 A 2 33.807
7.060 3.559 Q842.d12 A 2 18.917 3.348 2.180 0260.v5.c36 A NC 80.819
13.873 43.483 3415.v1.c1 A 2 46.266 4.830 4.596 3365.v2.c2 A 2
54.620 8.493 5.802 191955_A11 A (T/F) NC 288.049 41.777 43.183
191084 B7-19 A (T/F) NC 34.834 4.607 1.917 9004SS_A3_4 A (T/F) NC
18.058 2.144 1.965 T257-31 CRF02_AG 3 426.998 >50 43.480 928-28
CRF02_AG 2 >528 >50 >50 263-8 CRF02_AG 2 22.824 4.205
4.064 T250-4 CRF02_AG 2 11.419 1.359 0.767 T251-18 CRF02_AG 3
371.838 >50 38.744 T278-50 CRF02_AG 3 >528 >50 >50
T255-34 CRF02_AG 2 131.913 15.603 12.016 211-9 CRF02_AG 2 291.355
42.611 24.418 235-47 CRF02_AG 2 87.864 9.609 6.028 620345.c01
CRF01_AE NC >528 >50 >50 CNE8 CRF01_AE NC 194.556 16.923
7.854 C1080.c03 CRF01_AE NC 483.323 >50 >50 R2184.c04
CRF01_AE NC 27.037 3.087 2.138 R1166.c01 CRF01_AE NC 130.381 29.864
24.622 R3265.c06 CRF01_AE NC 440.886 >50 >50 C2101.c01
CRF01_AE NC 92.755 14.543 16.106 C3347.c11 CRF01_AE NC 10.921 1.730
1.808 C4118.c09 CRF01_AE NC 117.159 17.416 16.615 CNE5 CRF01_AE NC
170.243 20.320 17.746 BJOX009000.02.4 CRF01_AE NC >528 >50
44.993 BJOX015000.11.5 CRF01_AE NC 250.047 >50 26.892
BJOXO10000.06.2 CRF01_AE NC >528 >50 >50 BJOX025000.01.1
CRF01 AE NC 328.505 >50 >50 BJOX028000.10.3 CRF01_AE NC
>528 >50 >50 X1193_c1 G NC 121.508 3.302 13.356
P0402_c2_11 G NC 48.896 >50 4.239 X1254_c3 G NC 159.002 8.668
11.873 X2088_c9 G NC >528 >50 >50 X2131_C1_B5 G NC 95.017
9.848 10.189 P1981_C5_3 G NC 90.229 >50 14.873 X1632_S2_B10 G NC
110.495 >50 16.335 3016.v5.c45 D NC >528 >50 >50
A07412M1.vrc12 D NC 62.198 >50 5.815 231965.c01 D NC 171.994
20.212 26.544 231966.c02 D NC 459.176 >50 >50 3817.v2.c59 CD
NC 58.502 >50 6.729 6480.v4.c25 CD NC 23.010 9.698 3.495
6952.v1.c20 CD NC 89.351 2.925 15.998 6811.v7.c18 CD NC 45.321
>50 6.443 89-F1_2_25 CD NC >528 >50 >50 3301.v1.c24 AC
NC 42.393 0.576 5.568 6041.v3.c23 AC NC 15.836 1.476 2.412
6540.v4.c1 AC NC 55.351 >50 11.334 6545.v4.c1 AC NC 113.948
>50 35.556 0815.v3.c3 ACD NC 26.284 1.644 4.530 3103.v3.c10 ACD
NC 215.876 17.045 30.725 MuLV Neg. Neg. >528 >50 >50 Pro
A/G = Affinity purified antibody from a Protein A/G column; gp120 =
Affinity purified antibody from a gp120 column; gp120-IgG1 =
Affinity purified antibody from a gp120 followed by IgG1 column;
IC50 = Inhibitory concentration 50 (ug/ml); T/F =
transmitted/founder; NC = not characterized.
[1023] Plasma from patient N60 was purified and tested against a
118 multitier and multiclade pseudovirus panel. Parent sample
demonstrates considerable breadth, which was also seen in the gp120
and gp120-IgG1 fractions.
TABLE-US-00007 TABLE 6 Plasma neutralization potency and breadth
from 2008-2013. Plasma from patient N60 was tested against a panel
of multiclade HIV pseudoviruses, demonstrating potency and breadth
for more than 4 years. Numerical values given as ID50, the
Inhibitory Dose 50. Plasma ID50 Titer in TZM.bl Cells (1/x) Oct. 1,
Oct. 12, Sep. 9, Jan. 10, Virus Tier Clade 2008 2009 2010 2013
6535.3 1B B 3,514 2,028 2,178 1,713 QH0692.42 2 B 530 422 545 335
SC422661.8 2 B 973 630 650 1,008 PVO.4 3 B 1,384 548 800 2,046
TRO.11 2 B 1,820 1,074 820 1,174 AC10.0.29 2 B 3,655 1,884 1,709
1,586 RHPA4259.7 2 B 1,988 1,543 3,259 2,089 THRO4156.18 2 B 1,149
721 438 506 REJO4541.67 2 B 2,112 1,576 1,133 2,143 TRJO4551.58 3 B
269 479 395 728 WITO4160.33 2 B 268 221 127 732 CAAN5342.A2 2 B
6,032 2,197 1,367 1,906 Du156.12 2 C NT 1,000 NT 1,343 Du172.17 2 C
NT 97 NT 468 Du422.1 2 C NT 636 NT 581 ZM53M.PB12 2 C NT 3,183 NT
1,715 ZM135M.PL10a 2 C NT 221 NT 425 ZM197M.PB7 1B C NT 455 NT
1,062 ZM214M.PL15 2 C NT 412 NT 338 Q23.17 1B A NT 3,592 NT 2,895
Q259.d2.17 2 A NT 2,873 NT 1,528 Q461.e2 2 A NT 77 NT 184 Q168.a2 2
A NT 1,303 NT 942 3415.v1.c1 2 A NT 1,097 NT 1,318 0439.v5.c1 2 A
NT 499 NT 588 0260.v5.c1 2 A NT 3,519 NT 1,957 3365.v2.c20 2 A NT
869 NT 1,425 T257-31 3 CRF02_AG NT 97 NT 316 263-8 2 CRF02 AG NT
493 NT 1,104 211-9 2 CRF02_AG NT 108 NT 780 MuLV (Neg) Neg control
Neg control 24 30 <20 186 NT = not tested
[1024] The broadly neutralizing plasma antibodies were isolated
from N60 plasma by affinity chromatography with monomeric gp120
(Sajadi et al., J Acquir Immune Defic Syndr 57, 9-15 (2011); Sajadi
et al., J Infect Dis 213, 156-164 (2016); Sajadi et al., J Virol
86, 5014-5025 (2012)) (Table 5). The recovered gp120 affinity
fraction from N60 is known represent approximately 2% of the
starting mass of IgG antibody. Similar recoveries (0.6%-2% of
starting mass of IgG antibody) of anti-gp120 antibodies were
obtained from the plasma of other HIV infected individuals. In
accordance with our previous studies of anti-HIV humoral responses
(Sajadi et al., J Acquir Immune Defic Syndr 57, 9-15 (2011); Sajadi
et al., J Infect Dis 213, 156-164 (2016); Sajadi et al., J Virol
86, 5014-5025 (2012)), broadly neutralizing activity in N60 plasma
was recovered by sequential protein A/G affinity chromatography,
anti-gp120, and anti-IgG1 affinity chromatography (Table 5).
[1025] Two lines of evidence showed that few if any epitope
specificities beyond those on monomeric gp120 were linked with the
N60 polyclonal neutralizing response. First, the plasma antibody
fraction that flowed through the gp120 affinity column exhibited
negligible neutralization activity against a panel of 12 HIV Tier
1-3 pseudoviruses, compared to unfractionated plasma (Table 5).
Second, the neutralizing breadth of purified N60 anti-gp120 IgG1 Ig
largely matched that of unfractionated plasma (Table 5).
TABLE-US-00008 TABLE 7 ID50 and ID80 of N60 Plasma and gp120-FT.
Plasma from patient N60 as well as gp120-FT (IgG that was passed
over a BaL- gp120 column) was tested against a panel of HIV
pseudoviruses for neutralization. Numerical values given as
dilutions of the Inhibitory Dose 50 (ID50) or the Effective Dose 50
(ED50). In each case, the gp120-FT loses potency compared to the
parent plasma, confirming that the fraction affinity purified
against the gp120 monomer contains the bulk of neutralizing
antibodies. N60 Plasma N60 gp120FT Virus ID Tier ID50 ID80 ID50
ID80 BaL.26 1B 1,968 574 <40 <40 QH0692.42 2 549 119 <40
<40 SC422661.8 2 752 276 <40 <40 PVO.4 3 905 308 55 <40
TRO.11 2 794 298 52 <40 AC10.0.29 2 1,040 335 <40 <40
RHPA4259.7 2 1,863 608 <40 <40 THRO4156.18 2 361 90 51 <40
REJO4541.67 2 919 333 <40 <40 TRJO4551.58 3 293 102 66 <40
WITO4160.33 2 164 45 <40 <40 CAAN5342.A2 2 851 360 <40
<40 MuLV Neg control 80 <40 <40 <40
[1026] We have previously shown a light chain bias exists in the
anti-HIV envelope response (Sajadi et al., J Infect Dis 213,
156-164 (2016)), so to better define the N60 neutralizing
antibodies, affinity purified anti-gp120 plasma antibodies were
further fractionated by affinity chromatography with antibodies
selective for human .kappa. or .lamda. light chains. The bulk
anti-gp120 IgG1 .kappa. or .lamda. Ig preparations were further
subjected to free flow isoelectric focusing (FFE) to separate
individual antibody species according to their pI. In our previous
study (Sajadi et al., J Virol 86, 5014-5025 (2012)), the broadly
neutralizing antibodies were localized to fractions with more basic
pIs. In the current study the fractions were tested for
neutralization against two Tier 2 pseudoviruses, confirming the
localization of broadly neutralizing antibodies to the basic
fractions (FIG. 1 and data not shown). ELISAs confirmed that the
broadly neutralizing antibody fractions contained IgG reactive with
gp120 and gp120 core; but were less reactive with FLSC, in which
the CD4 binding site is blocked, and did not bind to D368R gp120,
whose single point mutation at position 368 abrogates binding of
CD4-BS antibodies to HIV-1 gp120 (FIG. 1) (Li et al., Nat Med 13,
1032-1034 (2007)). In comparison, more acidic fractions favored
binding to gp120, FLSC, D368R gp120, but not the YU2-core. (FIG. 1)
(Li et al., Nat Med 13, 1032-1034 (2007)).
[1027] Our basic strategy for deconvoluting the plasma anti-gp120
polyclonal response proceeded as follows. First, fractionated
immunoglobulin (see below) was subjected to enzymatic digestion
with trypsin, chymotrypsin, and/or Glu-C(see Methods). Peptide
fragments were subjected to LC-MS to calculate mass assignments,
from which their amino acid sequences could be deduced. Next, the
peptide sequences were used to identify the Ig H and L chain genes
from which they originated based on a selection algorithm (see
below). Identified genes then served as a means to artificially
reproduce each plasma anti-gp120 monoclonal antibody, which could
be examined under various conditions.
[1028] Peptide sequences were aligned and assembled using as
templates authentically paired Ig H and L chain amino acid
sequences translated from an N60-specific Ig gene database (see
Methods) derived by single-cell sequencing from bone marrow
mononuclear cells and circulating plasmablasts (see Methods). One
caveat to the alignment operation was that certain peptides
(typically from framework regions) could redundantly align with
multiple Ig H and L template pairs, thus creating random peptide
assemblages. This confound was mitigated by rank ordering the Ig H
and L templates according to the number of "unique" peptide
alignments (i.e. did not occur match any other Ig sequence in the
database; see Methods for details) they comprised. False discovery
rates were held at 5% to further increase the probability that
peptide sequences were properly grouped and aligned within a full
length Ig sequence (see Methods). It was also important to consider
that similar degrees of total template "coverage" by plasma amino
acid sequences could differ substantially in the numbers of unique
peptide alignments. An example of this caveat is shown in FIG. 2
with respect to H chain alignments. In both cases, there is good
overall coverage, the heavy chain in FIG. 2A possessing 60%
coverage by 21 peptides, and the heavy chain in FIG. 2B possessing
69% coverage derived by 25 peptides. The heavy chain in FIG. 2A
matches but only one unique, template-specific alignment (pink).
The other covered areas (blue) involve sequences that bind multiple
Ig gene templates, mostly in the framework regions. Alignments such
as these were taken as false sequence assemblages. Indeed, antibody
proteins reconstructed from such cases did not neutralize HIV or
bind HIV envelope (not shown). Conversely, FIG. 2B represents a
case where the alignment includes multiple peptides unique to the
template sequence (including the CDRH1 region). Further, unique
peptide matches were favored over redundant ones. These
characteristics were taken to indicate valid sequence assemblages.
In agreement, the antibody constructed from the Ig H and L template
pair represented in FIG. 2B bound gp120 (N60P2.1) and was broadly
neutralizing (see below).
[1029] The selection algorithm was applied to peptide sequences
derived from three complementary fractionation approaches (FIG. 3).
The criteria for identifying an H and L template pair as the
genetic source of a plasma antibody was .gtoreq.4 unique peptides
and 50% coverage in at least one of the H and L chain of each pair
(with .gtoreq.4 unique peptides required in each H and L chain for
the combined fractions), accommodating the designated false
discovery rate cutoff.
[1030] In the primary approach, FFE fractions of anti-gp120 plasma
antibodies were evaluated individually to score and select
corresponding H and L template pairs. As expected, adjacent
fractions rendered similar determinations within certain portions
of the FFE fraction series. This operation identified 8 paired H
and L Ig genes encoding plasma antibodies targeting 3 epitopes. A
second approach applied the bulk polyclonal anti-gp120 antibodies
to preparative IEF gels. Immunoglobulins were extracted from
sequential slices of the gels and digested to obtain peptide
sequences, which were then compared against the entire Ig gene
database. This operation identified all but one of the H and L
sequence pairs found in the primary approach as well as 4
additional ones. A third approach generated peptides and their
corresponding sequences directly from bulk anti-gp120 plasma
antibodies and combining this with the gel digests. This exercise
mitigated the risk that sequences were overlooked in the other
methods due to protein loss but necessitated combining 27 separate
digests. This approach identified most of the same H and L sequence
pairs found by the other approaches (missing 2 but identifying 1
additional one).
[1031] The Fab sequences of the 14 identified H and L gene pairs
were combined with a generic IgG1 Fc domain (CH1-3 from IGHG1*03)
in order to construct synthetic monoclonal antibody expression
plasmids from which to generate protein (Guan et al., Proc Natl
Acad Sci USA 106, 3952-3957 (2009); Guan et al., Proc Natl Acad Sci
USA 110, E69-78 (2013)). This construction strategy was
appropriate, as the native plasma neutralizing antibodies were of
the IgG1 isotype (Table 5).
[1032] FFE was then used to compare the electrophoretic behaviors
of the reconstructed mAbs versus bulk polyclonal anti-gp120 plasma
antibodies. As shown in FIG. 3, the plasma antibodies tended to
elute at highest concentrations within two series of fractions
peaking at lower and higher pH ranges in the gradient (which ranged
pH 6.5 to pH 9.5). Fractions containing plasma antibody
peptide/sequences that facilitated mAb reconstruction (see above
and Methods) overlapped these regions. In the case of IgG .kappa.
certain fractions near the center of the gradient (.about.45-55)
did not yield any unique antibodies (the peptides that derived from
this region did match some of the neighboring mAbs on either side,
but at a lower frequency). Similarly for IgG .lamda., fractions
above pH 8 contained too little protein to perform downstream
analysis. Importantly, the pI values of the reconstructed mAbs
derived from the FFE or gel isoelectric focusing approaches
corresponded to those of the plasma fractions that yielded their
identifying peptides (compare bars and arrows in FIG. 3). This
consistency indicated that the identified and reconstructed mAbs
contained assemblages of amino acid sequences authentic to the
plasma antibodies.
[1033] The reconstructed mAbs were characterized for source-cell
subset and lineage relationships (Table 8, FIG. 4). All of the
anti-gp120 mAb sequences were found in bone marrow 138- and 138+
populations by single cell PCR (summarized in Table 8). Only one
mab (N60P22) could be detected in the circulating plasmablast
population (Table 8). This mAb had the second highest frequency of
any in the bone marrow, so it could be that the frequency of the
mAbs in the plasmablast population is less than the bone marrow, or
they can only be detected for a short time, as occurs with
vaccination or acute infections. A homology search (multiple
sequence alignment) of the bone marrow database did not reveal any
of the ancestral forms of any of the mAbs identified, implying that
even though the mAbs were found in all bone marrow compartments,
including the long-lived plasma cells (CD138+, CD19-), their
longevity may be limited.
TABLE-US-00009 TABLE 8 Characteristics of anti-gp120 plasma
antibodies isolated. Frequency of CDR3 (per 1000) Single Cell
Sequencing SUM Bone Bone Heavy Light (Heavy/ Peripheral marrow
marrow mAb Epitope Chain chain Light) plasmablast 138- 138+ Lineage
1 N60P2.1 CD4-BS 1-2 .kappa. 1-5 38%/29% 0 2.48 0 N60P1.1 CD4-BS
1-2 .kappa. 1-5 36%/26% 0 2.48 1.62 N60P25.1 CD4-BS 1-2 .kappa. 1-5
33%/26% 0 2.48 0 N60P31.1 CD4-BS 1-2 .kappa. 1-5 42%/35% 0 2.48 0
Lineage 2 N60P22 CD4-BS 4-31 .kappa. 3-20 9%/11% 1.62 2.48 9.69
N60P38 CD4-BS 4-31 .kappa. 3-20 9%/11% 0 2.48 0 Lineage 3 N60P30
CD4i 1-2 .kappa. 3-20 21%/12% 0 2.48 0 (Cluster A) Lineage 4 N60P36
CoR-BS 1-69 .kappa. 3-20 11%/9% 0 4.96 4.85 (Cluster C) Lineage 5
N60P39 CoR-BS 1-69 .kappa. 3-20 11%/9% 0 2.48 1.62 (Cluster C)
N6039.1 CoR-BS 1-69 .kappa. 3-20 11%/9% 0 2.48 1.62 (Cluster C)
N60P47 CoR-BS 1-69 .kappa. 3-20 16%/6% 0 2.48 0 (Cluster C) N60P48
CoR-BS 1-69 .kappa. 3-20 15%/6% 0 4.96 6.46 (Cluster C) Lineage 6
N60P51 CoR-BS 1-69 .kappa. 3-20 20%/9% 0 12.4 3.38 (Cluster C)
Lineage 7 N60P35 V3 5-51 .lamda. 6-57 18%/14% 0 2.48 4.85 N60P37 V3
5-51 .lamda. 6-57 17%/16% 0 2.48 6.46 mAb = monoclonal antibody.
SHM = somatic hypermutation. CD4-BS = CD4-binding site antibody.
CoR-BS = Co-Receptor binding site antibody. Cluster A = competes
with A32. Cluster C = competes with 19e and/or 17b.
[1034] Overall, the dominant N60 plasma anti-gp120 response arose
from 7 distinct lineages (Table 8), as shown in the
neighbor-joining phylogeny tree (see Methods) of the entire BM
antibodies (FIG. 4). Lineage 1 was distinguished by 1-2 heavy chain
and 1-5 .kappa. light chain gene usage as well as a relatively high
degree of somatic hypermutation (33-42% in the heavy chain).
Lineage 1 mAbs resemble previously reported broadly neutralizing
anti-CD4-BS antibodies, which are also assigned to VH1-2 and
V.kappa.1-5 gene families that exhibit the signature deletion in
the CDRL3 (Scharf et al., Proc Natl Acad Sci USA 110, 6049-6054
(2013); West et al., Proc Natl Acad Sci USA 109, E2083-2090 (2012);
Zhou et al., Science 329, 811-817 (2010)). These antibodies had
basic pIs. Two mAbs (N60P1.1 and N602.1) bound gp120 on Elisa and
SPR, and but not the D368R point mutant, and thus are CD4 binding
site antibodies (FIGS. 5 and 6). However, mAbs N60P25.1 and
N60P31.1 in this family did not bind gp120 in the standard antigen
capture ELISA format (FIG. 5) using plates coated with antibody
D7324 directed against the gp120 C terminal region (Sajadi et al.,
J Acquir Immune Defic Syndr 57, 9-15 (2011); Sajadi et al., J Virol
86, 5014-5025 (2012); Guan et al., Proc Natl Acad Sci USA 106,
3952-3957 (2009)), nor in the reverse format coating plates first
with mAbs (not shown). N60P25.1, when bound to protein A, did bind
to gp120 in SPR, while N6031.1 did not (FIG. 6). Additionally, we
did see binding to gp120 in accordance with their retention on the
gp120 affinity column (26% recovery for N60P25.1, 5% recovery for
N60P31.1, <1% for control mAb Synagis).
[1035] Lineage 2 was distinguished by 4-31 heavy chain and 3-20
.kappa. light chain usage and a much lower degree of hypermutation
(9% in the heavy chain). The two members of this lineage also had
basic pIs and appeared to be directed against the CD4 binding site
(FIGS. 5 and 6) as determined by ELISA (FIG. 5). These mAbs were
distinguished from Lineage 1 antibodies by the capacity to
recognize a YU2 gp120 core antigen. Genes encoding one mAb in this
lineage (mAb N60P22) were detected in circulating plasmablasts.
[1036] Lineage 3 contained one member (mAb N60P30) with 1-2 heavy
chain and 3-20 .kappa. light chain usage and a moderate degree of
hypermutation (21% in the heavy chain). N60P30 had a basic pI,
bound well to FLSC, but not to gp120 or YU2-core in ELISA (FIG. 5),
indicating a specificity for CD4-induced epitopes. Competition
Elisa testing revealed that N60P30 competed with A32 but not 17b,
signifying Cluster A specificity (data not shown).
[1037] Lineage 4 contained one member (mAb N60P36) with 1-69 heavy
chain and 3-20 .kappa. light chain usage and a relatively low
degree of hypermutation (11% in the heavy chain). N60P36 had a
neutral pI. Binding assays (FIG. 5) and competition ELISAs with
CD4i mAbs (data not shown) indicated that mAbs in this lineage
recognize the Cluster C epitope in the coreceptor binding site.
