TREA

POLYPEPTIDES FOR DETECTION AND TREATMENT OF CORONAVIRUS INFECTION

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Information

  • Patent Application
  • 20250026814
  • Publication Number
    20250026814
  • Date Filed
    November 16, 2022
    2 years ago
  • Date Published
    January 23, 2025
    a month ago
Information
Abstract
Here, the inventors report that natural WT SARS-CoV-2 infection induces memory B cells expressing potently neutralizing antibodies against VOCs. Moreover, natural WT infection largely induced antibodies against spike epitopes outside of the RBD, most of which were non-neutralizing against WT and VOCs. Additionally. RBD-binding antibodies could be categorized into 3 distinct classes based on their binding profiles against RBD mutant constructs. The inventors identified VOC-neutralizing antibodies against three distinct regions of the spike protein, including the two epitopes on the RBD and one epitope in the NTD. Together, this study identifies that natural WT infection induces memory B cells that can produce neutralizing antibodies against recent SARS-CoV-2 VOCs and have the potential to be recalled by vaccination.
Description
SEQUENCE LISTING

The application contains a Sequence Listing prepared in compliance with ST.26 format and is hereby incorporated by reference in its entirety. Said Sequence Listing, created on Nov. 11, 2022 is named ARCDP0724WO.xml and is 1,777,457 bytes in size.


BACKGROUND
I. Field of the Invention

Aspects of the invention relate to at least the fields of virology and molecular biology.


II. Background

The emergence of novel circulating SARS-CoV-2 variants of concern (VOCs) have recently proven to undermine the protective effects of infection- and vaccination-induced humoral immunity1-4. All approved vaccines against SARS-CoV-2 drive a neutralizing antibody response against the spike protein, the major target of neutralizing antibodies elicited by natural infection3, 5. However, protective humoral immunity against the spike protein induced by vaccination or infection with the original wildtype (WT) virus may be attenuated due to the widespread circulation of variants2. The first reported mutation of the SARS-CoV-2 spike protein, D614G, arose in the C-terminal domain (CTD) and evolved due to increased stability of the spike rather than a mutation to escape host immunity6. More recently, mutations have arisen within the receptor-binding domain (RBD), N-terminal domain (NTD) of S1, and S2 that have resulted in emergence of several circulating viral variants that are rapidly becoming the dominant strains around the globe2. The B.1.1.7 lineage or alpha VOC, first found in the United Kingdom, has been reported to have a >50% increased transmissibility among humans7-10. Of greatest concern is the substitution at position 484 in the RBD, which is exclusively shared by the VOCs, variants of interest (VOIs) and variants under monitoring (VUMs) originally identified in South Africa (B.1.351; beta), Brazil (P.1; gamma), Texas (R.1), Columbia (B.1.621; mu), New York (B.1.526; iota) and India (B.1.617.1; kappa)2, 3, 11-15. VOCs possessing a mutation at E484, either E484K and E484Q, can partially evade neutralizing humoral immunity induced by either natural infection or vaccination and, in rare cases, lead to reinfection and infection, respectively11-13, 16-18. Other emerging variants have acquired a mutation at L452R within the RBD, which is found in B.1.1.298, a variant capable of interspecies transmission between humans and minks, and B.1.427/B.1.429 (epsilon) isolated in southern California19. Moreover, the B.1.617.1 (kappa) found in India possesses both L452R and E484Q mutations within the RBD15, 20. The most recent VOC, B.1.617.2 (delta), is responsible for a surge in both cases and fatalities in several countries, especially where vaccination rates are low4, 21-23. Intriguingly, the B. 1.617 lineages contain P681R, a mutation that enhances and accelerates viral fusion24 and which is also present in the dominant variant in Uganda, A.23.125. Thus, understanding the impact of these various mutations on the neutralization capacity of antibodies elicited by current vaccine formulations or natural exposure to wildtype (WT) SARS-CoV-2 is urgently needed to develop critical next-generation vaccine strategies against SARS-CoV-2 variants.