[1038] Lineage 5 mAbs were distinguished by 1-69 heavy chain and
3-20 .kappa. light chain usage and a moderate degree of
hypermutation (11-16% in the heavy chains). This Lineage comprised
of 3 members (mAbs N60P39, N60P39.1, and N60P48). Binding assays
(FIG. 5) and competition ELISAs with CD4i mAbs (data not shown)
indicated that mAbs in this lineage recognize the Cluster C epitope
in the coreceptor binding site. We identified one additional mAb
that was not picked up with the above methods by a homology search
of the bone marrow database. This mAb (N60P47) had no binding to
gp120 on elisa, and thus had either no binding to gp120, as in the
case of antibodies targeted at the hybrid epitope of CD4 and gp120,
or bound to gp120 so weakly that too little was recovered to
identify correctly.
[1039] Lineage 6 contained one member (mAb N60P51) with 1-69 heavy
chain and 3-20 .kappa. light chain usage and a moderate degree of
hypermutation (20% in the heavy chain). Binding assays (FIG. 5) and
competition ELISAs with CD4i mAbs (data not shown) indicated
recognition of Cluster C epitope in the coreceptor binding
site.
[1040] Lineage 7 was distinguished by 5-51 heavy chain and 3-20
.lamda. light chain usage and a moderate degree of hypermutation
(17-18% in the heavy chains). mAbs in this family had more neutral
pIs. Binding analyses indicated that the two members of this
lineage bound Yu2 core+V3, but not the Yu2 core on Elisa (FIG. 5).
Additionally, both mAbs bound the HIV-1 MN Complete V3 Loop Peptide
on Elisa (FIG. 5), indicating that these mAbs recognize the V3 loop
of HIV-1.
[1041] In a previous study of N60 (Sajadi et al., J Infect Dis 213,
156-164 (2016)), we determined that roughly 50% of the total
anti-gp120 plasma response involved antibodies with .lamda. light
chains. As only Lineage 7 expressed .lamda. light chains, it is
evident that cross-reactive anti-V3 antibodies account for the bulk
of the circulating anti-gp120 response in N60 (potentially up to 1%
of the total circulating IgG). Such representation in the
polyclonal anti-gp120 response is in accordance with the
immunodominant nature of the V3 loop as evinced in studies of
anti-gp120 responses in other cohorts (Javaherian et al., Proc Natl
Acad Sci USA 86, 6768-6772 (1989); LaRosa et al., Science 249,
932-935 (1990); Vogel et al., J Immunol 153, 1895-1904 (1994)).
[1042] Preliminary screening of the mAbs for neutralizing activity
against 15 tiers 1-3 pseudoviruses showed that Lineage 1 comprised
the most broad and potent activity, followed by Lineages 2, 7, and
5 (Table 9).
TABLE-US-00010 TABLE 9 mAb screening ELISA and neutralization. For
BaL-gp120 ELISA binding, background subtracted OD results shown for
mAbs tested at 8 ug/ml. For HIV-1 neutralization, a neutralization
was carried out against a panel of Tier 1-3 pseudoviruses (see
Methods). mAb Epitope SF162.LS BaL.26 SS1196.1 6535.3 QH0692.42
SC422661.8 PVO.4 TRO.11 AC10.0.29 Lineage N60P1.1 CD4-BS 12.919
>50 0.612 3.835 15.479 0.75 0.456 6.315 >25 1 N60P2.1 CD4-BS
>50 >50 1.836 >25 2.995 12.690 1.683 19.597 >25
N60P25.1 CD4-BS 30.992 >50 0.246 15.725 32.942 2.056 6.454
23.528 >50 N60P31.1 CD4-BS >50 >50 >50 >50 >50
>50 >50 1.807 >50 Lineage N60P22 CD4-BS 1.275 5.532 5.673
10.641 36.840 >50 >50 >50 >50 2 N60P38 CD4-BS 5.765
>50 7.979 >50 >50 >50 >50 >50 >50 Lineage
N60P30 CD4i >50 >50 >50 >50 >50 >50 >50 >50
>50 3 (ClusterA) Lineage N60P36 CoR-BS >50 >50 >50
>50 >50 >50 >50 >50 >50 4 (ClusterC) N60P39
CoR-BS 3.189 >50 4.611 >50 >50 >50 >50 >50 >50
(ClusterC) Lineage N6039.1 CoR-BS 0.482 14.124 1.205 >50 45.230
>50 >50 >50 >50 5 (ClusterC) N60P47 CoR-BS 0.684 20.084
1.905 >40 >40 >40 >40 >40 >40 (ClusterC) N60P48
CoR-BS 0.395 12.729 .907 >40 20.238 >40 >40 >40 >40
(ClusterC) Lineage N60P51 CoR-BS .318 8.963 1.033 >25 >25
>25 >25 >25 >25 6 (ClusterC) Lineage N60P35 V3 .021
4.68 1.113 >25 >25 >25 >25 >25 >25 7 N60P37 V3
0.03 4.076 .991 >25 >25 >25 >25 >25 mAb Epitope
RHPA4259.7 THRO4156.18 REJO4541.67 TRJO4551.58 WITO4160.33
CAAN5342.A2 Lineage N60P1.1 CD4-BS 4.218 >25 1.581 7.195 >25
1.635 1 N60P2.1 CD4-BS 15.684 >25 >25 >25 >25 6.733
N60P25.1 CD4-BS 1.448 >50 2.454 >50 >50 2.502 N60P31.1
CD4-BS >50 31.038 >50 >50 >50 >50 Lineage N60P22
CD4-BS >50 36.501 >50 >50 >50 >50 2 N60P38 CD4-BS
>50 >50 >50 >50 >50 >50 Lineage N60P30 CD4i
>50 >50 >50 >50 >50 >50 3 (ClusterA) Lineage
N60P36 CoR-BS >50 >50 >50 >50 >50 >50 4
(ClusterC) N60P39 CoR-BS >50 >50 >50 >50 >50 >50
(ClusterC) Lineage N6039.1 CoR-BS >50 >50 >50 >50
>50 >50 5 (ClusterC) N60P47 CoR-BS >40 >40 >40
>40 >40 >40 (ClusterC) N60P48 CoR-BS >40 >40 >40
>40 >40 >40 (ClusterC) Lineage N60P51 CoR-BS >25 >25
>25 >25 >25 >25 6 (ClusterC) Lineage N60P35 V3 3.733
>25 >25 >25 >25 >25 7 N60P37 V3 11.624 >25 >25
>25 >25 >25
[1043] Expanded testing of Lineage 1 mAbs revealed neutralization
breadth approaching the coverage observed with the polyclonal
plasma anti-gp120 kappa Ig (FIG. 7). Two mAbs, N60P1.1 and
N60P25.1, demonstrated particularly strong neutralizing activity
(FIG. 7), matching 70% and 73% of the affinity purified plasma Ig
breadth, respectively. Thus, broad plasma neutralizing activity in
N60 appears to largely arise from Lineage 1, representing a
monospecific fraction of the anti-gp120 repertoire at the time
point evaluated. Anti-CD4BS mAbs from Lineage 2, which appeared in
high frequency but did not have strong breadth and potency,
contributed minimally to the overall plasma profile. In any case,
the concurrence of other types of poorly neutralizing anti-gp120
antibodies does not appear to abrogate the presence and activity of
broadly neutralizing antibodies in circulation.
[1044] Despite their breadth and potency, none of the anti-CD4BS
mAbs from Lineage 1 matched the full breadth of the polyclonal
plasma anti-gp120 Ig recovered from N60. Considered collectively,
the anti-CD4BS mAbs neutralized 89% of the viruses that were
sensitive to bulk anti-gp120 plasma Ig. Resistance to the mAbs was
independent of virus clade or Tier (FIG. 7). Notably, one resistant
pseudovirus was neutralized by the Lineage 5 anti-CD4i mAb, N60P39.
Thus, the combined profiles of six mAbs including N60P39 could
cover 90% of the viruses neutralized by bulk anti-gp120 plasma Ig.
To determine if greater breadth could be established by mAb
mixtures, the panel of viruses sensitive to bulk anti-gp120 plasma
Ig were tested against an equimolar pool of all anti-CD4 BS mAbs,
or an equimolar combination of represented mAbs from all lineages
(related clones with <5% amino acid sequence diversity were not
included). These mAb pools covered, respectively, 89 and 79% of the
neutralizing activity breadth mediated by the plasma Ig (FIG. 7).
These results suggest that the plasma neutralizing response in N60
could involve a cryptic anti-gp120 specificity (active against a
small subset of test viruses resistant to the identified mAbs)
and/or a molar ratio of specificities that we could not readily
duplicate in vitro.
[1045] Previously we reported that multiple Clade B HIV infected
patients expressed broadly neutralizing plasma antibody responses
with similar biochemical characteristics (Sajadi et al., J Acquir
Immune Defic Syndr 57, 9-15 (2011); Sajadi et al., J Infect Dis
213, 156-164 (2016).
[1046] Sajadi et al., J Virol 86, 5014-5025 (2012)), such as basic
pIs. We posited that this trend reflected shared inter-subject
specificity for neutralizing gp120 epitopes. To test this
hypothesis, we applied the same deconvolution procedures and
selection algorithms described above to another NVS cohort subject,
N49, who exhibited a very broad neutralization response against 99%
of a 117 virus panel (FIG. 8). Similar to the N60 responses, the
neutralizing antibodies from N49 plasma could be recovered from
plasma by gp120 affinity chromatography (recovered gp120 affinity
fraction known to be approximately 1% of the starting mass of IgG
antibody for this patient); however, in this case the .lamda.
fraction contained the broad neutralizing antibodies.
[1047] The broadly neutralizing antibodies in N49 plasma fell into
two lineages, distinguished by different light chain gene usage
(Table 10). Similar to the N60 Lineage 1 broadly neutralizing
antibodies, the N49 mAbs all exhibited basic pIs and VH1-2 gene
usage. However, all of the N49 mAbs used .lamda. light chain genes,
while also containing a CDRL3 deletion. The binding characteristics
of this N49 lineage also matched the N60 neutralizing antibodies,
reflecting anti-CD4BS specificity. These antibodies bind to
monomeric gp120, have little to no binding to D368R and FLSC in
both Elisa and biacore (FIGS. 9 and 10).
TABLE-US-00011 TABLE 10 Properties of mAbs engineered from NVS49.
Frequency of CDR3 (per 1000) Heavy Light Lambda Heavy Peripheral
Bone marrow Bone marrow mAb Epitope pI chain chain Constant
mutation plasmablast 138- 138+ N49P6 CD4-BS 8.9 1-2 2-11 LC7
42%/28% 0 0 0.49 N49P7 CD4-BS 8.8 1-2 2-11 LC2 38%/31% 0 0 0.49
N49P7.1 CD4-BS 8.8 1-2 2-11 LC2 38%/31% 0 0 0.49 N49P11 CD4-BS 8.4
1-2 2-11 LC2 35%/30% 3.18 0 0 N49P9 CD4-BS 8.7 1-2 2-23 LC7 38%/42%
3.18 0 0.49 mAb = monoclonal antibody. VDJ = Variable Diversity
Junction. LC = Lambda constant. AA = amino acid. Mutation = somatic
hypermutation given as a percent of germline V region for heavy
chains, and VJ region for light chains. NT = not tested
[1048] A distinguishing feature of the N49 anti-CD4BS mAbs was that
they exhibited remarkably broad neutralizing activity when tested
against a multi-clade, tier 1-3 panel of 117 pseudoviruses. As
shown in FIG. 8, N49 mAbs N49P6, N49P7, and N49P11 individually
neutralized 100% of the viruses. The N49 P series mAbs also had
high potency, with ability to neutralize 41.5-86.4% of all viruses
at under 1 ug/ml. MAb N49 P7 had complete breadth (ability to
neutralize all 117 pseudoviruses) and the highest potency (86.4%).
The breadth and potency of the N49 group of mAbs was compared other
mAbs reported to have substantial breadth (PGT121, PGT128, PGT145,
PGDM1400, PGT151,10-1074,10E8, PG9, PG16, 3BNC117, NIH45-46,
8ANC195, VRC07, and VRC01), using the same neutralization assay and
panel. The breadth of the N49 mAbs surpassed those of all mAbs
tested (Table 11). Although, we did not test another recently
reported broad neutralizing antibody against the CD4BS, N6
(Williams et al., Science Immunology 2, (2017)), four of the N49
mAbs could neutralize T278-50, which is N6 is resistant to. N49 was
fundamentally distinguished from N60 in the sense that three
identified plasma mAbs (N49P6, N49P7, and N49P11) completely
recapitulated the antiviral breadth of affinity purified anti-gp120
plasma IgG.
TABLE-US-00012 TABLE 11 Comparison of neutralization breadth
between those derived from NVS49 and those in the literature.
Percentages are given as values of viruses neutralized (IC50 <
50 ug/ml)/viruses tested. All testing was done in the same lab. N49
P series tested against the full 117 virus panel. All other mAbs
tested against 114-117 pseudoviruses, except for VRC01, which was
tested against 96. Neutralization at titers >50 .mu.g/mL were
considered non-neutralizing. % mAb neutralization N49P6 100% N49P7
100% N49P7.1 .sup. 99% N49P11 100% N49P9 .sup. 89% PGT121 65.8%
PGT128 59.8% PGT145 .sup. 74% PGDM1400 79.8% PGT151 65.5% 10-1074
56.8% 10E8 94.9% PG9 84.7% PG16 82.2% 3BNC117 .sup. 90% NIH 45-46
86.4% 8ANC195 65.2% VRC07 91.5% VRC01 87.6%
Materials and Methods
Patients.
[1049] The patients identified for this study was selected from the
NVS study (Sajadi et al., J Acquir Immune Defic Syndr 57, 9-15
(2011); Sajadi et al., J Acquir Immune Defic Syndr 50, 403-408
(2009); Sajadi et al., AIDS 21, 517-519 (2007)). NVS patients are
defined as having HIV-1 by Western Blot while having an HIV-1 RNA
<400 copies/ml for at least 4 measurements and 2 years. N60 met
the above definition, while N49 had a higher viral load setpoint,
averaging 7,854 HIV-1 copies/ml over 9 years. Both of the patients'
serum were identified as having broad neutralizing activity based
on Tier 2 activity and a cross-clade neutralization panel (Sajadi
et al., J Acquir Immune Defic Syndr 57, 9-15 (2011); Sajadi et al.,
J Infect Dis 213, 156-164 (2016); Sajadi et al., J Virol 86,
5014-5025 (2012).
Proteins and Antigens.
[1050] Recombinant HIV-1 antigens were generated as described
previously (31). Test antigens included the YU2 gp120 core, from
which V1, V2, and V3 have been deleted (Wu et al., Nature 384,
179-183 (1996)); the YU2 gp120 core containing the V3 loop (YU2
gp120 core +V3) (Wu et al., Nature 384, 179-183 (1996)); monomeric
HIV-1 Ba-L gp120 (Fouts et al., J Virol 74, 111427-111436 (2000));
D368R Ba-L gp120, which has a single point mutation at position 387
(Li et al., Nat Med 13, 1032-1034 (2007)); and a single chain
gp120-CD4 complex (FLSC) presenting a full length CD4-induced
Ba-Lgp120 structure in which the CD4 binding site is occupied
(Fouts et al., J Virol 74, 111427-111436 (2000)). Two monoclonals
specific for the C-terminal peptide of HIV-1 gp120 were sued: an
affinity-purified goat Ab, D7324, purchased from Cliniqa (San
Marcos, Calif.) and JR52 a mouse monoclonal. All proteins were
expressed by transient transfection of 293T cells as previously
describe and purified by lectin affinity chromatography as
previously described and dialyzed against PBS prior to use (Fouts
et al., J Virol 74, 111427-111436 (2000)). The following reagent
was obtained through the NIH AIDS Reagent Program, AIDS Program,
NIAID, NIH: HIV-1 V3 Peptides from the Division of AIDS, NIAID.
Isolation of Plasma Antibody Species.
[1051] Whole plasma IgG was purified on a Protein A or Protein A/G
affinity chromatography column (GE Healthcare, Piscataway, N.J.)
according to the manufacturer's instructions and dialyzed against
PBS prior to use. Affinity chromatography columns were made with
activated CH Sepharose beads (GE Healthcare, Piscataway, N.J.)
coupled to 2 mg of recombinant HIV-1 Ba-L gp120 (Fouts et al., J
Virol 74, 111427-111436 (2000)), as described previously (Guan et
al., Proc Natl Acad Sci USA 106, 3952-3957 (2009)). Beads specific
for human IgG1, human .kappa. chain, and human .lamda. chain were
purchased from Capture Select (Naarden, Netherlands). The columns
were used to purify antigen-specific IgG (anti-gp120), fractionate
IgG1 from whole IgG, or fractionate IgG into .kappa. and .lamda.
fractions, as previously described (Sajadi et al., J Acquir Immune
Defic Syndr 57, 9-15 (2011); Guan et al., Proc Natl Acad Sci USA
106, 3952-3957 (2009). Briefly, IgG was incubated with beads at
37.degree. C. for one hour prior to extensive washing with PBS.
Columns were eluted at room temperature with pH 2.8 0.2M glycine
(for elution of .kappa. antibodies pH 2.0 was used) and dialyzed
against 4 liters PBS 3 times (a minimum of 24 hours total) prior to
testing. Dedicated columns were used for each subject and antigen.
IgG concentration was measured using an in-house quantitative ELISA
as previously described (Guan et al., Proc Natl Acad Sci USA 106,
3952-3957 (2009)). After a series of steps, the plasma was
fractionated into IgG1 .kappa. and IgG1 .lamda. antibodies
(plasma->protein A column->IgG1 column->kappa and lambda
columns), anti-gp120 .kappa. and anti-gp120 .lamda. antibodies
(plasma->protein A column->gp120 column->kappa and lambda
columns), or anti-gp120 antibodies (plasma->protein A
column->gp120 column).
[1052] Affinity purified and fractioned antibody was subjected to
free flow electrophoresis on the BD Free Flow Electrophoresis
System (BD, Franklin Lakes, N.J.). The separation, stabilization
and counter flow media was freshly prepared according to
instructions of the manufacturer. The separation and counter flow
media contained 0.2% hydroxypropyl methylcellulose (HPMC). The pH
range of separation media was 0.88 to 12.8. The media flow rate in
the separation chamber was 41 mL/hour. The antibodies (200 to 350
.mu.g/ml) were introduced to separation chamber at the rate of 560
.mu.l/h in the electrical field of 2300V/10 mA/24 W. IEF
fractionated samples collected in a 96 deep-well polystyrene
microtiter plate, with each well containing 1-2 ml. Approximately
half of these wells contained antibody fractionated based on PI.
Fractionation was confirmed with pH reading of individual fractions
(FIG. 1), as well as an IEF gel. Separately, affinity purified
antibody fractions (prior to FFE) were also run on IEF gels.
[1053] Neutralization assay. HIV-1 neutralization testing was
performed using a luciferase-based assay in TZM.b1 cells as
previously described (Sajadi et al., J Acquir Immune Defic Syndr
57, 9-15 (2011); Li et al., J Virol 79, 10108-10125 (2005)). This
assay measures the reduction in luciferase expression following a
single round of virus infection. Stocks of Env-pseudotyped viruses
were prepared by transfection of 293T/17 cells as previously
described (Li et al., J Virol 79, 10108-10125 (2005)). Unfractioned
serum samples, affinity purified antibody, fractionated affinity
purified IgG samples, and mAbs were tested against MuLV control and
a panel of psuedoviruses. Three-fold serial dilutions of IgG were
tested in duplicate (96-well flat bottom plate) in 10% D-MEM growth
medium (100 ul/well). 200 TCID50 of pseudovirus was added to each
well in a volume of 50 ul and the plates were incubated for 1 hour
at 37.degree. C. TZM.b1 cells were then added
(1.times.10.sup.4/well in 100 ul volume) in 10% D-MEM growth medium
containing DEAE-Dextran (Sigma, St. Louis, Mo.) at a final
concentration of 11 ug/ml. The final volume for each well was 250
ul. Assay controls included replicate wells of TZM.b1 cells alone
(cell control), TZM.b1 cells with virus (virus control), and MuLV
control. Following a 48 hour incubation at 37.degree. C., 150 ul of
assay medium was removed from each well and 100 ul of Bright-Glo
luciferase reagent (Promega, Madison, Wis.) was added. The cells
were allowed to lyse for 2 minutes, then 150 ul of the cell lysate
was transferred to a 96-well black solid plate and luminescence was
measured using a Victor 3 luminometer (Perkin Elmer, Waltham,
Mass.). The 50% inhibitory concentration (IC50) and 80% inhibitory
concentration (IC80) titers were calculated as the immunoglobulin
concentration that caused a 50% or 80% reduction in relative
luminescence units (RLU) compared to the virus control wells after
subtraction of cell control RLUs (Li et al., J Virol 79,
10108-10125 (2005)).
ELISA.
[1054] HIV-1 envelope capture ELISAs were performed as previously
described (Guan et al., Proc Natl Acad Sci USA 106, 3952-3957
(2009)) with various antigens (as indicated in the text) that were
directly coated (HIV-1 Ba-L SOSIP trimer, 1 ug/ml; YU2 gp120 core
construct and YU2 gp120 core plus V3; 2 ug/ml) or captured
(Bal-gp120 or FLSC at a concentration of 0.15 ug/ml) by antibody
D7324 or JR52 that had been adsorbed to the solid phase at 2 ug/ml.
For IEF-fractionated affinity purified IgG, 5 ng from each fraction
was tested in a total assay volume of 50 ul. All IgG preparations
were incubated with antigens for 1 hour at 37.degree. C. Bound Abs
were then detected with 1:1,000-diluted alkaline phosphatase
(AP)-goat antihuman IgG (Southern Biotech; Birmingham, Ala.) and
detected with Blue Phos Microwell Phosphatase Substrate System
(KPL, Gaithersburg, Md.). All assays were performed in duplicate or
repeated several times. Negative control assays were carried out
with secondary antibody; background values were subtracted from all
test absorbance readings.
Isolation of Plasma mAbs.
[1055] Antibody species that were isolated to individual fractions
were subjected to LC-MS (in addition to FFE fractions, several
experiments were carried out with affinity purified fractions or
cut-out IEF bands from an IEF gel). Antibody was digested with
trypsin, chymotrypsin, or Glu-C overnight at 37.degree. C., the
peptides evaporated to 15u1. The LC-MS system consisted of a Thermo
Electron Orbitrap Velow ETD mass spectrometer with a Protana
nanospray ion source interfaced with a Phenomenex Jupiter C18
reversed-phase capillary column. The peptide digest was fragmented
with both CID and HCD. LC-MS was performed at the University of
Maryland School of Pharmacy and Northwestern Proteomics Center of
Excellence, none of which were involved in the data analysis. The
spectra were searched with Peaks software (Bioinformatics Solutions
Inc, Ontario, Calif.) against multiple B cell databases generated
from the patient described below.
Single Cell Sorting.
[1056] Single-cell sorting and sequencing was done at Atreca
(Redwood City, Calif.) on PBMC memory B cells (Yu2-gp140 reactive),
PBMC plasmablasts, and bone marrow plasma cells and
patient-specific B cell databases generated. All paired chain
antibody sequencing was carried out on IgG cells sorted into
microtiter plates at one cell per well by FACS. IgG plasmablasts
were enriched from cryopreserved peripheral blood mononuclear cells
(PBMCs) by gating for
CD3-CD14-CD16-CD19+CD20-CD27+CD38.sup.hirIgA-IgM-IgD-cells.
Antigen-specific cells were isolated from PBMCs using
fluorescently-labeled YU2 gp140 (43) and cultured for 4 days prior
to single cell sorting in IMDM medium (Invitrogen) in the presence
of FBS, Pen/Strep, IL-2 (PeproTech), IL-21 (PeproTech), and rCD40
ligand (R&D Systems). In some experiments, the bone marrow
plasma cells (CD3-CD14-CD16-CD38.sup.hiIgA-IgM-IgD-) were further
sorted and analyzed based on CD19 and CD138.
Paired Chain Antibody Sequencing.
[1057] Generation of barcoded cDNA, PCR ampification, and 454
sequencing of IgG were performed as described in Tan et al. 2014,
with the following modifications: biotinylated Oligo(dT) and RT
maxima H- (Fisher Scientific Company) were used for reverse
transcription, cDNA was extracted using Streptavidin C1 beads (Life
Technologies), DNA concentrations were determined using qPCR (KAPA
SYBR.RTM. FAST qPCR Kit for Titanium, Kapabiosystems), and
amplicons were sequenced using Roche 454 Titanium sequencing.
Barcode Assignment, Sequence Assembly, Assignment of V(D)J and
Identification of Mutations.
[1058] These steps were performed as previously described (Tan et
al., Clin Immunol 151, 55-65 (2014)), except for the following: a
minimum coverage of 10 reads was required for each heavy and light
chain assembly to be acceptable. Wells with more than one contig
for a chain were rejected from consideration unless one of the
contigs included at least 90% of the reads. V(D)J assignment and
mutation identification was performed using a variant of SoDA
(Volpe et al., Bioinformatics 22, 438-444 (2006)). Antibody amino
acid sequences were aligned to heavy and light chain hidden Markov
models using hmmalign (http://hmmer.org). The resulting multiple
sequence alignments were used to generate a neighbor-joining tree
with RapidNJ (Simonsen M, Pedersen CNS, in WABI 2008, L. J.
Crandall K A, Ed. (Springer, Heidelberg, 2008), vol. 5251, pp.
113-122).
Mass Spectrometry Analysis and Generation of Plasma Antibodies.
[1059] Antibody species that were isolated to individual fractions
were subjected to LC-MS (in addition to FFE fractions, several
experiments were carried out with affinity purified fractions or
cut-out IEF bands from an IEF gel). Antibody was digested with
trypsin, chymotrypsin, or Glu-C overnight at 37.degree. C., the
peptides evaporated to 15 .mu.l. The LC-MS system consisted of a
Thermo Electron Orbitrap Velow ETD mass spectrometer with a Protana
nanospray ion source interfaced with a Phenomenex Jupiter C18
reversed-phase capillary column. The peptide digest was fragmented
with both CID and HCD. LC-MS was performed at the University of
Maryland School of Pharmacy and Northwestern Proteomics Center of
Excellence, none of which were involved in the data analysis. The
spectra were searched with Peaks software (Bioinformatics Solutions
Inc., Ontario, Calif.) against multiple B cell databases generated
from the patient described above.
[1060] An array of whole IgG H and L amino acid sequences were
translated from the database and used as a basis for interpreting
the peptide data. The LC-MS derived spectra were searched against
the databases independently using the following settings: Parent
Mass Error Tolerance 5.0 ppm, Fragment Mass Error Tolerance 0.5 Da,
Fixed modification of Carboxymethyl (58.01), False Discovery Rate
for peptides 5%. Potential antibodies were ranked based on number
of unique peptides in the heavy and light chain sequences
(.gtoreq.4 unique peptides and 50% coverage in at least one of the
H and L chain of each pair or with .gtoreq.4 unique peptides
required in each H and L chain for the combined fractions). The
identified VH or VL region clones were cloned into an expression
vector upstream to human IgG1 constant domain sequence. Minipreps
of these DNA pools, derived from suspension bacterial cultures,
were used to transiently transfect 293 Freestyle cells.
Transfectant supernatants containing recombinant antibodies were
screened in ELISA and neutralization assays.
[1061] One caveat of the alignment algorithm is that certain
peptides (typically from framework regions) can redundantly align
with multiple 1 g H and L template pairs, thus creating random
peptide assemblages. This caveat was mitigated by rank ordering the
Ig H and L templates according to the number of "unique" peptide
alignments (i.e. not matching any other 1 g sequence in the
database; see Methods for details) they comprised. False discovery
rates were held at 5% to further increase the probability that
peptide sequences were properly grouped and aligned within a
full-length 1 g sequence. It was also important to consider that
similar degrees of total template "coverage" by plasma amino acid
sequences could differ substantially in the numbers of unique
peptide alignments.
[1062] In the primary approach, FFE fractions of affinity-isolated
anti-gp120 plasma antibodies were evaluated individually to score
and select corresponding H and L template pairs. This identified 8
paired Hand L 1 g genes encoding plasma mAbs N60P1.1, N60P22,
N6025.1, N60P36, N60P38, N60P39.1, N60P35, and N60P37. A second
approach applied the bulk polyclonal anti-gp120 antibodies to
preparative isoelectric focusing (IEF) gels. lmmunoglobulins were
extracted from sequential slices of the gels and digested to obtain
peptide sequences, which were then compared against the
patient-specific 1 g gene database. This operation identified all
but one of the H and L sequence pairs found in the primary approach
as well as 4 additional ones: N60P2.1, N60P30, N60P31.1, N60P48.1,
and N60P51. A third approach generated peptides and their
corresponding sequences directly from affinity-enriched anti-gp120
plasma antibodies and combining this information with the gel
digests from the second approach. This exercise mitigated the risk
that sequences were overlooked in the other methods due to protein
loss but required combining 27 separate digests. Even so, this
approach identified most of the same H and L sequence pairs found
by the other approaches (missing 2 but identifying 1 additional
mAb-N60P39. We identified one additional mAb that was not picked up
with the above methods by a homology search of the bone marrow
database. This mAb (N60P47) had no binding to gp120 on Elisa, and
thus had either no binding to gp120, as in the case of antibodies
targeted at the hybrid epitope of CD4 and gp120, or bound to gp120
so weakly that too little was recovered to identify correctly.
Example 2. Broadly Neutralizing HIV Antibodies
[1063] Using a method for isolating monoclonal antibodies that
match the circulating antibodies in circulation, we have isolated a
series of broadly neutralizing antibodies against HIV-1. The
subject these antibodies were isolated from (NVS49, also referred
to as Subject 8 in previous publications) has extremely potent
antibodies against HIV-1 (Saj adi et al., J Acquir Immune Defic
Syndr 57, 9-15 (2011); Sajadi et al,. J Virol 86, 5014-5025 (2012);
Sajadi et al., J Infect Dis 213, 156-164 (2016)). At the point of
testing, the patient had HIV for at least 21 years. The patient's
plasma was the time point closest to when the antibodies were
derived from was able to neutralize 99% of HIV strains from around
the world (Excel file "N49 neutralization and sequences"),
including strains that other HIV mAbs that are undergoing clinical
testing are resistant to.
[1064] We have been able to isolate 2 distinct families of
antibodies from this patient. All of these antibodies have been
engineered with the same IgG1 heavy chain backbone (not obtained
from patient NVS49 and in fact found in a different racial group),
along with VDJ sequences obtained from patient NVS49. In addition,
various clones have mutations in the VDJ or constant regions, and
some antibodies have swapped Lambda constant regions.
[1065] The first family comprises of N49P6, N49P7, N49P11, N49P18
and their various clones (N49P6.1, N49P6.2, N40P7.1, N49P7.2,
N49P11.1, N49P18.1). The second family comprises of N49P9 and its
clone N49P9.1. Both family of antibodies use the 1-2 Heavy chain
family, while using 2 different Lambda light chain gene families
(Lambda 2-11 and Lambda 2-23) (see Table 12 and FIG. 11 for more
details).
TABLE-US-00013 TABLE 12 Properties of mAbs engineered from NVS49.
Heavy Light Lambda Heavy Light mAb chain chain Constant mutation
mutation pI Notes N49P6 1-2 2-11 LC7 42% 28% 8.9 N49P6.1 1-2 2-11
LC7 42% 28% 9.0 VDJ identical to N49P6 Heavy constant: 1 AA
difference with N49P6 N49P6.2 1-2 2-11 LC2 42% 28% 9.0 VDJ
identical to N49P6 Heavy constant: Same as N49P6.1 Lambda constant:
1 AA difference with N49P6/6.1, also LC2 not LC7 N49P7 1-2 2-11 LC2
38% 31% 8.8 N49P7.1 1-2 2-11 LC2 38% 31% 8.8 VDJ identical to N49P7
Heavy constant: 1AA difference with N49P7 Lambda constant: 1AA
difference with N49P7 N49P7.2 1-2 2-11 LC2 38% 29% 8.8 Heavy: 8 AA
mutation VDJ with N49P7/7.1 Heavy constant- 1 AA difference with
N49P7.1 Light: DJ identical to N49P7/7.1 Light: V region 2 AA
difference with N49P7/7.1 N49P11 1-2 2-11 LC2 35% 30% 8.4 Lambda
constant: 1 AA mutation N49P18 1-2 2-11 LC2 38% 29% 8.7 Lambda
constant: 1 AA mutation N49P18.1 1-2 2-11 LC2 34% 31% 8.7 Heavy: V
region 4 AA difference with N49P18 Heavy constant: 1 AA difference
with N49P18 Light: V region 3 AA difference with N49P18 N49P19 1-2
2-11 LC2 39% 28% 8.9 Lambda constant: 1 AA mutation N49P9 1-2 2-23
LC7 38% 42% 8.65 Lambda constant: 1 AA mutation N49P9.1 1-2 2-23
LC2 38% 42% NT Lambda constant: Contains N49P9 mutation but LC2
instead of LC7. mAb = monoclonal antibody. VDJ = Variable Diversity
Junction. LC = Lambda constant. AA = amino acid. Mutation = somatic
hypermutation given as a percent of germline V region for heavy
chains, and VJ region for light chains. NT = not tested
[1066] The antibodies from these 2 families target the CD4-binding
site region of HIV-gp120. Currently, we have several lines of
evidence to support this. Inspection of the protein sequence of the
antibodies reveal characteristic phenotype of CD4-BS antibodies:
[1067] 1) Heavy chain: usage of the 1-2 Heavy chain, usage of
Trp50, Asn58, and Arg71 at the noted positions [1068] 2) Light
Chain: usage of a deletion in CDRL3 rendering it 5 amino acids
long, as well as a deletion in CDRL1 (FIG. 12). [1069] 3) Basic
isoelectric point
[1070] None of the antibodies tested thus far can bind BaL D368R
mutant, while they can bind the BaL gp120 monomer. The difference
in the 2 antigens is a single point mutation at position 368, which
abrogates binding of CD4-BS antibodies to HIV-1 gp120 (Li et al.,
Nat Med 13, 1032-1034 (2007)) (FIG. 12). Finally, crystallography
reveals binding the region of the CD4-BS.
[1071] Antibodies N49P6, N49P7, N49P9, and N49P11 were evaluated by
their ability to neutralize HIV-1 against a panel of pseudoviruses
in our lab. N49P6 and N49P7 demonstrated the best neutralization
with ability to neutralize all the viruses tested (see FIG. 13 for
N49P7 neutralization).
[1072] The following antibodies were sent for extensive testing at
Dr. Michael Seaman's lab at Harvard University: N49P6, N49P7,
N49P7.1, N49P11, and N49P9. Dr. Seaman uses a panel of 118 HIV-1
pseudoviruses that represent multi-clade and difficult to
neutralize strains from around the world. Dr. Seaman's lab is a
reference lab for neutralization testing, and he has worked with
all of the major HIV-1 broadly neutralizing antibodies that have
been created. In Dr. Seaman's panel, the antibodies tested
performed better than all the antibodies he has worked with before.
Specifically: N49P6, N49P7, and N49P11 demonstrated 100%
neutralization breadth (able to neutralize all the viruses by IC50
in the panel), N49P7.1 demonstrated 99% neutralization, and N49P9
demonstrated 89% neutralization (Individual IC50 and IC80 values
against each pseudovirus are in the Excel file "N49 neutralization
and sequences").
[1073] Beyond their ability to neutralize 100% of the viruses, the
importance of these antibodies are that they can neutralize viruses
that other broadly neutralizing antibodies are resistant to. The
antibodies from N49 were able to neutralize all the viruses that
the other mAbs were resistant to (importantly all the
neutralization data was from the same lab). A summary of the
neutralization breadth of the NVS49 antibodies compared to the
others described are provided in Table 13 below.
TABLE-US-00014 TABLE 13 Comparison of neutralization breadth
between those derived from NVS49 and those in the literature.
Percentages are given as values of viruses neutralized (IC50 <
50 ug/ml)/viruses tested. All testing was carried independent of
the inventors by Dr. Seaman at Harvard. mAb % neutralization N49P6
100% N49P7 100% N49P7.1 .sup. 99% N49P11 100% N49P9 .sup. 89%
PGT121 65.8% PGT128 59.8% PGT145 .sup. 74% PGDM1400 79.8% PGT151
65.5% 10-1074 56.8% 10E8 94.9% PG9 84.7% PG16 82.2% 3BNC117 .sup.
90% NIH 45-46 86.4% 8ANC195 65.2% VRC07 91.5% VRC01 87.6%
Recently, there has been a report of a new broadly neutralizing
antibody, N6, which has more breadth than other HIV broadly
neutralizing antibodies (Huang et al,. Immunity 45, 1108-1121
(2016)). Dr. Seaman has only tested this antibody against a Clade C
panel, and so we can not compare N6 with our antibodies directly.
However, N49 P6, N49P7, and N49P11 has the ability to neutralize
viruses that N6 was unable to (such as T278-50). These results show
that the antibodies engineered from NVS49 are truly unique and are
the broadest mAbs against HIV-1 that have been described to date.
Currently, there are a variety of human and animal clinical trials
that are addressing the utility of anti-HIV monoclonal antibodies
for the prevention, treatment, or cure of HIV-1. These take the
form of either using broadly neutralizing antibodies or their
derivatives (engineered to have longer half-life, activity coupled
with drugs, etc.). We anticipate that the extreme breadth and
potency of the antibodies described above will make them highly
useful in HIV research and for the prevention, treatment, or cure
of HIV-1. In addition these mAbs can be used to select (purify)
native trimers.
Example 3. Antibody Variants
[1074] This example contains additional details about modifications
made to antibodies and contains a number of new antibodies. All
antibody numbering is now based on IMGT (see FIGS. 14, 15, and 16),
so a few of the individual positions are different than what was
listed before (see also FIGS. 17 and 18 for aligned N49P6 and N49P7
mutants). Variants are described in Table 4, above.
Modifications of antibodies: [1075] 1) Modifications to improve
stability. [1076] Heavy chain modifications: Substitution at
position 1.4 of CH1 (1' amino acid of the constant region) to A
from P or S. Substitution at position 120 of CH1 to R. Substitution
at position 12 of CH3 to E, at position 14 of CH3 to M. [1077]
Light chain modifications: modifications to change the unpaired
cysteine to another amino acid that has potentially better
pharmacokinetic properties: substitutions at IMGT position 42
(Cysteine) to A, S, Y, or F. Other light chain modifications
include substitution at position 1.5 of the light chain constant
region (1' amino acid of the constant region) from R to S or G for
those that use LC2, or from S to R or G for those that use LC7.
[1078] 2) Modifications to improve antibody function (binding,
neutralization, complement fixation, ADCC, ADCP). [1079] Heavy
chain modifications: Dual substitution at positions 59 and 62 to T
and Y, respectively. Substitution of Y, F, W, or H at position 62.
Substitution at position 1.4 of CH1 (1' amino acid of the constant
region) to G from P or S. Substitution at position 120 of CH1 to R.
Substitution at position 12 of CH3 to E, at position 14 of CH3 to
M. [1080] Light chain modifications: Substitution at position 1.5
of the light chain constant region (1' amino acid of the constant
region) from R to S or G for those that use LC2, or from S to R or
G for those that use LC7. [1081] 3) Modifications to improve
antibody half-life. [1082] Heavy chain modifications with
combinations of any of the following substitutions: Substitution at
position 120 of CH1 to R. Substitution at position 12 of CH3 to E,
at position 14 of CH3 to M. Substitution at position 101 of CH3 to
I, 107 of CH3 to L, position 113 of C.sub.H3 to S, position 115 to
R. [1083] 4) Constant region swapping: Swapping of light chain
constant region: light chain constant region swapped to another
lambda constant region (LC1-7) for improved stability and function.
Another method of swapping will be used to make monoclonals that
are "rhesus-ized," that is, retain the variable regions in the
heavy and light chains, but use constant regions from rhesus lambda
chain (such as LC3), as well as rhesus IgG1. These mAbs can also
have the half-life extending mutations noted above in the
corresponding amino acids of the rhesus IgG1 constant region.
[1084] 5) Swapping of heavy and light chain variable regions: These
include taking a native or modified antibody listed in this
application and mixing and matching the heavy and light chains to
improve antibody stability or function. For example, one such
antibody is made from the heavy chain of the parent antibody
N49P7.1 (a variant of sequence 2) with the light chain from the
parent antibody N49P9 (a variant of sequence 18). We have already
made a number of these. As they can be readily expressed suggests
the similarity in the gene family usage, and targeted epitopes
makes these mAb swaps feasible to make and test. These swaps can
also be made with other antibodies that target the same epitope
(such as N60P1, N60P1.1, N60P2.1, N60P23, N60P31.1, N60P44, N60P45,
VRC01, N6, etc.). [1085] 6) CDR replacement mutants: These include
taking the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and/or CDRL3 from one
of the natural or modified antibodies listed in this application
and inserting into the corresponding CDR another natural or
modified antibody from this application. For example, we have made
an antibody with the CDR3 of sequence 2, inserted and replacing the
CDR3 of N49P9 (a variant of sequence 18). [1086] 7) Antibody-drug
conjugates: The natural and modified antibodies listed here can be
conjugated (covalently or non-covalently) to markers (florescent
dye or radionuclides), toxins, or therapeutic agents. We have
constructed a conjugate between N49P7 and auristatin (a microtubule
toxin). [1087] 8) Pharmaceutical compositions: These can include
antibodies (pre-made in a variety of vehicles) delivered via
injection, or genes encoding antibodies delivered via a viral or
other vector. [1088] 9) Antibody-bead conjugates. The modified
antibodies listed here can be conjugated to agarose or other beads
by a variety of chemical reactions (such as but not limited to
Cyanogen Bromide-Activated and NHS esters) for the purpose of
creating affinity purification columns that can bind (and purify)
gp120 and its mutants, gp160 and its mutants, HIV trimers, or HIV-1
virus. [1089] 10) Antibodies, their modifications, and fragments,
can be used for the purpose of HIV prevention, treatment, or cure,
and can be done individually or in combination with any number of
anti-HIV treatments.
Example 4. Crystallographic Analysis of the Broadly Neutralizing
Antibodies
[1090] To define the molecular basis for the broad potencies of N60
and N49 P mAbs series we solved the crystal structures of N60P23
and N49P7 Fabs in complex with HIV-1 93TH0S7 gp120 (Table 14).
TABLE-US-00015 TABLE 14 Data collection and refinement statistics.
N49-P7 N60-P23 Fab-gp120.sub.93TH057 Fab-gp120.sub.93TH057
core.sub.e core.sub.e Data collection Wavelength, {acute over
(.ANG.)} 0.979 0.979 Space group P2.sub.12.sub.12.sub.1 C2 Cell
parameters a, b, c, .ANG. 61.4, 63.9, 255.3 127.6, 68.6, 119.4
.alpha., .beta., .gamma., .degree. 90, 90, 90 90, 111.4, 90
Complexes/a.u. 1 1 Resolution, (.ANG.) 50-2.69 (2.74-2.69) 50-2.38
(2.43-2.38) # of reflections Total 73,281 139,212 Unique 23,639
38,617 R.sub.merge.sup.b, % 13.1 (74.9) 16.0 (90.8)
R.sub.pim.sup.c, % 7.7 (42.9) 9.7 (62.5) CC.sub.1/2.sup.d 0.99
(0.67) 0.99 (0.47) Wilson B.sub.factor (1/.ANG..sup.2).sup.e 53 30
I/.sigma. 9.3 (1.1) 9.7 (1.2) Completeness, % 80.6 (72.2) 100
(99.0) Redundancy 3.1 (3.2) 3.6 (2.9) Refinement Statistics
Resolution, .ANG. 50.0-2.7 50.0-2.4 R.sup.f, % 22.5 21.4
R.sub.free.sup.g, % 28.5 25.8 # of atoms Protein 5,822 5,905 Water
27 222 Ligand/Ion 170 133 Overall B value (.ANG.).sup.2 Protein 50
44 Water 33 36 Ligand/Ion 64 59 Root mean square deviation Bond
lengths, .ANG. 0.014 0.009 Bond angles, .degree. 1.2 1.4
Ramachandran.sup.h favored, % 89.0 93.5 allowed, % 9.7 5.8
outliers, % 1.3 0.7 PDB ID 6BCK 5WB9 Values in parentheses are for
highest-resolution shell .sup.bR.sub.merge = .SIGMA. | I -
<I> |/.SIGMA.I, where I is the observed intensity and
<I> is the average intensity obtained from multiple
observations of symmetry-related reflections after rejections
.sup.cR.sub.pim = as defined in (Weiss, 2001) .sup.dCC.sub.1/2 = as
defined by Karplus and Diederichs (Karplus and Diederichs, 2012)
.sup.eWilson B.sub.factor as calculated in (Popov and Bourenkov,
2003) .sup.fR = .SIGMA. || F.sub.o | - | F.sub.c ||/.SIGMA. |
F.sub.o |, where F.sub.o and F.sub.c are the observed and
calculated structure factors, respectively .sup.gR.sub.free = as
defined by Brunger (Brunger, 1997) .sup.hCalculated with
MolProbity.
[1091] N60P23, a clone of N60 P1.1 that has a 1 amino acid (aa)
difference in the light chain, exhibited an epitope footprint with
intermolecular contacts similar to those of VRCO1 and other
previously described CD4bs antibodies (FIG. 19 and Table 15). In
contrast, N49P7 bound to gp120 in a unique manner (FIG. 20).
TABLE-US-00016 TABLE 15 Details of the N49_P7-gp120.sub.93TH057
core.sub.e, N60_P23-gp120.sub.93TH057 core.sub.e,
N6-gp120.sub.93TH057 core.sub.e, and VRCO1-gp120.sub.93TH057
core.sub.e interfaces. Results as calculated by the EBI PISA server
(http://www.ebi.ac.uk/msd-srv/prot_int/cgi-bin/piserver). N49_P7
N60_P23 N6 Fab- VRCO1- Fab- Fab- gp120.sub.93TH057
gp120.sub.93TH057 gp120.sub.93TH057 gp120.sub.93TH057 core.sub.e
core.sub.e core.sub.e core.sub.e (5te6) (3ngb) Buried gp120total
981 939 1132 1143 Surface Outer domain (OD) 774 872 1000 1036 Area,
.ANG..sup.2 Inner domain (ID) 207 67 132 107 Ratio of OD/ID 3.74
13.01 7.58 9.68 Loop D of OD 339 346 332 322 CD4 binding loop of
186 202 206 188 OD Loop V5 of OD 164 209 339 301 Heavy chain 821
726 928 897 total FWR 54 158 146 136 CDR H1 4 20 38 3 CDR H2 489
435 621 598 CDRH3 274 113 123 160 Light chain 138 243 251 306 total
FWR 0 0 36 124 CDR L1 9 67 43 50 CDR L2 0 0 0 0 CDR L3 129 176 172
132 Heavy and light 959 969 1179 1203 chain total
[1092] The deletion in the CDRL1 (not found in N6) combined with
the rotation/tilting of the light chain `opens` the variable light
(V1) side of the N49P7 antigen binding site to accommodate
different lengths of the highly variable loops D, E and VS (FIG.
21). Changes in the length of gp120 loop VS and the length (and
glycosylation status) of loop E that cause steric clashes with an
antibody light chain were described previously as mechanisms of
HIV-I resistance to VRC01-class antibodies (Lynch et al., 2015).
These signatures, along with a long CDRH3 (19 aa) and unique
sequence signatures within CDR.B2 (not seen in VRCO1 and N6, FIG.
21), allow N49P7 to bypass the Phe43 cavity affording it an unusual
capacity to contact the gp120 inner domain at residues 97, 102 and
124 of Layer 2, and 472-480 of Layer 3 (FIG. 18). Overall N49P7
contributes 207 .ANG..sup.2 of its buried surface area (BSA) to the
gp120 inner domain which is much higher than N6 and the VRC0I Abs
class (Table 15). The gp120 inner domain harbors some of the most
conserved amino acid sequences in the HIV envelope, located within
structural Layers 1, 2 and 3 and a consolidation of 8 P-strands
(Finzi et al., 2010). Other CD4bs antibodies such as N6 and VRC0I
also display contacts with the inner domain; however, these are
less prominent. Although NIH 45-46 is not as broad and potent and
N49P7, it has previously shown to have more contacts with the inner
domain (mostly Layer 2) than VRC0I (Diskin et al., 2011), and it
was postulated that this may be the reason for the breadth. N49P7
is unique in the number of inner domain contacts (especially Layer
3). N49P7 exhibits a lower outer domain to inner domain buried
surface area ratio (3.74) compared to N6 (7.58) and VRC01 (9.68),
which shows it has significantly more contacts with the inner
domain (Table 15). Thus, the N49P7 paratope recognizes a mixed
inner domain/CD4-binding site (termed here the iCD4bs) containing
some of the most conserved sequences in gp120. These features help
explain the extreme neutralization breadth of the antibody.
Methods
Crystallization
[1093] Initial crystal screens were done in robotic vapor-diffusion
sitting drop trials using a Gryphon Protein Crystallization Robot
(Art Robbins Instruments) with commercially available sparse matrix
crystallization screens from Molecular Dimensions (Proplex and
MacroSol), Emerald Biosystems (Precipitant Wizard Screen) and
Emerald BioSystems (Synergy Screen). The screens were monitored
periodically for protein crystals. Conditions that produced micro
crystals were then reproduced and optimized using the hanging-drop,
vapor diffusion method with drops of 0.5 .mu.l protein and 0.5
.mu.l precipitant solution. For the N60P23 complex conditions
producing diffraction quality crystals came from 0.1 M Magnesium
acetate hexahydrate, 0.065.M NaCl and 0.1 M MOPS pH 7.5 after
incubation at 22.degree. C. N49P7 complex crystals came from 10%
PEG 5000 MME, 12% isopropanol, and 0.1 MMES pH 6.5. Crystals were
frozen in liquid nitrogen after a brief soak in mother liquor
supplemented with 20% MPD prior to being used for data
collection.
Data Collection and Structure Solution and Refinement.
[1094] Diffraction data for N60P23 Fab- and N49P7 Fab-gp 12093TH057
core.sub.e complexes were collected at the Stanford Synchrotron
Radiation Light Source (SSRL) at the beam line BL14 1 (N60P23) and
BL12-2 (N49P7) equipped with Marmosaic 325 or Pilatus area
detectors respectively. N60P23 crystals belong to a space group C2
with the unit-cell parameters a=127.6, b=68. 6, c=119.4 A and
=111.4.degree. with one N60P23 Fab-gp120.sub.93TH057 core.sub.e
complex present in the asymmetric unit (ASU). N49P7 crystals belong
to space group P2.sub.12.sub.12.sub.1 with the unit-cell parameters
a=61.4, b=63.9, and c=255.3 .ANG. with one N49P7 Fab-gp12093THo57
core.sub.e complex present in the ASU. Data was processed and
reduced with HKL2000, as previously described (Guan et al., 2013).
The data for the N49P7 complex was highly anisotropic and was
further processed using the STARANISO server (Global Phasing Ltd.
[http://staraniso.globalphasing.org/cgi-bin/staraniso.cgi]). The
N60P23 structure was solved by molecular replacement with Phaser
from the CCP4 suite based on the coordinates of gp120 (PDB: 3TGT)
and the VRCO1 Fab (PDB: 4RFE) for the N6P23 Fab. N49P7 was solved
using coordinates of gp120 (PDB: 3TGT) and N5-I5 Fab (PDB: 3TNN)
for the N49P7 Fab. Refinement was done with Refmac and/or Phenix,
coupled with manual refitting and rebuilding using COOT, as
previously described (Guan et al., 2013). The N60P23 complex
complex was refined to an R-factor of 0.214 and an R-free of 0.258
and the N49P7 complex was refined to an R-factor of 0.225 and
R-free of 0.285. Data collection and refinement statistics are
shown in (Table 14).
Structure Validation and Analysis.
[1095] The quality of the final refined model was monitored using
the program MolProbity, as previously described (Guan et al.,
2013). Structural alignments were performed using the Dali server
and the program lsqkab from CCP4 suite. The PISA webserver was used
to determine contact smfaces and interface residues. All
illustrations were prepared with the PyMol Molecular Graphic suite
(http://pymol.org) (DeLano Scientific, San Carlos, Calif.,
USA).
Data Availablity.
[1096] The data reported in this paper are archived at the
following databases: GenBank and Protein Data Bank (PDB).
Example 5. Neutralization Assays of HIV Antibody Variants
[1097] Shown in this example are neutralization assay data of
various anti-HIV antibodies of the invention across an Env
pseudovirus panel (See Table).
TABLE-US-00017 TABLE 16 Neutralization assay data of mAbs against
Env pseudovirus panel. mAbs tested at primary concentration of 50
ug/ml, 25 ug/ml, or 17 ug/ml and titrated 5-fold 7x (duplicate
wells). Titer in TZM.bl cells (ug/ml) TABLE 16 N49P7A N49P7S
N49P7-54TY N49P7YTE Virus ID Clade* IC50 IC80 MPI IC50 IC80 MPI
IC50 IC80 MPI IC50 IC80 MP PVO.4 B 0.079 0.205 100 0.035 0.132 100
0.079 0.314 100 0.088 0.394 100 AC10.0.29 B >17 >17 45 36.004
>50 55 >25 >25 40 >50 >50 28 62357_14_D3_4589 B
(T/F) 0.031 0.105 100 0.020 0.074 100 0.055 0.192 100 0.039 0.173
100 Du172.17 C 0.088 0.376 100 0.055 0.282 100 0.124 0.529 100
0.283 0.953 100 Du422.1 C 2.417 13.266 85 6.131 48.813 82 0.402
2.022 96 13.224 >50 76 CAP210.2.00.E8 C 0.729 5.618 94 0.640
3.233 100 0.691 3.329 97 3.109 13.903 99 Ce1086_B2 C (T/F) 0.072
0.349 100 0.042 0.166 100 0.067 0.339 100 0.113 0.530 99 Ce1172_H1
C (T/F) >17 >17 4 >50 >50 1 >25 >25 23 >50
>50 12 CNE20 BC 0.045 0.122 100 0.038 0.141 100 0.046 0.160 100
0.110 0.317 99 Q259.d2.17 A 0.273 2.511 93 0.814 6.528 91 0.132
1.129 95 5.340 44.139 82 191955_A11 A (T/F) 3.118 >17 75 10.158
>50 72 3.045 >25 72 39.028 >50 56 T250-4 CRF02_AG 2.460
>17 74 12.223 >50 65 1.020 19.555 83 >50 >50 43
620345.c01 CRF01_AE >17 >17 0 >50 >50 0 >25 >25 0
>50 >50 0 R1166.c01 CRF01_AE 0.076 0.349 100 0.050 0.172 100
0.131 0.470 100 0.232 0.782 100 BJOX028000.10.3 CRF01_AE 0.029
0.177 100 0.009 0.034 100 0.009 0.044 100 0.018 0.155 100 (T/F)
X1254_c3 G 3.732 >17 71 16.977 >50 71 0.145 0.599 100 26.154
>50 59 X2088_c9 G 0.084 0.381 100 0.083 0.275 100 0.172 0.572
100 0.329 1.060 100 3016.v5.c45 D 0.275 1.801 92 0.635 6.393 92
0.206 1.908 92 1.151 9.654 89 6952.v1.c20 CD >17 >17 16
>50 >50 18 >25 >25 20 >50 >50 13 6545.v4.c1 6.807
>17 62 12.387 >50 63 3.014 >25 74 >50 >50 45
3103.v3.c10 ACD 0.061 0.239 100 0.057 0.168 100 0.151 0.550 100
0.322 0.583 100 MuLV Neg. >17 >17 0 >50 >50 0 >25
>25 0 >50 >50 4 Control indicates data missing or
illegible when filed
Example 6. Neutralization Assays of Hiv Antibody Variants
[1098] Shown in this example are neutralization assay data of
various HIV antibodies of the invention and known HIV antibodies
across an extended multiclade virus panel (See Tables 17-25).
TABLE-US-00018 TABLE 17 Neutralization assay data of NS49 plasma
and NS49 P6 mAbs against extended multiclade virus panel. mAbs
tested at primary concentration of 50 ug/ml and titrated 5-fold 7x
(duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 17 NVS49
Plasma NVS49 P6 Virus ID Clade* ID50 ID80 IC50 IC80 MPI 6535.3 B
460 93 0.417 1.341 100 QH0692.42 B 207 71 0.652 2.276 100
SC422661.8 B 427 125 0.129 0.360 100 PVO.4 B 543 143 0.128 0.357
100 TRO.11 B 568 208 0.061 0.190 100 AC10.0.29 B 114 <40 32.310
>50 67 RHPA4259.7 B 830 346 0.117 0.443 100 THRO4156.18 B 144 46
12.487 38.403 89 REJO4541.67 B 925 244 0.066 0.215 100 TRJO4551.58
B 356 134 0.255 0.874 100 WITO4160.33 B 641 170 0.096 0.277 100
CAAN5342.A2 B 342 103 0.657 1.829 100 WEAU_d15_410_787 B (T/F) 709
271 0.070 0.188 100 1006_11_C3_1601 B (T/F) 879 293 0.068 0.209 100
1054_07_TC4_1499 B (T/F) 163 <40 0.624 2.848 100
1056_10_TA11_1826 B (T/F) 314 51 0.209 0.606 100 1012_11_TC21_3257
B (T/F) 354 83 0.137 0.502 100 6240_08_TA5_4622 B (T/F) 127 <40
0.567 1.757 100 6244_13_B5_4576 B (T/F) 318 78 0.095 0.328 100
62357_14_D3_4589 B (T/F) 363 112 0.098 0.296 100 SC05_8C11_2344 B
(T/F) 355 90 0.266 0.911 100 Du156.12 C 1,519 355 0.082 0.280 100
Du172.17 C 687 100 20.759 >50 74 Du422.1 C 160 <40 44.007
>50 57 ZM197M.PB7 C 251 63 3.001 12.401 98 ZM214M.PL15 C 295 41
0.510 1.802 100 ZM233M.PB6 C 250 56 1.233 4.005 99 ZM249M.PL1 C 345
116 0.112 0.376 100 ZM53M.PB12 C 121 42 0.538 1.706 100 ZM109F.PB4
C 591 170 0.084 0.290 99 ZM135M.PL10a C 438 68 0.494 1.775 99
CAP45.2.00.G3 C 398 67 21.663 >50 75 CAP210.2.00.E8 C 104 <40
22.582 >50 73 HIV-001428-2.42 C 1,810 764 0.016 0.050 100
HIV-0013095-2.11 C 330 96 0.971 8.044 96 HIV-16055-2.3 C 774 200
0.117 0.586 100 HIV-16845-2.22 C 254 52 0.692 3.754 100 Ce1086_B2 C
(T/F) 680 148 0.581 4.086 98 Ce0393_C3 C (T/F) 496 79 0.608 3.249
100 Ce1176_A3 C (T/F) 327 52 0.594 2.114 100 Ce2010_F5 C (T/F) 386
83 0.124 0.749 100 Ce0682_E4 C (T/F) 1,378 246 0.095 0.315 100
Ce1172_H1 C (T/F) 112 <40 14.353 47.253 82 Ce2060_G9 C (T/F) 146
<40 0.888 4.812 100 Ce703010054_2A2 C (T/F) 837 155 0.245 0.841
100 BF1266.431a C (T/F) 1,228 255 0.083 0.283 100 246F C1G C (T/F)
727 240 0.513 2.510 99 249M B10 C (T/F) 296 95 0.122 0.549 100
ZM247v1(Rev-) C (T/F) 274 60 0.063 0.170 100 7030102001E5(Rev-) C
(T/F) 515 161 0.354 1.171 100 1394C9G1(Rev-) C (T/F) 230 59 17.498
>50 80 Ce704809221_1B3 C (T/F) 534 139 1.667 12.774 97 CNE19 BC
1,095 289 0.044 0.156 100 CNE20 BC 233 40 2.739 15.642 95 CNE21 BC
174 43 0.832 6.517 99 CNE17 BC 172 <40 0.340 2.103 100 CNE30 BC
159 57 0.457 1.536 100 CNE52 BC 1,078 467 0.028 0.095 100 CNE53 BC
457 151 0.249 0.871 99 CNE58 BC 1,025 352 0.036 0.100 100 MS208.A1
A 578 102 0.110 0.436 100 Q23.17 A 496 184 0.052 0.185 100 Q461.e2
A 199 68 0.173 0.622 100 Q769.d22 A 498 169 0.072 0.318 100
Q259.d2.17 A 316 88 24.376 >50 75 Q842.d12 A 1,430 546 0.034
0.091 100 3415.v1.c1 A 491 170 0.188 0.648 100 3365.v2.c2 A 521 193
0.129 0.347 100 0260.v5.c36 A 173 <40 0.485 1.551 100 191955_A11
A (T/F) 151 44 0.124 0.344 100 191084 B7-19 A (T/F) 552 184 0.062
0.257 100 9004SS_A3_4 A (T/F) 783 202 0.181 0.817 100 T257-31
CRF02_AG 330 105 0.147 0.535 100 928-28 CRF02_AG 178 50 1.242 5.604
99 263-8 CRF02_AG 1,091 321 0.116 0.438 100 T250-4 CRF02_AG 631 167
21.927 >50 68 T251-18 CRF02_AG 263 83 0.344 0.929 100 T278-50
CRF02_AG 45 <40 25.690 >50 67 T255-34 CRF02_AG 1,005 295
0.076 0.392 100 211-9 CRF02_AG 403 85 8.494 27.679 93 235-47
CRF02_AG 984 379 12.976 46.426 82 620345.c01 CRF01_AE <40 <40
22.899 >50 70 CNE8 CRF01_AE 688 244 0.072 0.245 100 C1080.c03
CRF01_AE 852 106 0.181 0.661 100 R2184.c04 CRF01_AE 2,504 535 0.028
0.077 100 R1166.c01 CRF01_AE 677 186 0.102 0.344 100 R3265.c06
CRF01_AE NT NT 0.101 0.443 100 C2101.c01 CRF01_AE 1,943 252 0.140
0.597 100 C3347.c11 CRF01_AE 1,772 405 0.080 0.266 100 C4118.c09
CRF01_AE 877 150 0.092 0.243 100 CNE5 CRF01_AE 401 93
BJOX009000.02.4 CRF01_AE 139 43 0.320 1.463 100 BJOX015000.11.5
CRF01_AE 783 133 0.070 0.312 100 (T/F) BJOX010000.06.2 CRF01_AE 230
54 0.681 3.529 100 (T/F) BJOX025000.01.1 CRF01_AE 422 59 14.946
>50 78 (T/F) BJOX028000.10.3 CRF01_AE 3,724 175 6.678 >50 77
(T/F) X1193_c1 G 993 185 0.074 0.224 100 P0402_c2_11 G 512 113
3.536 18.954 99 X1254_c3 G 172 63 15.739 34.230 91 X2088_c9 G 133
46 27.036 >50 65 X2131_C1_B5 G 600 97 0.174 0.720 100 P1981_C5_3
G 293 91 0.310 0.708 100 X1632_S2_B10 G 97 <40 23.063 >50 69
3016.v5.c45 D 234 52 21.668 >50 72 A07412M1.vrc12 D 233 54 0.229
0.786 100 231965.c01 D 136 46 9.245 39.386 87 231966.c02 D 258 94
0.339 1.621 100 3817.v2.c59 CD 54 <40 16.922 >50 78
6480.v4.c25 CD 1,140 246 0.089 0.427 100 6952.v1.c20 CD 328 91
16.912 >50 78 6811.v7.c18 CD 164 48 0.238 1.008 100 89-F1_2_25
CD 78 <40 33.639 >50 61 3301.v1.c24 AC 1,006 268 0.054 0.149
100 6041.v3.c23 AC 1,317 281 5.525 43.153 88 6540.v4.c1 AC 766 245
13.973 47.540 81 6545.v4.c1 AC 165 49 24.487 >50 76 0815.v3.c3
ACD 2,249 346 0.194 1.251 100 3103.v3.c10 ACD 324 87 0.582 1.567
100 MuLV Neg. Control <40 <40 >50 >50 0 *(T/F):
Transmitted/Founder Virus
TABLE-US-00019 TABLE 18 Neutralization assay data of NS49 P7 and
NS49 P7.1 mAbs against extended multiclade virus panel. mAbs tested
at primary concentration of 50 ug/ml and titrated 5-fold 7x
(duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 18 NVS49 P7
NVS49 P7.1 Virus ID Clade* IC50 IC80 MPI IC50 IC80 MPI 6535.3 B
0.186 0.598 100 0.224 0.715 100 QH0692.42 B 0.663 2.411 100 0.764
2.710 100 SC422661.8 B 0.114 0.320 100 0.125 0.417 100 PVO.4 B
0.107 0.365 100 0.124 0.421 100 TRO.11 B 0.044 0.160 100 0.055
0.191 100 AC10.0.29 B 5.034 36.661 89 5.308 46.750 85 RHPA4259.7 B
0.083 0.246 100 0.108 0.292 100 THRO4156.18 B 2.341 12.410 99 3.068
12.603 98 REJO4541.67 B 0.015 0.049 100 0.022 0.088 100 TRJO4551.58
B 0.104 0.351 100 0.156 0.529 100 WITO4160.33 B 0.084 0.248 100
0.121 0.326 100 CAAN5342.A2 B 0.409 1.211 100 0.550 1.589 100
WEAU_d15_410_787 B (T/F) 0.045 0.117 100 0.058 0.142 100
1006_11_C3_1601 B (T/F) 0.044 0.158 100 0.061 0.193 100
1054_07_TC4_1499 B (T/F) 0.494 2.308 100 0.627 2.980 100
1056_10_TA11_1826 B (T/F) 0.141 0.468 100 0.171 0.603 100
1012_11_TC21_3257 B (T/F) 0.046 0.125 100 0.063 0.176 100
6240_08_TA5_4622 B (T/F) 0.457 1.728 100 0.509 1.951 100
6244_13_B5_4576 B (T/F) 0.111 0.386 100 0.184 0.493 100
62357_14_D3_4589 B (T/F) 0.025 0.102 100 0.028 0.150 100
SC05_8C11_2344 B (T/F) 0.164 0.403 100 0.189 0.688 100 Du156.12 C
0.032 0.086 100 0.045 0.131 100 Du172.17 C 0.102 0.668 100 0.185
0.748 100 Du422.1 C 4.496 19.548 93 3.763 15.661 93 ZM197M.PB7 C
0.109 0.347 100 0.144 0.539 100 ZM214M.PL15 C 0.213 0.953 100 0.257
0.853 100 ZM233M.PB6 C 0.226 0.774 100 0.355 1.246 100 ZM249M.PL1 C
0.039 0.134 100 0.071 0.239 100 ZM53M.PB12 C 0.251 0.800 100 0.287
1.003 100 ZM109F.PB4 C 0.034 0.153 100 0.055 0.199 100 ZM135M.PL10a
C 0.200 0.960 100 0.314 1.107 99 CAP45.2.00.G3 C 0.060 0.290 100
0.086 0.567 100 CAP210.2.00.E8 C 1.817 6.485 100 2.033 7.298 99
HIV-001428-2.42 C 0.006 0.020 100 0.009 0.029 100 HIV-0013095-2.11
C 0.073 0.253 100 0.105 0.374 100 HIV-16055-2.3 C 0.057 0.280 100
0.088 0.318 100 HIV-16845-2.22 C 0.950 3.935 100 1.075 5.400 100
Ce1086_B2 C (T/F) 0.089 0.568 100 0.121 0.742 99 Ce0393_C3 C (T/F)
0.195 0.802 100 0.230 1.017 100 Ce1176_A3 C (T/F) 0.204 0.589 100
0.279 1.012 100 Ce2010_F5 C (T/F) 0.130 0.547 100 0.055 0.208 100
Ce0682_E4 C (T/F) 0.041 0.131 100 0.026 0.099 100 Ce1172_H1 C (T/F)
8.499 37.520 92 17.063 >50 78 Ce2060_G9 C (T/F) 0.661 2.547 100
0.473 2.410 100 Ce703010054_2A2 C (T/F) 0.132 0.466 100 0.085 0.364
100 BF1266.431a C (T/F) 0.057 0.199 100 0.033 0.110 100 246F C1G C
(T/F) 0.094 0.255 100 0.049 0.165 100 249M B10 C (T/F) 0.081 0.377
100 0.053 0.225 100 ZM247v1(Rev-) C (T/F) 0.062 0.214 100 0.038
0.176 100 7030102001E5(Rev-) C (T/F) 0.184 0.832 100 0.110 0.498
100 1394C9G1(Rev-) C (T/F) 3.841 21.069 94 4.369 30.932 88
Ce704809221_1B3 C (T/F) 0.141 0.932 100 0.211 1.355 100 CNE19 BC
0.009 0.041 100 0.027 0.128 100 CNE20 BC 0.028 0.100 100 0.079
0.224 100 CNE21 BC 0.756 6.020 97 1.584 12.250 96 CNE17 BC 0.126
0.460 100 0.254 0.860 100 CNE30 BC 0.180 0.609 100 0.307 1.013 100
CNE52 BC 0.008 0.023 100 0.021 0.058 100 CNE53 BC 0.035 0.124 100
0.066 0.228 100 CNE58 BC 0.029 0.067 100 0.049 0.107 100 MS208A1 A
0.120 0.479 100 0.120 0.431 100 Q23.17 A 0.052 0.210 100 0.077
0.208 100 Q461.e2 A 0.261 0.922 100 0.329 1.143 100 Q769.d22 A
0.025 0.111 100 0.044 0.163 100 Q259.d2.17 A 0.332 2.474 98 0.505
4.233 97 Q842.d12 A 0.021 0.060 100 0.028 0.080 100 3415.v1.c1 A
0.160 0.550 100 0.191 0.647 100 3365.v2.c2 A 0.070 0.186 100 0.088
0.289 100 0260.v5.c36 A 0.354 0.884 100 0.497 1.515 100 191955_A11
A (T/F) 1.811 8.870 99 1.994 10.089 98 191084 B7-19 A (T/F) 0.047
0.142 100 0.069 0.200 100 9004SS_A3_4 A (T/F) 0.125 0.390 100 0.221
0.841 100 T257-31 CRF02_AG 0.158 0.619 100 0.209 1.039 100 928-28
CRF02_AG 0.167 0.579 100 0.230 0.775 100 263-8 CRF02_AG 0.056 0.201
100 0.104 0.392 100 T250-4 CRF02_AG 2.070 21.419 91 2.271 24.731 89
T251-18 CRF02_AG 0.178 0.620 100 0.229 0.794 100 T278-50 CRF02_AG
22.274 >50 75 42.378 >50 56 T255-34 CRF02_AG 0.053 0.262 100
0.094 0.447 100 211-9 CRF02_AG 0.220 0.767 100 0.340 1.165 100
235-47 CRF02_AG 0.045 0.300 99 0.078 0.419 97 620345.c01 CRF01_AE
23.174 47.935 82 >50 >50 47 CNE8 CRF01_AE 0.037 0.125 100
0.048 0.167 100 C1080.c03 CRF01_AE 0.114 0.765 100 0.144 1.046 100
R2184.c04 CRF01_AE 0.011 0.031 100 0.018 0.040 100 R1166.c01
CRF01_AE 0.092 0.313 100 0.136 0.461 100 R3265.c06 CRF01_AE 0.048
0.282 100 0.059 0.328 100 C2101.c01 CRF01_AE 0.060 0.340 100 0.076
0.425 100 C3347.c11 CRF01_AE 0.024 0.067 100 0.048 0.161 100
C4118.c09 CRF01_AE 0.043 0.147 100 0.048 0.216 100 CNE5 CRF01_AE
BJOX009000.02.4 CRF01_AE 0.113 0.506 100 0.219 0.756 100
BJOX015000.11.5 CRF01_AE 0.036 0.157 100 0.111 0.487 100 (T/F)
BJOX010000.06.2 CRF01_AE 0.085 0.592 100 0.132 0.623 100 (T/F)
BJOX025000.01.1 CRF01_AE 0.038 0.236 100 0.057 0.378 100 (T/F)
BJOX028000.10.3 CRF01_AE 0.020 0.123 100 0.031 0.290 100 (T/F)
X1193_c1 G 0.016 0.060 100 0.035 0.144 100 P0402_c2_11 G 0.014
0.061 100 0.029 0.115 100 X1254_c3 G 2.969 13.594 100 3.963 18.205
96 X2088_c9 G 0.116 0.338 100 0.199 0.726 100 X2131_C1_B5 G 0.081
0.273 100 0.129 0.431 100 P1981_C5_3 G 0.113 0.274 100 0.216 0.494
100 X1632_S2_B10 G 12.046 40.378 85 17.861 >50 65 3016.v5.c45 D
0.221 1.037 100 0.559 2.542 100 A07412M1.vrc12 D 0.108 0.645 100
0.232 1.070 100 231965.c01 D 0.054 0.193 100 0.106 0.364 100
231966.c02 D 0.102 0.430 100 0.203 0.705 100 3817.v2.c59 CD 0.716
3.726 99 1.484 8.359 97 6480.v4.c25 CD 0.031 0.113 100 0.056 0.192
100 6952.v1.c20 CD 18.386 38.898 91 26.274 >50 71 6811.v7.c18 CD
0.229 0.992 100 0.321 1.460 100 89-F1_2_25 CD 21.631 >50 80
41.582 >50 58 3301.v1.c24 AC 0.025 0.069 100 0.041 0.111 100
6041.v3.c23 AC 0.047 0.222 100 0.078 0.366 100 6540.v4.c1 AC 11.747
33.167 92 14.695 >50 75 6545.v4.c1 AC 2.001 14.657 96 1.147
15.962 92 0815.v3.c3 ACD 0.016 0.053 100 0.023 0.064 100
3103.v3.c10 ACD 0.158 0.509 100 0.229 0.772 100 MuLV Neg. Control
>50 >50 9 >50 >50 4 *(T/F): Transmitted/Founder
Virus
TABLE-US-00020 TABLE 19 Neutralization assay data ofNS49 P7.2, NS49
P11, and NS49P18.1 mAbs against extended multiclade virus panel.
mAbs tested at primary concentration of 50 ug/ml and titrated
5-fold 7x (duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 19
N49P7.2 NVS49 P11 N49P18.1 Virus ID Clade* IC50 IC80 MPI IC50 IC80
MPI IC50 IC80 MPI 6535.3 B 0.152 0.784 100 8.224 17.196 100 2.064
11.368 100 QH0692.42 B 1.263 4.424 100 0.550 2.645 100 >50
>50 43 SC422661.8 B 0.119 0.564 100 0.729 3.489 100 14.050
43.430 84 PVO.4 B 0.237 0.831 100 0.248 1.169 100 9.650 40.160 84
TRO.11 B 0.113 0.306 100 0.179 0.937 100 4.248 11.683 99 AC10.0.29
B 44.175 >50 53 5.523 19.972 100 20.021 >50 71 RHPA4259.7 B
0.100 0.289 100 0.202 0.956 100 4.340 21.426 98 THRO4156.18 B 6.293
33.287 94 1.838 10.368 100 >50 >50 19 REJO4541.67 B 0.018
0.080 100 10.785 27.072 100 4.079 30.128 89 TRJO4551.58 B 0.210
0.673 100 0.183 0.656 100 4.437 14.717 99 WITO4160.33 B 0.051 0.215
100 4.857 13.218 100 10.999 37.591 87 CAAN5342.A2 B 0.809 2.805 100
9.027 20.805 100 16.089 49.066 83 WEAU_d15_410_787 B (T/F) 0.052
0.150 100 1.703 6.019 100 4.266 15.463 98 1006_11_C3_1601 B (T/F)
0.085 0.237 100 0.125 0.487 100 2.804 9.658 99 1054_07_TC4_1499 B
(T/F) 2.036 10.723 99 2.915 13.091 100 >50 >50 0
1056_10_TA11_1826 B (T/F) 0.114 0.771 100 4.774 14.202 100 30.532
>50 62 1012_11_TC21_3257 B (T/F) 0.060 0.285 100 10.593 29.254
100 16.105 >50 79 6240_08_TA5_4622 B (T/F) 0.812 2.869 100 0.720
2.998 100 35.211 >50 60 6244_13_B5_4576 B (T/F) 0.331 1.043 100
1.119 5.446 100 33.375 >50 61 62357_14_D3_4589 B (T/F) 0.030
0.121 100 0.599 3.561 100 10.408 47.969 82 SC05_8C11_2344 B (T/F)
0.326 1.135 100 5.419 20.488 100 17.283 >50 79 Du156.12 C 0.058
0.210 100 2.396 12.008 100 1.877 6.812 100 Du172.17 C 0.290 1.078
100 5.653 17.918 100 6.516 21.335 92 Du422.1 C >50 >50 22
8.815 21.224 100 21.519 >50 75 ZM197M.PB7 C 0.223 1.371 100
0.303 1.591 100 12.493 49.791 84 ZM214M.PL15 C 0.559 4.532 100
1.347 8.976 100 >50 >50 20 ZM233M.PB6 C 0.475 2.137 99 5.922
18.544 100 38.427 >50 57 ZM249M.PL1 C 0.073 0.256 100 3.637
17.421 100 4.159 19.807 98 ZM53M.PB12 C 0.477 1.728 100 1.051 6.531
100 1.302 4.506 99 ZM109F.PB4 C 0.065 0.321 99 5.203 19.443 100
26.597 >50 69 ZM135M.PL10a C 0.596 2.801 99 3.968 16.630 100
>50 >50 46 CAP45.2.00.G3 C 0.162 2.490 95 5.253 23.977 100
5.140 33.068 88 CAP210.2.00.E8 C 3.943 21.717 95 5.119 19.418 100
>50 >50 11 HIV-001428-2.42 C 0.010 0.036 100 0.221 1.643 100
1.131 8.312 100 HIV-0013095-2.11 C 0.183 0.931 97 5.849 17.771 100
>50 >50 48 HIV-16055-2.3 C 0.204 0.721 100 0.091 0.503 100
8.035 22.606 97 HIV-16845-2.22 C 3.910 18.221 98 1.723 8.152 100
>50 >50 23 Ce1086_B2 C (T/F) 0.166 1.005 100 2.187 11.745 100
8.979 48.001 92 Ce0393_C3 C (T/F) 0.137 0.368 100 1.507 9.715 100
10.321 24.836 92 Ce1176_A3 C (T/F) 0.332 1.079 100 0.946 6.047 100
32.478 >50 61 Ce2010_F5 C (T/F) 0.398 1.294 100 0.380 3.266 100
28.999 >50 68 Ce0682_E4 C (T/F) 0.067 0.233 100 0.091 0.387 100
3.946 21.075 96 Ce1172_H1 C (T/F) >50 >50 6 3.548 19.204 100
46.416 >50 52 Ce2060_G9 C (T/F) 0.821 2.809 100 3.333 13.172 100
>50 >50 37 Ce703010054_2A2 C (T/F) 0.124 0.576 100 1.423
7.511 100 4.150 11.552 98 BF1266.431a C (T/F) 0.029 0.159 100 0.998
7.128 100 3.482 20.778 93 246F C1G C (T/F) 0.049 0.192 100 8.481
20.920 100 3.395 20.214 97 249M B10 C (T/F) 0.095 0.349 100 3.544
12.947 100 5.706 23.139 94 ZM247v1(Rev-) C (T/F) 0.177 2.497 96
7.483 21.473 100 10.869 >50 79 7030102001E5(Rev-) C (T/F) 0.313
1.034 100 0.635 2.285 100 6.353 17.738 98 1394C9G1(Rev-) C (T/F)
>50 >50 20 6.129 22.341 100 >50 >50 17 Ce704809221_1B3
C (T/F) 0.874 3.880 100 0.644 3.296 100 41.584 >50 59 CNE19 BC
0.033 0.129 100 0.437 5.503 100 2.343 9.638 99 CNE20 BC 0.119 0.574
99 5.194 22.606 100 1.329 6.364 100 CNE21 BC 48.266 >50 51 7.399
21.949 100 7.933 29.198 95 CNE17 BC 0.376 1.238 100 6.682 25.594
100 39.715 >50 56 CNE30 BC 0.362 1.197 100 0.889 4.452 100
13.131 32.152 93 CNE52 BC 0.030 0.088 100 0.060 0.307 100 2.458
6.649 100 CNE53 BC 0.100 0.277 100 0.430 2.880 100 4.083 21.770 97
CNE58 BC 0.045 0.129 100 0.038 0.135 100 1.917 5.258 100 MS208.A1 A
0.186 0.966 100 0.259 1.944 100 8.315 33.318 88 Q23.17 A 0.051
0.200 100 0.034 0.254 100 1.160 6.932 100 Q461.e2 A 0.472 2.237 100
0.363 2.150 100 24.690 >50 68 Q769.d22 A 0.029 0.140 100 0.048
0.308 100 4.916 18.335 97 Q259.d2.17 A 38.484 >50 54 8.419
21.433 100 >50 >50 37 Q842.d12 A 0.045 0.200 100 0.027 0.103
100 3.041 8.132 100 3415.v1.c1 A 0.381 1.580 100 1.862 10.264 100
>50 >50 48 3365.v2.c2 A 0.066 0.267 100 0.064 0.452 100 4.725
14.309 99 0260.v5.c36 A 0.644 1.800 100 0.438 1.469 100 16.179
47.836 81 191955_A11 A (T/F) 44.507 >50 56 2.741 15.296 100
>50 >50 33 191084 B7-19 A (T/F) 0.102 0.290 100 0.065 0.276
100 5.588 16.863 98 9004SS_A3_4 A (T/F) 0.266 1.618 100 0.296 3.242
100 3.021 13.950 99 T257-31 CRF02_AG 0.627 1.786 100 0.700 2.901
100 >50 >50 48 928-28 CRF02_AG 0.347 1.107 100 5.456 24.965
100 22.732 >50 71 263-8 CRF02_AG 0.095 0.641 100 0.064 0.259 100
3.964 41.037 90 T250-4 CRF02_AG >50 >50 15 6.278 25.585 100
4.863 15.084 94 T251-18 CRF02_AG 0.222 0.741 100 3.054 16.697 100
22.990 >50 70 T278-50 CRF02_AG >50 >50 33 7.628 25.130 100
>50 >50 36 T255-34 CRF02_AG 0.167 0.527 100 0.418 3.830 100
10.413 33.757 90 211-9 CRF02_AG 0.363 1.220 100 5.672 18.196 100
18.321 >50 73 235-47 CRF02_AG 0.127 1.034 90 3.876 21.250 100
23.013 >50 66 620345.c01 CRF01_AE >50 >50 0 11.662 27.932
100 >50 >50 0 CNE8 CRF01_AE 0.073 0.240 100 0.165 1.237 100
16.158 44.673 83 C1080.c03 CRF01_AE 0.279 1.757 100 0.162 1.452 100
>50 >50 50 R2184.c04 CRF01_AE 0.020 0.047 100 0.034 0.120 100
3.376 11.753 100 R1166.c01 CRF01_AE 0.267 0.852 100 0.060 0.336 100
19.190 >50 78 R3265.c06 CRF01_AE 0.153 0.985 100 0.161 0.971 100
27.947 >50 66 C2101.c01 CRF01_AE 0.162 0.727 100 0.084 0.505 100
15.305 41.944 85 C3347.c11 CRF01_AE 0.047 0.154 100 0.055 0.192 100
4.201 14.261 99 C4118.c09 CRF01_AE 0.079 0.292 100 0.094 0.346 100
8.627 23.239 93 CNE5 CRF01_AE 0.206 0.893 100 19.516 >50 72
BJOX009000.02.4 CRF01_AE >50 >50 43 2.841 10.644 100 0.418
1.428 100 BJOX015000.11.5 CRF01_AE 0.289 1.264 100 0.288 1.276 100
27.277 >50 67 (T/F) BJOX010000.06.2 CRF01_AE 0.267 1.111 100
6.810 21.831 100 >50 >50 39 (T/F) BJOX025000.01.1 CRF01_AE
0.102 0.831 100 0.361 2.580 100 7.667 39.071 85 (T/F)
BJOX028000.10.3 CRF01_AE 0.322 1.491 100 5.330 46.666 100 34.001
>50 64 (T/F) X1193_c1 G 0.014 0.101 100 0.179 1.086 100 3.121
23.883 94 P0402_c2_11 G 0.106 0.400 100 0.091 0.698 100 5.470
20.782 98 X1254_c3 G 27.526 >50 53 5.987 20.682 100 24.797
>50 61 X2088_c9 G 0.377 2.030 99 6.816 21.955 100 9.084 34.895
88 X2131_C1_B5 G 0.161 0.671 100 5.364 18.369 100 30.361 >50 75
P1981_C5_3 G 0.258 0.716 100 5.293 16.523 100 19.315 45.400 83
X1632_S2_B10 G >50 >50 22 9.727 26.077 100 >50 >50 19
3016.v5.c45 D 2.765 23.879 90 8.749 21.450 100 >50 >50 49
A07412M1.vrc12 D 0.768 2.319 100 2.517 12.862 100 41.253 >50 54
231965.c01 D 0.316 1.063 100 9.778 24.225 100 >50 >50 31
231966.c02 D 0.233 1.110 100 4.308 15.953 100 29.943 >50 67
3817.v2.c59 CD 9.833 >50 68 4.724 15.901 100 >50 >50 34
6480.v4.c25 CD 0.098 0.371 100 0.227 1.032 100 2.968 17.293 99
6952.v1.c20 CD >50 >50 0 6.569 22.666 100 >50 >50 30
6811.v7.c18 CD 0.541 2.550 100 3.677 14.637 100 7.427 31.872 94
89-F1_2_25 CD >50 >50 18 4.237 16.633 100 >50 >50 9
3301.v1.c24 AC 0.050 0.137 100 1.978 15.720 100 3.247 11.319 99
6041.v3.c23 AC 0.309 5.114 94 4.422 17.592 100 3.050 12.169 96
6540.v4.c1 AC >50 >50 33 3.052 16.320 100 >50 >50 35
6545.v4.c1 AC >50 >50 4 6.471 22.906 100 >50 >50 0
0815.v3.c3 ACD 0.023 0.103 100 0.106 0.372 100 0.741 8.454 99
3103.v3.c10 ACD 0.222 0.570 100 12.621 26.396 100 8.561 32.418 93
MuLV Neg. Control >50 >50 4 >50 >50 0 *(T/F):
Transmitted/Founder Virus
TABLE-US-00021 TABLE 20 Neutralization assay data of N49 P19, NVS49
P9, and NVS49 P9.1 mAbs against extended multiclade virus panel.
mAbs tested at primary concentration of 50 ug/ml and titrated
5-fold 7x (duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 20
N49P19 NVS49 P9 NVS49 P9.1 Virus ID Clade* IC50 IC80 MPI IC50 IC80
MPI IC50 IC80 MPI 6535.3 B 9.091 28.290 95 0.552 2.256 100 0.232
2.062 100 QH0692.42 B 2.560 13.420 98 0.352 1.210 100 0.107 0.709
100 SC422661.8 B 0.425 1.415 100 0.241 0.691 100 0.127 0.468 100
PVO.4 B 0.850 2.946 100 0.179 0.628 100 0.181 0.874 100 TRO.11 B
0.394 1.301 100 0.044 0.177 100 0.052 0.196 100 AC10.0.29 B >50
>50 13 0.285 0.986 100 0.360 1.877 99 RHPA4259.7 B >50 >50
42 0.023 0.078 100 0.021 0.066 100 THRO4156.18 B 17.077 >50 69
1.407 8.213 99 1.650 9.443 99 REJO4541.67 B 0.169 0.859 100 0.071
0.291 100 0.064 0.231 100 TRJO4551.58 B 1.230 5.404 99 0.036 0.128
100 0.035 0.120 100 WITO4160.33 B 0.263 1.291 100 0.058 0.165 100
0.051 0.241 100 CAAN5342.A2 B 1.241 4.402 100 2.091 7.380 100 2.160
8.001 99 WEAU_d15_410_787 B (T/F) 0.177 0.612 100 0.063 0.162 100
0.068 0.253 100 1006_11_C3_1601 B (T/F) 0.400 1.330 100 0.076 0.231
100 0.135 0.448 100 1054_07_TC4_1499 B (T/F) 2.854 11.746 99 0.885
2.445 100 1.798 7.198 100 1056_10_TA11_1826 B (T/F) 0.925 3.154 100
0.386 1.325 100 0.617 3.028 100 1012_11_TC21_3257 B (T/F) 0.204
0.895 100 0.194 0.591 100 0.382 1.448 100 6240_08_TA5_4622 B (T/F)
2.102 7.516 100 0.308 1.259 100 0.716 2.552 100 6244_13_B5_4576 B
(T/F) 0.571 1.818 100 0.132 0.366 100 0.343 1.504 100
62357_14_D3_4589 B (T/F) 37.353 >50 51 0.074 0.307 100 0.227
1.086 99 SC05_8C11_2344 B (T/F) 0.954 3.296 100 0.473 1.608 100
1.302 4.392 100 Du156.12 C 2.175 17.013 87 0.043 0.130 100 0.066
0.252 100 Du172.17 C >50 >50 30 0.023 0.178 100 0.026 0.182
100 Du422.1 C >50 >50 30 >50 >50 17 >50 >50 17
ZM197M.PB7 C 38.389 >50 56 0.083 0.339 100 0.049 0.283 100
ZM214M.PL15 C 1.850 14.820 98 0.477 1.989 100 0.561 2.963 100
ZM233M.PB6 C >50 >50 4 >50 >50 48 >50 >50 6
ZM249M.PL1 C >50 >50 33 0.152 0.801 97 0.206 1.916 95
ZM53M.PB12 C 1.187 4.143 100 0.362 1.137 100 0.447 1.287 100
ZM109F.PB4 C 0.282 2.660 92 0.075 0.349 99 0.116 0.497 95
ZM135M.PL10a C >50 >50 0 0.224 0.863 97 0.332 1.529 98
CAP45.2.00.G3 C >50 >50 5 0.294 1.986 98 1.722 19.580 88
CAP210.2.00.E8 C >50 >50 0 >50 >50 32 >50 >50 2
HIV-001428-2.42 C >50 >50 44 0.022 0.106 99 0.037 0.120 99
HIV-0013095-2.11 C >50 >50 18 0.179 0.635 100 0.358 1.262 100
HIV-16055-2.3 C >50 >50 30 0.077 0.274 100 0.102 0.362 100
HIV-16845-2.22 C 14.499 >50 73 1.090 9.957 98 2.131 10.747 98
Ce1086_B2 C (T/F) 0.613 2.680 97 0.341 1.687 97 0.814 4.077 96
Ce0393_C3 C (T/F) >50 >50 31 0.189 0.595 100 0.284 1.221 100
Ce1176_A3 C (T/F) 1.567 9.839 99 0.258 0.919 100 0.440 0.998 100
Ce2010_F5 C (T/F) 7.660 45.381 82 0.089 0.271 100 0.120 0.380 100
Ce0682_E4 C (T/F) 0.607 2.323 98 0.049 0.185 100 0.076 0.264 100
Ce1172_H1 C (T/F) >50 >50 3 8.796 >50 70 >50 >50 42
Ce2060_G9 C (T/F) 1.056 5.615 98 0.419 2.190 100 0.781 3.540 100
Ce703010054_2A2 C (T/F) >50 >50 0 0.187 0.898 98 0.433 3.177
96 BF1266.431a C (T/F) >50 >50 15 0.154 0.519 99 0.808 3.142
95 246F C1G C (T/F) >50 >50 19 >50 >50 48 >50 >50
11 249M B10 C (T/F) >50 >50 39 0.203 1.411 97 0.305 1.644 96
ZM247v1(Rev-) C (T/F) >50 >50 5 0.622 3.301 100 1.878 17.837
87 7030102001E5(Rev-) C (T/F) 0.950 4.701 100 0.453 2.028 100 0.635
2.016 100 1394C9G1(Rev-) C (T/F) >50 >50 17 >50 >50 40
>50 >50 6 Ce704809221_1B3 C (T/F) 3.746 19.191 93 0.133 0.605
100 0.162 0.661 100 CNE19 BC 20.710 >50 59 0.031 0.136 100 0.033
0.146 100 CNE20 BC 0.124 0.817 99 0.465 2.432 97 1.514 16.392 90
CNE21 BC >50 >50 21 >50 >50 36 >50 >50 15 CNE17
BC >50 >50 30 0.364 1.699 100 0.251 1.231 100 CNE30 BC 1.269
4.275 100 0.259 0.693 100 0.271 0.971 100 CNE52 BC 0.175 0.491 100
0.026 0.090 100 0.043 0.122 100 CNE53 BC 1.501 >50 78 0.123
0.462 99 0.140 0.647 99 CNE58 BC >50 >50 43 0.030 0.081 100
0.027 0.074 100 MS208.A1 A 0.501 1.987 99 0.080 0.294 100 0.082
0.248 100 Q23.17 A 0.234 1.368 100 0.032 0.091 100 0.029 0.106 100
Q461.e2 A 0.774 4.053 100 0.271 0.953 100 0.363 1.146 100 Q769.d22
A 0.140 0.519 100 0.036 0.123 100 0.039 0.148 100 Q259.d2.17 A
>50 >50 11 0.807 >50 74 >50 >50 48 Q842.d12 A 0.182
0.601 100 0.019 0.057 100 0.027 0.075 100 3415.v1.c1 A 0.462 2.038
100 0.137 0.502 100 0.210 1.372 100 3365.v2.c2 A 0.579 2.091 99
0.059 0.198 100 0.055 0.725 100 0260.v5.c36 A 1.250 8.524 99 0.466
1.852 100 0.519 0.151 100 191955_A11 A (T/F) >50 >50 16
>50 >50 35 >50 >50 26 191084 B7-19 A (T/F) 0.357 1.340
100 0.042 0.129 100 0.097 0.259 100 9004SS_A3_4 A (T/F) 0.661 3.086
100 0.175 0.751 100 0.323 1.129 100 T257-31 CRF02_AG 0.661 2.995
100 0.216 0.821 100 0.508 1.819 100 928-28 CRF02_AG 2.726 9.630 97
0.094 0.339 100 0.163 0.695 100 263-8 CRF02_AG 0.344 1.510 99 0.032
0.161 100 0.049 0.170 100 T250-4 CRF02_AG >50 >50 7 >50
>50 25 >50 >50 7 T251-18 CRF02_AG 0.938 4.204 100 0.147
0.517 100 0.127 0.352 100 T278-50 CRF02_AG >50 >50 35 >50
>50 25 >50 >50 5 T255-34 CRF02_AG 0.948 6.223 97 0.051
0.247 100 0.092 0.286 100 211-9 CRF02_AG 3.230 18.983 93 0.136
0.485 100 0.170 0.579 100 235-47 CRF02_AG 0.440 3.227 89 0.072
0.271 98 0.045 0.352 98 620345.c01 CRF01_AE >50 >50 0 >50
>50 9 >50 >50 7 CNE8 CRF01_AE 0.772 4.840 97 0.056 0.260
100 0.228 0.921 100 C1080.c03 CRF01_AE 0.682 3.053 100 0.119 0.575
100 0.156 0.939 100 R2184.c04 CRF01_AE 0.132 0.445 100 0.015 0.034
100 0.019 0.057 100 R1166.c01 CRF01_AE 0.629 2.693 100 0.064 0.223
100 0.073 0.232 100 R3265.c06 CRF01_AE 0.634 2.735 100 0.135 0.812
100 0.469 1.621 100 C2101.c01 CRF01_AE 0.978 4.192 100 0.051 0.209
100 0.085 0.227 100 C3347.c11 CRF01_AE 3.943 25.715 87 0.023 0.065
100 0.029 0.083 100 C4118.c09 CRF01_AE 0.386 1.361 100 0.072 0.200
100 0.062 0.218 100 CNE5 CRF01_AE 0.748 3.290 100 0.183 0.641 100
BJOX009000.02.4 CRF01_AE 3.664 25.579 87 0.727 3.293 100 0.965
3.934 100 BJOX015000.11.5 CRF01_AE 0.756 3.165 99 0.089 0.375 100
0.068 0.478 100 (T/F) BJOX010000.06.2 CRF01_AE 4.159 19.069 96
0.482 2.337 100 0.883 4.259 100 (T/F) BJOX025000.01.1 CRF01_AE
>50 >50 24 0.055 0.252 100 0.131 0.670 100 (T/F)
BJOX028000.10.3 CRF01_AE 6.996 >50 80 0.031 0.134 100 0.040
0.200 100 (T/F) X1193_c1 G 0.540 3.147 99 0.025 0.081 100 0.042
0.150 100 P0402_c2_11 G 0.448 2.630 100 0.028 0.085 100 0.060 0.163
100 X1254_c3 G >50 >50 48 0.040 0.104 100 0.101 0.278 100
X2088_c9 G 1.402 3.760 99 0.070 0.252 100 0.091 0.392 100
X2131_C1_B5 G 2.522 14.446 91 0.082 0.274 100 0.143 0.476 100
P1981_C5_3 G 20.237 >50 68 0.308 0.701 100 0.469 1.523 100
X1632_S2_B10 G >50 >50 14 46.721 >50 51 >50 >50 10
3016.v5.c45 D >50 >50 9 0.060 0.209 100 0.076 0.223 100
A07412M1.vrc12 D 3.892 48.832 80 0.142 0.636 100 0.189 0.947 100
231965.c01 D >50 >50 22 0.253 1.159 100 0.474 2.239 100
231966.c02 D 0.653 4.553 100 0.074 0.244 100 0.067 0.237 100
3817.v2.c59 CD >50 >50 26 1.092 5.859 100 1.347 8.262 95
6480.v4.c25 CD 3.035 28.156 87 0.017 0.047 100 0.030 0.082 100
6952.v1.c20 CD >50 >50 0 0.095 0.258 100 0.119 0.389 100
6811.v7.c18 CD 1.305 4.709 97 0.249 1.195 99 0.398 1.757 97
89-F1_2_25 CD >50 >50 7 >50 >50 23 >50 >50 23
3301.v1.c24 AC 0.302 1.423 98 0.072 0.246 100 0.059 0.178 100
6041.v3.c23 AC >50 >50 32 0.089 0.777 95 0.282 6.781 90
6540.v4.c1 AC 11.229 >50 63 >50 >50 49 >50 >50 30
6545.v4.c1 AC >50 >50 2 >50 >50 20 >50 >50 6
0815.v3.c3 ACD 0.176 0.743 100 0.020 0.057 100 0.012 0.041 100
3103.v3.c10 ACD >50 >50 0 17.571 >50 55 >50 >50 45
MuLV Neg. Control >50 >50 0 >50 >50 13 21.396 22.133
*(T/F): Transmitted/Founder Virus
TABLE-US-00022 TABLE 21 Neutralization assay data of N49 P23,
N40P22, and PGT121 mAbs against extended multiclade virus panel.
mAbs tested at primary concentration of 50 ug/ml and titrated
5-fold 7x (duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 21
N49P23 N49P22 PGT121 Virus ID Clade* IC50 IC80 MPI IC50 IC80 MPI
IC50 IC80 6535.3 B 0.127 0.855 100 >50 >50 5 0.002 0.008
QH0692.42 B 0.557 2.513 100 0.592 2.024 100 0.302 2.314 SC422661.8
B 0.069 0.245 100 0.120 0.544 100 0.038 0.177 PVO.4 B 0.087 0.430
100 0.433 1.492 100 0.098 0.343 TRO.11 B 0.094 0.336 100 0.283
1.365 99 0.005 0.025 AC10.0.29 B >50 >50 0 >50 >50 0
0.024 0.073 RHPA4259.7 B 0.010 0.040 100 0.637 5.596 92 0.015 0.035
THRO4156.18 B 1.979 10.746 97 >50 >50 32 >50 >50
REJO4541.67 B 0.008 0.050 100 0.792 12.089 84 4.774 >50
TRJO4551.58 B 0.016 0.068 100 >50 >50 28 1.314 37.88
WITO4160.33 B 0.045 0.205 100 4.862 >50 74 0.334 2.351
CAAN5342.A2 B 0.412 1.381 100 0.425 1.884 99 0.007 0.023
WEAU_d15_410_787 B (T/F) 0.009 0.031 100 1.541 >50 76 0.026
0.077 1006_11_C3_1601 B (T/F) 0.015 0.054 100 0.898 14.693 83 0.002
0.007 1054_07_TC4_1499 B (T/F) 0.272 1.211 100 0.654 2.893 100
0.064 0.304 1056_10_TA11_1826 B (T/F) 0.075 0.483 100 2.991 >50
69 0.004 0.081 1012_11_TC21_3257 B (T/F) 0.013 0.085 100 15.726
>50 53 0.003 0.017 6240_08_TA5_4622 B (T/F) 0.215 1.000 100
2.330 9.760 93 0.033 0.127 6244_13_B5_4576 B (T/F) 0.151 0.570 100
0.565 2.482 97 0.061 0.347 62357_14_D3_4589 B (T/F) 0.057 0.760 95
>50 >50 13 2.597 >50 SC05_8C11_2344 B (T/F) 0.133 0.548
100 0.251 2.159 97 0.019 0.071 Du156.12 C >50 >50 0 >50
>50 4 0.004 0.017 Du172.17 C >50 >50 45 >50 >50 4
0.033 0.257 Du422.1 C >50 >50 4 >50 >50 4 0.039 0.143
ZM197M.PB7 C 0.100 0.385 100 2.583 25.090 84 >50 >50
ZM214M.PL15 C 0.061 0.614 100 >50 >50 25 0.460 2.039
ZM233M.PB6 C >50 >50 14 >50 >50 2 3.689 #####
ZM249M.PL1 C >50 >50 2 >50 >50 0 >50 >50
ZM53M.PB12 C 0.135 0.651 100 1.197 11.765 91 <0.001 0.004
ZM109F.PB4 C 0.039 0.180 100 >50 >50 1 8.639 >50
ZM135M.PL10a C >50 >50 36 >50 >50 27 0.716 5.246
CAP45.2.00.G3 C >50 >50 0 >50 >50 0 1.634 >50
CAP210.2.00.E8 C >50 >50 2 >50 >50 6 26.301 >50
HIV-001428-2.42 C 0.036 0.241 98 0.730 7.097 91 0.014 0.051
HIV-0013095-2.11 C 0.114 0.899 96 >50 >50 9 >50 >50
HIV-16055-2.3 C >50 >50 17 4.655 39.690 83 0.153 4.804
HIV-16845-2.22 C >50 >50 20 4.600 41.933 87 3.969 44.570
Ce1086_B2 C (T/F) 0.063 0.303 100 >50 >50 0 <0.001
<0.001 Ce0393_C3 C (T/F) >50 >50 29 >50 >50 12
>50 >50 Ce1176_A3 C (T/F) 0.297 1.384 100 >50 >50 23
0.013 0.035 Ce2010_F5 C (T/F) 1.590 11.612 91 2.053 11.680 93
>50 >50 Ce0682_E4 C (T/F) 1.391 >50 76 1.132 >50 75
>50 >50 Ce1172_H1 C (T/F) >50 >50 0 >50 >50 0
0.011 0.036 Ce2060_G9 C (T/F) 0.180 0.849 99 >50 >50 19
>50 >50 Ce703010054_2A2 C (T/F) >50 >50 35 >50
>50 0 >50 >50 BF1266.431a C (T/F) 0.083 0.440 99 >50
>50 0 >50 >50 246F C1G C (T/F) >50 >50 11 >50
>50 10 0.041 0.140 249M B10 C (T/F) >50 >50 20 >50
>50 4 >50 >50 ZM247v1(Rev-) C (T/F) >50 >50 24
>50 >50 11 0.028 0.082 7030102001E5(Rev-) C (T/F) 0.172 0.797
100 >50 >50 21 0.009 0.027 1394C9G1(Rev-) C (T/F) >50
>50 34 >50 >50 35 0.264 1.948 Ce704809221_1B3 C (T/F)
0.083 0.643 100 15.799 >50 60 0.025 0.126 CNE19 BC >50 >50
40 0.873 8.185 92 0.008 0.105 CNE20 BC 45.443 >50 51 >50
>50 18 <0.001 0.002 CNE21 BC >50 >50 0 >50 >50 0
0.007 0.035 CNE17 BC 0.221 0.809 100 46.299 >50 53 7.600 >50
CNE30 BC 0.143 0.680 100 >50 >50 30 0.078 0.291 CNE52 BC
0.014 0.051 100 1.701 10.016 91 2.045 18.929 CNE53 BC 0.026 0.095
100 0.779 5.111 93 0.007 0.024 CNE58 BC >50 >50 9 28.372
>50 57 >50 >50 MS208.A1 A 0.048 0.279 100 >50 >50 17
>50 >50 Q23.17 A 0.010 0.046 100 0.321 2.400 96 <0.001
0.005 Q461.e2 A 0.099 0.464 100 11.157 >50 66 >50 >50
Q769.d22 A 0.005 0.025 100 0.043 0.259 100 >50 >50 Q259.d2.17
A 0.362 7.795 91 >50 >50 15 15.379 >50 Q842.d12 A 0.007
0.022 100 0.079 0.359 100 0.005 0.022 3415.v1.c1 A 0.054 0.190 100
0.198 1.410 96 NT NT 3365.v2.c2 A 0.017 0.053 100 0.254 0.857 98 NT
NT 0260.v5.c36 A 0.261 0.919 100 1.673 14.382 93 0.053 0.197
191955_A11 A (T/F) >50 >50 31 >50 >50 9 >50 >50
191084 B7-19 A (T/F) 0.013 0.043 100 0.343 1.639 98 0.011 0.032
9004SS_A3_4 A (T/F) 0.043 0.223 100 >50 >50 42 <0.001
0.003 T257-31 CRF02_AG 0.178 1.167 100 >50 >50 43 >50
>50 928-28 CRF02_AG 0.021 0.122 100 >50 >50 32 44.189
>50 263-8 CRF02_AG 0.012 0.096 100 1.829 18.462 89 0.648 3.961
T250-4 CRF02_AG >50 >50 0 >50 >50 5 <0.001 0.005
T251-18 CRF02_AG >50 >50 18 0.580 3.092 99 29.016 >50
T278-50 CRF02_AG >50 >50 22 >50 >50 25 >50 >50
T255-34 CRF02_AG >50 >50 20 38.766 >50 55 18.695 >50
211-9 CRF02_AG >50 >50 14 >50 >50 18 0.852 4.202 235-47
CRF02_AG 0.085 0.749 90 0.037 0.373 99 0.137 0.727 620345.c01
CRF01_AE >50 >50 0 >50 >50 0 >50 >50 CNE8
CRF01_AE 6.353 47.322 81 5.350 40.442 86 >50 >50 C1080.c03
CRF01_AE 1.328 11.328 96 15.863 >50 64 >50 >50 R2184.c04
CRF01_AE 0.008 0.032 100 0.077 0.342 100 >50 >50 R1166.c01
CRF01_AE 0.123 0.455 100 0.232 0.799 100 >50 >50 R3265.c06
CRF01_AE >50 >50 0 3.575 >50 67 >50 >50 C2101.c01
CRF01_AE 0.056 0.362 100 0.171 1.059 99 NT NT C3347.c11 CRF01_AE
0.007 0.032 100 1.181 12.263 89 >50 >50 C4118.c09 CRF01_AE
0.026 0.120 100 1.821 26.577 93 >50 >50 CNE5 CRF01_AE 0.058
0.226 100 0.281 1.553 96 >50 >50 BJOX009000.02.4 CRF01_AE
>50 >50 8 17.324 >50 64 2.858 31.728 BJOX015000.11.5
CRF01_AE >50 >50 0 1.258 10.790 89 >50 >50 (T/F)
BJOX010000.06.2 CRF01_AE 0.284 2.078 100 >50 >50 0 >50
>50 (T/F) BJOX025000.01.1 CRF01_AE >50 >50 0 >50 >50
0 >50 >50 (T/F) BJOX028000.10.3 CRF01_AE 0.021 0.123 98
>50 >50 0 >50 >50 (T/F) X1193_c1 G 0.008 0.038 100
3.492 28.543 85 0.016 0.086 P0402_c2_11 G 0.022 0.065 100 5.928
>50 73 0.005 0.016 X1254_c3 G 0.022 0.111 100 3.055 29.794 84
0.014 0.080 X2088_c9 G >50 >50 10 >50 >50 8 0.003 0.013
X2131_C1_B5 G 0.080 0.280 100 >50 >50 44 0.004 0.023
P1981_C5_3 G 0.096 0.264 100 >50 >50 48 <0.001 <0.001
X1632_S2_B10 G 0.130 >50 62 >50 >50 0 >50 >50
3016.v5.c45 D 0.027 0.092 100 >50 >50 23 >50 >50
A07412M1.vrc12 D 0.114 0.830 97 9.600 >50 63 0.009 0.075
231965.c01 D >50 >50 35 2.044 35.200 83 >50 >50
231966.c02 D 0.035 0.158 100 3.351 >50 69 >50 >50
3817.v2.c59 CD >50 >50 41 >50 >50 12 18.888 >50
6480.v4.c25 CD >50 >50 29 0.809 32.124 86 <0.001 0.004
6952.v1.c20 CD 0.007 0.023 100 33.248 >50 56 0.056 0.420
6811.v7.c18 CD 17.656 >50 61 1.003 9.719 92 <0.001 0.001
89-F1_2_25 CD >50 >50 5 >50 >50 10 >50 >50
3301.v1.c24 AC 0.017 0.058 100 2.819 48.778 80 0.008 0.019
6041.v3.c23 AC 7.466 >50 63 7.547 >50 66 >50 >50
6540.v4.c1 AC >50 >50 29 >50 >50 29 >50 >50
6545.v4.c1 AC >50 >50 10 >50 >50 17 >50 >50
0815.v3.c3 ACD 0.004 0.014 100 0.161 1.080 98 0.025 0.111
3103.v3.c10 ACD 43.751 >50 54 >50 >50 16 0.009 0.028 MuLV
Neg. Control >50 >50 9 >50 >50 8 *(T/F):
Transmitted/Founder Virus
TABLE-US-00023 TABLE 22 Neutralization assay data of PGT128,
PGT145, PGDM1400, and PGT151 mAbs against extended multiclade virus
panel. mAbs tested at primary concentration of 50 ug/ml and
titrated 5-fold 7x (duplicate wells). Titer in TZM.bl cells (ug/ml)
TABLE 22 PGT128 PGT145 PGDM1400 PGT151 Virus ID Clade* IC50 IC80
IC50 IC80 IC50 IC80 IC50 IC80 6535.3 B 0.004 0.016 >50 >50
>50 >50 <0.001 0.012 QH0692.42 B 0.029 0.081 >50 >50
>50 >50 0.029 0.522 SC422661.8 B 1.078 18.4 0.024 0.082 0.436
6.530 0.005 0.028 PVO.4 B 0.011 0.028 0.192 0.870 0.484 6.487 0.017
>50 TRO.11 B 0.019 0.045 0.040 0.118 0.283 1.376 >50 >50
AC10.0.29 B 0.008 0.018 0.010 0.025 0.105 0.869 0.007 0.023
RHPA4259.7 B 0.026 0.109 0.029 0.095 0.447 2.194 0.006 0.033
THRO4156.18 B >50 >50 0.010 0.029 0.072 0.348 >50 >50
REJO4541.67 B >50 >50 <0.001 0.001 0.028 0.992 0.018 0.119
TRJO4551.58 B 0.018 0.041 >50 >50 >50 >50 0.496 4.217
WITO4160.33 B >50 >50 <0.001 0.001 <0.001 0.008 0.002
0.021 CAAN5342.A2 B 0.514 >50 6.675 25.524 >50 >50 0.005
0.038 WEAU_d15_410_787 B (T/F) 0.032 0.153 1.951 31.540 0.103 1.366
0.010 >50 1006_11_C3_1601 B (T/F) 0.011 0.040 >50 >50
4.318 >50 2.891 >50 1054_07_TC4_1499 B (T/F) 0.035 0.312
>50 >50 >50 >50 0.008 0.032 1056_10_TA11_1826 B (T/F)
<0.001 0.008 0.230 0.938 3.258 11.840 0.008 0.048
1012_11_TC21_3257 B (T/F) 0.011 0.033 0.009 0.025 0.049 0.230
>50 >50 6240_08_TA5_4622 B (T/F) 0.019 0.055 >50 >50
>50 >50 0.046 0.420 6244_13_B5_4576 B (T/F) 0.020 0.076 7.266
44.473 >50 >50 >50 >50 62357_14_D3_4589 B (T/F) 1.144
>50 >50 >50 >50 >50 0.004 0.023 SC05_8C11_2344 B
(T/F) 0.017 0.041 0.093 0.248 1.264 3.587 0.060 >50 Du156.12 C
0.017 0.046 0.001 0.018 0.002 0.008 0.005 0.023 Du172.17 C 0.028
0.080 >50 >50 5.179 21.980 0.003 0.013 Du422.1 C 0.039 0.113
22.564 >50 0.694 >50 4.604 >50 ZM197M.PB7 C >50 >50
0.628 5.239 0.063 0.285 0.003 0.033 ZM214M.PL15 C 1.498 29.44
>50 >50 >50 >50 0.008 0.045 ZM233M.PB6 C >50 >50
0.025 0.680 <0.001 0.001 0.027 5.156 ZM249M.PL1 C 39.66 >50
1.442 >50 0.016 0.701 0.004 0.015 ZM53M.PB12 C >50 >50
0.367 11.774 0.002 0.011 >50 >50 ZM109F.PB4 C >50 >50
0.042 0.234 0.057 0.382 0.609 >50 ZM135M.PL10a C >50 >50
>50 >50 >50 >50 >50 >50 CAP45.2.00.G3 C >50
>50 0.001 0.007 <0.001 0.002 0.007 >50 CAP210.2.00.E8 C
>50 >50 37.807 >50 0.034 0.514 0.010 0.208 HIV-001428-2.42
C 0.026 0.095 0.001 0.083 <0.001 0.027 0.027 >50
HIV-0013095-2.11 C >50 >50 9.271 >50 0.003 0.012 >50
>50 HIV-16055-2.3 C >50 >50 0.003 0.051 <0.001 0.003
0.143 >50 HIV-16845-2.22 C 0.181 0.834 >50 >50 >50
>50 >50 >50 >50 >50 Ce1086_B2 C (T/F) >50 >50
>50 >50 >50 >50 2.653 >50 Ce0393_C3 C (T/F) >50
>50 0.112 1.225 0.015 0.044 >50 >50 Ce1176_A3 C (T/F)
0.009 0.026 >50 >50 0.587 11.619 0.006 0.018 Ce2010_F5 C
(T/F) >50 >50 >50 >50 >50 >50 >50 >50
Ce0682_E4 C (T/F) >50 >50 33.578 >50 0.010 0.043 >50
>50 Ce1172_H1 C (T/F) 0.013 0.038 0.260 2.062 0.021 0.060 >50
>50 Ce2060_G9 C (T/F) >50 >50 0.016 0.205 0.001 0.007
0.135 >50 Ce703010054_2A2 C (T/F) >50 >50 >50 >50
0.015 0.260 0.013 0.075 BF1266.431a C (T/F) >50 >50 1.345
18.508 0.003 0.011 >50 >50 246F C1G C (T/F) 0.005 0.014
>50 >50 >50 >50 >50 >50 249M B10 C (T/F) 7.868
>50 0.947 41.307 0.039 0.786 0.007 0.023 ZM247v1(Rev-) C (T/F)
0.021 0.081 7.190 >50 0.019 0.051 0.009 >50
7030102001E5(Rev-) C (T/F) 0.007 0.022 >50 >50 >50 >50
0.001 0.011 1394C9G1(Rev-) C (T/F) 0.011 0.034 0.001 0.005
<0.001 0.004 0.022 0.733 Ce704809221_1B3 C (T/F) 0.026 0.072
0.102 0.710 0.280 1.099 >50 >50 CNE19 BC >50 >50 0.103
1.128 0.001 0.007 0.014 >50 CNE20 BC 0.001 0.004 0.318 6.970
0.004 0.014 >50 >50 CNE21 BC 0.010 0.026 <0.001 0.009
<0.001 0.002 0.004 0.012 CNE17 BC 0.432 1.993 0.091 1.156 0.007
0.021 0.093 >50 CNE30 BC 2.055 12.610 >50 >50 >50
>50 >50 >50 CNE52 BC >50 >50 0.020 0.091 1.147 9.970
0.004 0.017 CNE53 BC 0.010 0.049 0.006 0.084 0.077 0.246 >50
>50 CNE58 BC 13.77 >50 0.183 7.407 0.004 0.014 0.004 0.016
MS208.A1 A >50 >50 0.334 17.97 <0.001 0.139 <0.001
0.003 Q23.17 A 0.009 0.024 1.317 >50 <0.001 0.003 0.007 0.045
Q461.e2 A >50 >50 7.801 >50 0.089 0.572 12.553 >50
Q769.d22 A >50 >50 0.260 25.47 0.002 0.018 >50 >50
Q259.d2.17 A >50 >50 44.232 >50 0.166 >50 >50 >50
Q842.d12 A 0.008 0.102 0.032 0.552 <0.001 0.002 0.001 0.014
3415.v1.c1 A NT NT NT NT NT NT NT NT 3365.v2.c2 A NT NT NT NT NT NT
NT NT 0260.v5.c36 A 0.058 0.162 >50 >50 0.033 0.175 0.427
>50 191955_A11 A (T/F) 14.2 >50 <0.001 <0.001 0.001
0.021 0.004 0.014 191084 B7-19 A (T/F) 0.022 0.152 0.028 0.345
<0.001 0.007 0.004 0.016 9004SS_A3_4 A (T/F) 0.002 0.010 0.018
0.419 <0.001 0.002 0.003 0.015 T257-31 CRF02_AG >50 >50
5.177 >50 0.002 0.031 0.003 0.010 928-28 CRF02_AG >50 >50
>50 >50 0.220 1.246 >50 >50 263-8 CRF02_AG 0.342 3.303
32.071 >50 0.020 0.103 >50 >50 T250-4 CRF02_AG <0.001
0.007 0.002 0.039 <0.001 <0.001 0.005 0.014 T251-18 CRF02_AG
>50 >50 0.351 1.393 8.615 43.108 0.327 >50 T278-50
CRF02_AG 0.031 0.089 10.324 >50 0.574 4.942 0.130 >50 T255-34
CRF02_AG >50 >50 >50 >50 0.654 >50 0.002 0.010 211-9
CRF02_AG 0.062 0.215 0.129 0.923 0.088 0.393 0.002 0.010 235-47
CRF02_AG >50 >50 3.212 36.02 0.005 0.032 38.12 >50
620345.c01 CRF01_AE >50 >50 0.241 19.74 0.009 40.337 >50
>50 CNE8 CRF01_AE 0.019 0.052 0.272 2.241 <0.001 0.010 >50
>50 C1080.c03 CRF01_AE 0.283 2.062 0.024 0.146 <0.001
<0.001 >50 >50 R2184.c04 CRF01_AE 20.056 >50 0.073
0.376 0.003 0.012 >50 >50 R1166.c01 CRF01_AE >50 >50
2.274 17.89 1.431 6.921 >50 >50 R3265.c06 CRF01_AE >50
>50 0.037 0.227 0.013 0.041 >50 >50 C2101.c01 CRF01_AE NT
NT NT NT 0.006 0.021 NT NT C3347.c11 CRF01_AE 0.001 0.007 0.005
0.044 0.011 0.051 >50 >50 C4118.c09 CRF01_AE >50 >50
<0.001 0.004 0.002 0.005 >50 >50 CNE5 CRF01_AE 0.018 0.253
0.001 0.013 <0.001 <0.001 >50 >50 BJOX009000.02.4
CRF01_AE <0.001 0.005 0.117 0.745 0.443 1.287 >50 >50
BJOX015000.11.5 CRF01_AE 0.001 0.011 >50 >50 0.520 10.577
>50 >50 (T/F) BJOX010000.06.2 CRF01_AE 4.817 >50 >50
>50 0.605 5.870 >50 >50 (T/F) BJOX025000.01.1 CRF01_AE
>50 >50 6.632 >50 0.087 0.573 >50 >50 (T/F)
BJOX028000.10.3 CRF01_AE 0.024 0.070 >50 >50 0.072 0.963
>50 >50 (T/F) X1193_c1 G >50 >50 0.013 0.091 0.219
0.781 0.004 0.027 P0402_c2_11 G 0.007 0.020 0.009 0.038 0.010 0.033
<0.001 0.004 X1254_c3 G >50 >50 5.597 >50 >50 >50
0.309 >50 X2088_c9 G >50 >50 >50 >50 >50 >50
>50 >50 X2131_C1_B5 G >50 >50 0.018 0.065 0.128 0.568
0.007 0.036 P1981_C5_3 G 0.019 0.088 5.413 >50 0.104 4.601 0.021
>50 X1632_S2_B10 G >50 >50 0.012 2.030 0.055 1.445 0.061
>50 3016.v5.c45 D >50 >50 >50 >50 >50 >50
0.174 40.676 A07412M1.vrc12 D >50 >50 0.002 0.023 0.032 0.127
0.246 >50 231965.c01 D >50 >50 0.403 14.96 0.025 1.280
<0.001 0.012 231966.c02 D 3.197 >50 <0.001 0.010 0.001
0.004 0.025 0.183 3817.v2.c59 CD 0.003 0.023 >50 >50 >50
>50 >50 >50 6480.v4.c25 CD 0.003 0.019 >50 >50
>50 >50 NT NT 6952.v1.c20 CD >50 >50 3.120 >50 0.501
11.839 49.232 >50 6811.v7.c18 CD 0.003 0.050 >50 >50
>50 >50 >50 >50 89-F1_2_25 CD >50 >50 0.800 19.97
0.001 0.005 22.889 >50 3301.v1.c24 AC 0.067 0.499 0.219 4.223
0.048 0.245 0.002 0.019 6041.v3.c23 AC >50 >50 0.964 >50
0.013 0.289 0.004 0.024 6540.v4.c1 AC 11.8 >50 0.080 5.086 0.004
0.028 0.006 0.030 6545.v4.c1 AC >50 >50 0.114 3.100 0.003
0.039 0.004 0.026 0815.v3.c3 ACD 0.030 0.137 >50 >50 >50
>50 >50 >50 3103.v3.c10 ACD 0.014 0.033 0.043 0.164 0.671
1.998 0.014 0.202 MuLV Neg. Control *(T/F): Transmitted/Founder
Virus
TABLE-US-00024 TABLE 23 Neutralization assay data of 10-1074, 10E8,
PG9, and PG16 mAbs against extended multiclade virus panel. mAbs
tested at primary concentration of 50 ug/ml and titrated 5-fold 7x
(duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 23 10-1074
10E8 PG9 PG16 Virus ID Clade* IC50 IC80 IC50 IC80 IC50 IC80 IC50
IC80 6535.3 B 0.014 0.026 0.081 1.32 0.176 0.627 0.653 >50
QH0692.42 B 0.191 0.929 0.442 4.046 >50 >50 >50 >50
SC422661.8 B 0.091 0.418 0.445 2.715 0.553 7.054 0.858 >50 PVO.4
B 0.074 0.360 0.747 >10 10.56 >50 15.27 >50 TRO.11 B 0.008
0.057 0.034 0.250 43.25 >50 1.922 49.59 AC10.0.29 B 0.022 0.110
0.132 1.534 0.117 0.845 0.023 0.417 RHPA4259.7 B 0.021 0.118 0.728
5.275 22.620 >50 0.375 3.925 THRO4156.18 B >50 >50 0.156
0.884 24.48 >50 6.825 >50 REJO4541.67 B >50 >50 0.203
1.686 0.012 0.163 0.039 13.36 TRJO4551.58 B 0.17 0.634 0.475 4.783
0.503 4.061 1.008 24.46 WITO4160.33 B 0.185 2.112 0.094 1.226 0.010
0.037 0.002 0.012 CAAN5342.A2 B 0.007 0.036 1.284 9.281 4.603 26.99
1.831 33.0 WEAU_d15_410_787 B (T/F) 0.104 0.375 >10 >10 4.078
>50 0.435 >50 1006_11_C3_1601 B (T/F) 0.003 0.013 0.172 2.999
0.366 1.906 >50 >50 1054_07_TC4_1499 B (T/F) 0.129 0.563
0.046 0.305 >50 >50 >50 >50 1056_10_TA11_1826 B (T/F)
0.038 0.272 0.134 1.028 6.339 38.26 0.315 1.952 1012_11_TC21_3257 B
(T/F) 0.008 0.059 0.244 4.211 0.172 0.605 0.030 0.219
6240_08_TA5_4622 B (T/F) 0.068 0.306 0.756 5.591 1.747 6.333 >50
>50 6244_13_B5_4576 B (T/F) 0.202 0.922 0.086 0.809 >50
>50 >50 >50 62357_14_D3_4589 B (T/F) >50 >50 0.119
1.060 >50 >50 >50 >50 SC05_8C11_2344 B (T/F) 0.052
0.123 0.665 2.736 0.892 4.283 0.070 1.616 Du156.12 C 0.015 0.076
0.034 0.144 0.026 0.190 0.006 0.026 Du172.17 C 0.121 0.430 0.109
0.837 0.606 1.604 0.033 0.213 Du422.1 C 0.045 0.166 0.351 1.883
0.614 10.4 0.261 33.84 ZM197M.PB7 C >50 >50 0.148 0.802 0.899
4.517 1.496 22.79 ZM214M.PL15 C 0.174 2.367 1.962 >10 >50
>50 >50 >50 ZM233M.PB6 C 0.06 0.349 0.442 2.393 0.010
0.026 0.002 0.006 ZM249M.PL1 C >50 >50 1.511 6.294 0.166
1.410 0.127 18.07 ZM53M.PB12 C >50 >50 3.985 >10 0.069
0.221 0.007 0.051 ZM109F.PB4 C >50 >50 0.295 1.888 0.256
6.689 7.033 >50 ZM135M.PL10a C 0.069 0.367 0.171 1.186 20.56
>50 >50 >50 CAP45.2.00.G3 C >50 >50 1.817 >10
0.007 0.029 0.001 0.003 CAP210.2.00.E8 C >50 >50 0.798 3.892
0.040 0.173 0.010 0.042 HIV-001428-2.42 C 0.044 0.261 0.809 7.298
0.101 0.250 0.039 0.250 HIV-0013095-2.11 C >50 >50 0.031
0.213 0.010 0.030 0.002 0.006 HIV-16055-2.3 C >50 >50 0.722
6.495 0.021 0.06 0.17 >0.250 HIV-16845-2.22 C 1.169 5.835 0.068
0.495 4.398 >50 3.126 >50 Ce1086_B2 C (T/F) >50 >50
1.162 6.934 >50 >50 >50 >50 Ce0393_C3 C (T/F) >50
>50 1.179 7.423 0.020 0.055 0.002 0.006 Ce1176_A3 C (T/F) 0.019
0.070 0.867 3.923 0.014 0.044 0.003 0.011 Ce2010_F5 C (T/F) >50
>50 1.844 8.612 >50 >50 >50 >50 Ce0682_E4 C (T/F)
>50 >50 1.215 7.709 0.196 0.698 0.026 0.202 Ce1172_H1 C (T/F)
0.047 0.166 0.722 4.818 0.070 0.206 0.007 0.037 Ce2060_G9 C (T/F)
>50 >50 3.520 >10 0.045 0.172 0.075 1.712 Ce703010054_2A2
C (T/F) >50 >50 2.299 8.579 0.022 0.103 0.008 0.053
BF1266.431a C (T/F) >50 >50 2.687 >10 0.026 0.088 0.003
0.009 246F C1G C (T/F) 0.022 0.111 2.217 9.937 >50 >50 >50
>50 249M B10 C (T/F) >50 >50 1.271 9.050 0.095 0.290 0.026
1.249 ZM247v1(Rev-) C (T/F) 0.042 0.186 0.506 6.745 0.112 0.323
0.016 0.189 7030102001E5(Rev-) C (T/F) 0.006 0.021 6.707 >10
>50 >50 >50 >50 1394C9G1(Rev-) C (T/F) 0.050 0.191
0.963 5.327 0.029 0.114 0.008 0.056 Ce704809221_1B3 C (T/F) 0.139
0.696 0.058 0.319 0.037 0.137 0.021 0.116 CNE19 BC 50.00 >50
0.666 6.485 0.024 0.146 0.024 3.070 CNE20 BC <0.001 0.005 1.246
6.577 0.052 0.278 3.633 47.170 CNE21 BC 0.067 0.181 1.900 >10
0.038 0.094 0.007 0.026 CNE17 BC 2.686 13.297 1.114 5.255 0.210
0.484 0.029 0.132 CNE30 BC 0.363 1.200 1.560 9.842 >50 >50
>50 >50 CNE52 BC 1.226 13.147 0.304 3.056 0.029 0.081 0.009
0.026 CNE53 BC 0.039 0.141 0.326 1.916 0.131 0.60 >50 >50
CNE58 BC 0.267 0.968 1.289 8.268 0.038 0.122 0.044 0.250 MS208.A1 A
>50 >50 0.609 3.717 0.005 0.014 0.002 0.004 Q23.17 A 0.006
0.021 1.637 7.040 0.027 0.082 0.008 0.043 Q461.e2 A >50 >50
2.111 >10 1.484 8.725 1.755 >50 Q769.d22 A >50 >50
1.667 10.000 0.025 0.068 0.005 0.018 Q259.d2.17 A >50 >50
4.587 >10 0.029 1.379 0.065 45.89 Q842.d12 A >50 >50 4.189
>10 0.023 0.081 0.032 >0.250 3415.v1.c1 A >50 >50 NT NT
NT NT NT NT 3365.v2.c2 A 0.131 0.450 NT NT NT NT NT NT 0260.v5.c36
A 0.099 0.160 >10 >10 1.693 9.0 1.538 36.08 191955_A11 A
(T/F) >50 >50 0.680 3.532 0.053 0.154 0.009 0.042 191084
B7-19 A (T/F) 0.032 0.128 5.156 >10 0.043 0.202 0.024 0.238
9004SS_A3_4 A (T/F) 0.011 0.030 1.160 6.761 0.088 0.251 0.020 0.111
T257-31 CRF02_AG >50 >50 0.880 5.779 0.037 0.124 0.007 0.021
928-28 CRF02_AG 0.847 4.696 0.384 1.962 0.101 0.450 0.034 0.237
263-8 CRF02_AG 0.666 6.527 0.196 1.728 0.293 1.050 0.347 4.975
T250-4 CRF02_AG <0.001 0.005 1.346 8.130 0.005 0.014 0.002 0.005
T251-18 CRF02_AG 1.081 7.395 2.357 >10 >50 >50 1.721 44.72
T278-50 CRF02_AG 2.146 18.276 0.949 7.460 0.393 3.192 0.227 18.65
T255-34 CRF02_AG >50 >50 0.778 4.207 0.023 0.134 0.024 0.125
211-9 CRF02_AG 0.112 0.425 1.091 6.508 0.049 0.243 0.029 0.144
235-47 CRF02_AG 0.05 0.163 0.384 2.072 0.233 1.201 0.092 4.506
620345.c01 CRF01_AE >50 >50 0.455 6.002 1.333 >50 >50
>50 CNE8 CRF01_AE >50 >50 NT NT NT NT NT NT C1080.c03
CRF01_AE >50 >50 0.061 0.731 0.004 0.013 0.001 0.003
R2184.c04 CRF01_AE >50 >50 0.272 2.455 0.255 1.237 0.670
>50 R1166.c01 CRF01_AE >50 >50 0.274 2.614 0.736 2.876
0.280 4.376 R3265.c06 CRF01_AE NT NT >10 >10 0.163 0.535
0.016 0.146 C2101.c01 CRF01_AE >50 >50 1.921 8.260 0.034
0.099 0.012 0.238 C3347.c11 CRF01_AE >50 >50 0.016 0.167
0.032 0.113 0.008 0.045 C4118.c09 CRF01_AE >50 >50 1.622
9.064 0.068 0.200 0.022 0.143 CNE5 CRF01_AE >50 >50 1.408
9.637 0.018 0.051 0.008 0.033 BJOX009000.02.4 CRF01_AE >50
>50 1.570 9.954 1.725 8.211 1.188 22.12 BJOX015000.11.5 CRF01_AE
>50 >50 0.051 1.909 0.322 1.489 3.129 >50 (T/F)
BJOX010000.06.2 CRF01_AE >50 >50 0.341 5.293 0.154 0.740
1.202 >50 (T/F) BJOX025000.01.1 CRF01_AE >50 >50 0.107
6.325 0.144 0.335 0.071 >50 (T/F) BJOX028000.10.3 CRF01_AE
>50 >50 0.665 7.361 1.100 21.5 >50 >50 (T/F) X1193_c1 G
0.083 0.475 0.497 4.195 0.105 0.304 0.018 0.110 P0402_c2_11 G 0.012
0.039 0.172 3.288 0.296 2.367 0.025 0.411 X1254_c3 G 0.089 0.297
4.753 >10 0.065 0.304 0.023 0.218 X2088_c9 G 0.003 0.014 >10
>10 >50 >50 >50 >50 X2131_C1_B5 G 0.016 0.064 0.189
0.974 0.084 0.286 0.024 0.139 P1981_C5_3 G 0.005 0.017 0.057 0.285
0.258 2.512 0.376 >50 X1632_S2_B10 G >50 >50 1.976 9.684
0.107 0.934 0.012 0.076 3016.v5.c45 D >50 >50 0.476 4.393
2.455 >50 >50 >50 A07412M1.vrc12 D <0.001 0.048 0.576
6.054 0.697 7.963 0.343 >50 231965.c01 D >50 >50 >10
>10 1.285 47.97 1.438 >50 231966.c02 D >50 >50 0.191
3.130 0.075 0.257 0.007 0.031 3817.v2.c59 CD 3.148 14.880 1.181
5.977 0.020 0.062 0.008 0.060 6480.v4.c25 CD 0.009 0.041 8.079
>10 >50 >50 >50 >50 6952.v1.c20 CD 0.037 0.138 0.343
1.907 >50 >50 21.87 >50 6811.v7.c18 CD 0.002 0.010 7.535
>10 >50 >50 >50 >50 89-F1_2_25 CD >50 >50
1.112 10.000 0.668 10.1 47.61 >50 3301.v1.c24 AC 0.013 0.042
4.628 >10 0.216 0.756 0.020 0.087 6041.v3.c23 AC >50 >50
2.333 9.766 0.244 3.639 0.048 0.256 6540.v4.c1 AC >50 >50
1.899 10.000 0.070 0.253 0.035 0.420 6545.v4.c1 AC >50 >50
1.778 8.229 0.099 0.351 0.044 1.561 0815.v3.c3 ACD 0.03 0.138 0.332
2.868 >50 >50 >50 >50 3103.v3.c10 ACD 0.037 0.101
>10 >10 28.004 >50 25.39 >50 MuLV Neg. Control *(T/F):
Transmitted/Founder Virus
TABLE-US-00025 TABLE 24 Neutralization assay data of 3BNC117,
45-46, 8ANC195, VRC07 mAbs against extended multiclade virus panel.
mAbs tested at primary concentration of 50 ug/ml and titrated
5-fold 7x (duplicate wells). Titer in TZM.bl cells (ug/ml) TABLE 24
3BNC117 45-46 8ANC195 VRC07 Virus ID Clade* IC50 IC80 IC50 IC80
IC50 IC80 IC50 IC80 6535.3 B 0.55 2.44 0.14 0.28 0.20 0.91 0.169
0.517 QH0692.42 B 0.13 0.49 0.55 1.56 2.71 17.08 0.500 1.861
SC422661.8 B 0.02 0.08 0.01 0.07 0.29 4.67 0.054 0.175 PVO.4 B
<0.09 0.19 0.17 0.47 0.52 1.87 0.063 0.226 TRO.11 B <0.09
<0.09 1.90 9.56 0.18 0.89 0.132 0.456 AC10.0.29 B 13.84 >50
0.42 1.49 0.88 7.00 0.282 0.986 RHPA4259.7 B <0.09 <0.09
<0.05 <0.05 0.34 1.56 0.017 0.048 THRO4156.18 B 1.76 10.14
1.59 6.02 >50 >50 2.404 12.200 REJO4541.67 B 0.01 0.05 0.003
0.010 0.08 0.68 0.011 0.037 TRJO4551.58 B 0.05 0.19 0.01 0.05 0.19
1.17 0.032 0.125 WITO4160.33 B 0.01 0.04 0.01 0.08 >50 >50
0.042 0.193 CAAN5342.A2 B 0.42 1.51 0.11 0.33 >50 >50 0.307
1.053 WEAU_d15_410_787 B (T/F) 0.05 0.19 0.01 0.03 >50 >50
0.034 0.115 1006_11_C3_1601 B (T/F) 0.03 0.10 0.05 0.31 0.43 1.98
0.015 0.046 1054_07_TC4_1499 B (T/F) 0.07 0.49 0.07 0.61 1.02 6.75
0.239 1.459 1056_10_TA11_1826 B (T/F) 0.30 1.82 0.12 0.59 >50
>50 0.239 1.110 1012_11_TC21_3257 B (T/F) 0.02 0.07 0.01 0.04
>50 >50 0.014 0.045 6240_08_TA5_4622 B (T/F) 0.33 1.17 0.44
1.55 >50 >50 0.448 1.540 6244_13_B5_4576 B (T/F) 0.04 0.15
0.07 0.26 >50 >50 0.065 0.230 62357_14_D3_4589 B (T/F) 0.06
0.26 0.05 0.22 >50 >50 0.075 0.256 SC05_8C11_2344 B (T/F)
0.15 0.51 0.14 0.38 0.47 3.06 0.133 0.401 Du156.12 C 0.02 0.08 0.01
0.05 0.22 1.56 0.041 0.149 Du172.17 C 1.19 8.90 >30 >30
>30 >30 0.796 3.661 Du422.1 C >50 >50 >50 >50
>50 >50 >50 >50 ZM197M.PB7 C 0.22 1.03 0.14 0.64 23.45
>50 0.307 1.275 ZM214M.PL15 C 0.06 0.52 0.05 0.39 0.91 12.30
0.198 1.417 ZM233M.PB6 C 0.13 0.85 1.86 16.52 7.39 43.45 0.152
0.625 ZM249M.PL1 C 0.03 0.11 0.02 0.06 >50 >50 0.041 0.145
ZM53M.PB12 C 0.21 0.85 0.65 0.65 >30 >30 0.275 1.294
ZM109F.PB4 C 0.14 0.88 0.22 0.22 >30 >30 0.112 0.389
ZM135M.PL10a C 0.03 0.13 0.36 3.11 >50 >50 0.104 0.383
CAP45.2.00.G3 C 3.88 >50 >50 >50 28.30 >50 0.355 3.087
CAP210.2.00.E8 C 17.22 >50 >50 >50 >50 >50 >50
>50 HIV-001428-2.42 C 0.003 0.02 <0.001 0.01 >50 >50
0.004 0.016 HIV-0013095-2.11 C 0.33 2.53 0.01 0.03 0.32 1.85 0.017
0.057 HIV-16055-2.3 C 5.60 >50 0.02 0.06 15.30 >50 0.025
0.135 HIV-16845-2.22 C 27.46 >50 2.05 12.10 3.30 20.06 1.207
6.154 Ce1086_B2 C (T/F) 0.09 0.31 0.04 0.28 4.42 19.11 0.128 0.840
Ce0393_C3 C (T/F) 0.20 0.67 0.32 1.07 6.77 >50 0.182 0.634
Ce1176_A3 C (T/F) 0.22 0.75 1.29 5.55 4.45 35.17 0.520 2.600
Ce2010_F5 C (T/F) 0.05 0.21 0.13 0.43 >50 >50 0.131 0.480
Ce0682_E4 C (T/F) 0.03 0.15 0.07 0.25 0.20 1.29 0.039 0.239
Ce1172_H1 C (T/F) >50 >50 >50 >50 42.30 >50 >50
>50 Ce2060_G9 C (T/F) 0.24 0.81 0.14 0.48 6.20 >50 0.085
0.422 Ce703010054_2A2 C (T/F) 0.37 1.67 0.22 0.97 13.62 >50
0.190 0.912 BF1266.431a C (T/F) 0.03 0.09 0.01 0.03 >50 >50
0.032 0.117 246F C1G C (T/F) 19.32 >50 >50 >50 12.81
>50 0.286 1.041 249M B10 C (T/F) 0.10 0.40 0.04 0.17 >50
>50 0.052 0.204 ZM247v1(Rev-) C (T/F) >50 >50 1.64 >50
3.41 25.12 0.041 0.189 7030102001E5(Rev-) C (T/F) 0.29 1.44 0.14
0.63 0.86 8.32 0.205 0.911 1394C9G1(Rev-) C (T/F) >50 >50
0.09 0.38 >50 >50 0.112 0.368 Ce704809221_1B3 C (T/F) 0.08
0.31 0.15 0.88 0.48 3.52 0.273 1.137 CNE19 BC 0.02 0.08 0.07 0.37
0.29 1.73 0.092 0.232 CNE20 BC >50 >50 8.71 47.01 0.50 3.19
0.060 0.129 CNE21 BC 45.38 >50 7.53 >50 0.27 1.52 0.050 0.222
CNE17 BC 5.76 42.98 0.15 0.55 2.59 11.07 0.136 0.651 CNE30 BC 0.26
0.85 0.34 1.48 7.52 40.45 0.326 1.084 CNE52 BC 0.02 0.06 0.03 0.12
5.59 43.09 0.042 0.142 CNE53 BC 0.08 0.99 0.01 0.04 >50 >50
0.031 0.086 CNE58 BC 0.25 2.03 0.25 1.49 >50 >50 0.110 0.298
MS208.A1 A 0.01 0.09 0.09 0.60 >50 >50 0.120 0.425 Q23.17 A
0.005 0.020 0.14 0.60 2.55 2.55 0.081 0.236 Q461.e2 A 0.03 0.09
0.06 0.32 0.63 2.51 0.282 1.025 Q769.d22 A 0.01 0.04 0.01 0.04 0.26
1.20 0.018 0.087 Q259.d2.17 A 0.01 0.05 0.01 0.06 >50 >50
0.024 0.100 Q842.d12 A <0.01 0.01 0.03 0.03 >30 >30 0.015
0.051 3415.v1.c1 A 0.17 0.47 0.07 0.07 17.74 17.74 0.036 0.152
3365.v2.c2 A 0.03 0.10 0.11 0.11 >30 >30 0.038 0.109
0260.v5.c36 A NT NT NT NT NT NT 0.448 1.619 191955_A11 A (T/F)
>50 >50 0.11 0.43 >50 >50 0.978 4.824 191084 B7-19 A
(T/F) 0.07 0.23 0.02 0.07 >50 >50 0.061 0.209 9004SS_A3_4 A
(T/F) 0.07 0.18 0.18 0.65 0.17 0.81 0.218 0.750 T257-31 CRF02_AG
0.06 0.37 0.23 1.11 0.32 3.89 0.421 3.172 928-28 CRF02_AG 0.15 0.55
0.10 0.39 >50 >50 0.278 0.957 263-8 CRF02_AG 0.005 0.040 0.05
0.10 >50 >50 0.103 0.282 T250-4 CRF02_AG >15 >15 >30
>30 >50 >50 >50 >50 T251-18 CRF02_AG 0.26 0.82 5.26
5.26 1.51 1.51 1.322 6.491 T278-50 CRF02_AG >15 >15 >30
>30 >50 >50 >50 >50 T255-34 CRF02_AG 0.02 0.14 0.23
2.38 0.54 8.09 0.227 0.987 211-9 CRF02_AG 0.35 1.28 >50 >50
1.34 8.43 5.919 37.988 235-47 CRF02_AG 0.03 0.12 0.30 1.49 >50
>50 0.024 0.075 620345.c01 CRF01_AE >15 >15 >30 >30
>50 >50 >50 >50 CNE8 CRF01_AE NT NT NT NT NT NT 0.450
1.563 C1080.c03 CRF01_AE 0.25 1.73 1.79 18.04 0.17 1.12 2.032 8.251
R2184.c04 CRF01_AE 0.03 0.10 0.03 0.12 0.09 12.98 0.020 0.104
R1166.c01 CRF01_AE 0.17 0.64 1.68 1.68 4.83 4.83 0.810 3.167
R3265.c06 CRF01_AE 0.48 13.04 0.04 0.44 50.00 >50 NT NT
C2101.c01 CRF01_AE 0.05 0.31 12.78 >50 0.48 3.54 0.238 1.404
C3347.c11 CRF01_AE 0.03 0.13 0.03 0.18 >50 >50 0.060 0.380
C4118.c09 CRF01_AE 0.09 0.52 0.14 0.91 0.20 0.71 0.121 0.444 CNE5
CRF01_AE 0.28 1.28 0.09 0.41 2.12 9.67 0.138 0.524 BJOX009000.02.4
CRF01_AE 0.40 1.79 0.26 1.16 0.64 3.09 0.806 2.899 BJOX015000.11.5
CRF01_AE 0.05 0.32 0.06 0.38 0.97 4.30 0.054 0.479 (T/F)
BJOX010000.06.2 CRF01_AE 1.58 10.45 0.87 6.37 0.85 5.84 1.061
10.035 (T/F) BJOX025000.01.1 CRF01_AE 0.05 0.20 0.18 10.00 4.96
>50 0.279 2.295 (T/F) BJOX028000.10.3 CRF01_AE 0.01 0.05 0.07
>50 0.45 2.83 0.011 0.069 (T/F) X1193_c1 G 0.06 0.25 0.04 0.16
0.27 1.66 0.037 0.249 P0402_c2_11 G 0.06 0.38 0.06 0.26 0.62 6.35
0.085 0.422 X1254_c3 G 0.08 0.27 0.08 0.08 6.95 6.95 0.041 0.200
X2088_c9 G >50 >50 >50 >50 >50 >50 >50 >50
X2131_C1_B5 G 0.43 1.96 0.20 0.90 3.47 >50 0.219 1.033
P1981_C5_3 G 0.74 3.62 0.05 0.22 0.14 1.15 0.213 0.609 X1632_S2_B10
G 15.69 >50 0.07 >50 0.47 4.11 0.023 0.107 3016.v5.c45 D 1.38
>30 >30 >30 0.87 >50 0.095 0.392 A07412M1.vrc12 D 0.02
0.10 0.03 0.13 2.25 7.49 0.110 0.353 231965.c01 D 0.05 0.22 0.10
0.10 2.36 2.36 0.085 0.263 231966.c02 D 0.29 2.37 1.11 11.36 0.54
2.98 0.105 0.471 3817.v2.c59 CD 0.15 0.52 >50 >50 1.00 5.30
1.900 19.842 6480.v4.c25 CD 0.01 0.04 0.02 0.08 0.16 1.13 0.032
0.134 6952.v1.c20 CD 0.15 0.75 0.02 0.07 1.38 7.22 0.064 0.181
6811.v7.c18 CD 0.03 0.17 0.03 0.13 5.34 27.63 0.093 0.435
89-F1_2_25 CD >50 >50 >50 >50 >50 >50 >50
>50 3301.v1.c24 AC 0.01 0.05 0.01 0.03 >50 >50 0.027 0.073
6041.v3.c23 AC 0.01 0.07 0.01 0.04 >50 >50 0.018 0.058
6540.v4.c1 AC >50 >50 >50 >50 >50 >50 >50
>50 6545.v4.c1 AC >50 >50 >50 >50 26.94 >50
>50 >50 0815.v3.c3 ACD 0.01 0.02 0.01 0.03 1.94 1.94 0.015
0.051 3103.v3.c10 ACD 0.22 0.85 1.66 6.57 48.07 >50 0.675 1.951
MuLV Neg. Control *(T/F): Transmitted/Founder Virus
TABLE-US-00026 TABLE 25 Neutralization assay data of VRC01 mAb
against extended multiclade virus panel. mAbs tested at primary
concentration of 50 ug/ml and titrated 5-fold 7x (duplicate wells).
Titer in TZM.bl cells (ug/ml) TABLE 25 VRC01 Virus ID Clade* IC50
IC80 6535.3 B 0.54 2.7 QH0692.42 B 1.50 4.8 SC422661.8 B 0.08 0.265
PVO.4 B 0.22 1.2 TRO.11 B 0.21 0.83 AC10.0.29 B 2.20 6.5 RHPA4259.7
B 0.06 0.185 THRO4156.18 B 2.30 23 REJO4541.67 B 0.06 0.25
TRJO4551.58 B 0.08 0.21 WITO4160.33 B 0.15 0.41 CAAN5342.A2 B 0.82
2.8 WEAU_d15_410_787 B (T/F) 0.12 0.26 1006_11_C3_1601 B (T/F) 0.15
0.39 1054_07_TC4_1499 B (T/F) 0.71 2.85 1056_10_TA11_1826 B (T/F)
0.92 3.28 1012_11_TC21_3257 B (T/F) 0.12 0.32 6240_08_TA5_4622 B
(T/F) 0.61 1.82 6244_13_B5_4576 B (T/F) 0.21 0.53 62357_14_D3_4589
B (T/F) 0.96 4.68 SC05_8C11_2344 B (T/F) 0.64 1.91 Du156.12 C 0.09
0.193 Du172.17 C >50 >50 Du422.1 C >50 >50 ZM197M.PB7 C
0.36 1.6 ZM214M.PL15 C 0.44 2.6 ZM233M.PB6 C 2.00 9.3 ZM249M.PL1 C
0.05 0.23 ZM53M.PB12 C 1.30 4 ZM109F.PB4 C 0.13 0.75 ZM135M.PL10a C
0.35 2.7 CAP45.2.00.G3 C 2.30 >50 CAP210.2.00.E8 C >50 >50
HIV-001428-2.42 C 0.02 0.06 HIV-0013095-2.11 C 0.11 0.33
HIV-16055-2.3 C 0.08 0.26 HIV-16845-2.22 C 2.80 12.69 Ce1086_B2 C
(T/F) 0.42 1.44 Ce0393_C3 C (T/F) 0.62 2.37 Ce1176_A3 C (T/F) 2.25
8.10 Ce2010_F5 C (T/F) 0.32 1.07 Ce0682_E4 C (T/F) 0.08 0.48
Ce1172_H1 C (T/F) >10 >10 Ce2060_G9 C (T/F) 0.29 1.48
Ce703010054_2A2 C (T/F) 0.53 1.84 BF1266.431a C (T/F) 0.07 0.23
246F C1G C (T/F) >10 >10 249M B10 C (T/F) 0.13 0.46
ZM247v1(Rev-) C (T/F) 0.35 1.29 7030102001E5(Rev-) C (T/F) 0.54
2.08 1394C9G1 (Rev-) C (T/F) 0.36 1.28 Ce704809221_1B3 C (T/F) 0.55
2.05 CNE19 BC NT NT CNE20 BC NT NT CNE21 BC NT NT CNE17 BC NT NT
CNE30 BC NT NT CNE52 BC NT NT CNE53 BC NT NT CNE58 BC NT NT
MS208.A1 A 0.10 0.46 Q23.17 A 0.09 0.261 Q461.e2 A 0.49 1.6
Q769.d22 A 0.08 0.29 Q259.d2.17 A 0.17 0.54 Q842.d12 A 0.03 0.096
3415.v1.c1 A 0.06 0.15 3365.v2.c2 A 0.06 0.17 0260.v5.c36 A NT NT
191955_A11 A (T/F) NT NT 191084 B7-19 A (T/F) NT NT 9004SS_A3_4 A
(T/F) NT NT T257-31 CRF02_AG 2.80 8.66 928-28 CRF02_AG 0.41 1.7
263-8 CRF02_AG 0.20 0.55 T250-4 CRF02_AG >50 >50 T251-18
CRF02_AG 2.50 11.17 T278-50 CRF02_AG >50 >50 T255-34 CRF02_AG
0.70 2.7 211-9 CRF02_AG 14.30 >50 235-47 CRF02_AG 0.04 0.17
620345.c01 CRF01_AE >50 >50 CNE8 CRF01_AE NT NT C1080.c03
CRF01_AE 3.40 14.37 R2184.c04 CRF01_AE 0.08 0.32 R1166.c01 CRF01_AE
1.70 4.58 R3265.c06 CRF01_AE 0.45 1.88 C2101.c01 CRF01_AE 0.36 1.17
C3347.c11 CRF01_AE 0.17 0.58 C4118.c09 CRF01_AE NT NT CNE5 CRF01_AE
0.37 1.1 BJOX009000.02.4 CRF01_AE NT NT BJOX015000.11.5 CRF01_AE NT
NT (T/F) BJOX010000.06.2 CRF01_AE NT NT (T/F) BJOX025000.01.1
CRF01_AE NT NT (T/F) BJOX028000.10.3 CRF01_AE NT NT (T/F) X1193_c1
G 0.11 0.32 P0402_c2_11 G 0.21 0.59 X1254_c3 G 0.07 0.19 X2088_c9 G
>50 >50 X2131_C1_B5 G 0.51 1.54 P1981_C5_3 G 0.46 1.26
X1632_S2_B10 G 0.12 0.74 3016.v5.c45 D 0.16 0.42 A07412M1.vrc12 D
NT NT 231965.c01 D 0.34 1.2 231966.c02 D NT NT 3817.v2.c59 CD
>50 >50 6480.v4.c25 CD 0.04 0.09 6952.v1.c20 CD 0.04 0.12
6811.v7.c18 CD 0.09 0.26 89-F1_2_25 CD NT NT 3301.v1.c24 AC 0.14
0.32 6041.v3.c23 AC 0.02 0.08 6540.v4.c1 AC >50 >50
6545.v4.c1 AC >50 >50 0815.v3.c3 ACD 0.06 0.13 3103.v3.c10
ACD 0.93 2.49 MuLV Neg. Control *(T/F): Transmitted/Founder
Virus
[1099] Throughout this disclosure, various publications, patents
and published patent specifications are referenced by an
identifying citation. The disclosures of these publications,
patents and published patent specifications are hereby incorporated
by reference into the present disclosure to more fully describe the
state of the art to which this invention pertains.
[1100] While the present teachings are described in conjunction
with various embodiments, it is not intended that the present
teachings be limited to such embodiments. On the contrary, the
present teachings encompass various alternatives, modifications,
and equivalents, as will be appreciated by those of skill in the
art.
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20200172601A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20200172601A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References