SUMMARY

Here, the inventors report that natural WT SARS-CoV-2 infection induces memory B cells expressing potently neutralizing antibodies against VOCs. Moreover, natural WT infection largely induced antibodies against spike epitopes outside of the RBD, most of which were non-neutralizing against WT and VOCs. Additionally, RBD-binding antibodies could be categorized into 3 distinct classes based on their binding profiles against RBD mutant constructs. The inventors identified VOC-neutralizing antibodies against three distinct regions of the spike protein, including the two epitopes on the RBD and one epitope in the NTD. Together, this study identifies that natural WT infection induces memory B cells that can produce neutralizing antibodies against recent SARS-CoV-2 VOCs and have the potential to be recalled by vaccination.


The disclosure describes novel antibody and antigen binding fragments. Also described are polypeptides comprising the antigen binding fragment(s) of the disclosure, and compositions comprising the polypeptides, antibodies, and/or antigen binding fragments of the disclosure. Also described are nucleic acids encoding an antibody or antigen binding fragment of the disclosure. The disclosure also relates to nucleic acids encoding an antibody heavy chain, wherein the nucleic acid has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to one of the nucleic acid sequences of a heavy chain of Table 2. Also described are nucleic acids encoding an antibody light chain of the disclosure, wherein the nucleic acid has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to one of the nucleic acid sequences of a light chain of Table 2. Also provided are vectors or expression vectors comprising nucleic acids of the disclosure and host cells comprising polypeptides, nucleic acids, vectors, antibodies, or antigen binding fragments of the disclosure. The nucleic acids of the disclosure may be DNA or RNA.


Also described is a method of a making a cell comprising transferring one or more nucleic acid(s) of the disclosure into a cell. The method may further comprise culturing the cell under conditions that allow for expression of a polypeptide from the nucleic acid. The method may further comprise isolating the expressed polypeptide. Also described is a method for producing a polypeptide comprising transferring one or more nucleic acid(s) or vector(s) of the disclosure into a cell and isolating polypeptides expressed from the nucleic acid. Methods also include a method for producing a polypeptide comprising culturing cells comprising nucleic acid(s) or vectors of the disclosure and isolating polypeptides expressed from the nucleic acid. The cell may be further defined as a human cell, B cell, T cell, Chinese hamster ovary, NS0 murine myeloma cell, PER.C6 cell, or a cell described herein.


Methods include a method for treating, preventing, vaccinating against, and/or inducing an immune response against a coronavirus infection in a subject, the method comprising administering to the subject an antibody, antigen binding fragment, polypeptide, nucleic acid, or host cell of the disclosure. Also provided is a method for evaluating a sample from a subject, the method comprising contacting a biological sample from the subject, or extract thereof, with at least one antibody, antigen binding fragment, or polypeptide of the disclosure. Also disclosed is a method for diagnosing a SARS-CoV-2 infection in a subject, the method comprising contacting a biological sample from the subject, or extract thereof, with at least one antibody, antigen binding fragment, or polypeptide of any one of the disclosure. The compositions of the disclosure may be formulated as a vaccine for the treatment or prevention of a coronavirus infection. The antibodies, antigen binding fragments, or compositions of the disclosure may be used in a vaccine for preventing coronaviral infections in a subject that does not have a coronaviral infection. The antibodies, antigen binding fragments, or compositions of the disclosure may be used to treat a subject having a coronaviral infection.


The disclosure describes an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region: (i) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1565, 1566, and 1567 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1572, 1573, and 1574; (ii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1457, 1458, and 1459 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1464, 1465, and 1466; or (iii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1492, 243, and 1493 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1497, 1498, and 1499.


The disclosure describes an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region: (i) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1565, 1566, and 1567 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1572, 1573, and 1574; (ii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1457, 1458, and 1459 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1464, 1465, and 1466; or (iii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1492, 243, and 1493 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1497, 1498, and 1499.


The antibody or antigen binding fragment may have a heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1565, 1566, and 1567 and a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 having the amino acid sequence of SEQ ID NOs: 1572, 1573, and 1574. The antibody or antigen binding fragment may have a heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1457, 1458, and 1459 and a light chain variable region comprising a LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NOs: 1464, 1465, and 1466. The antibody or antigen binding fragment may have a heavy chain variable region comprising a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1492, 243, and 1493 and a light chain variable region having the amino acid sequence of SEQ ID NOs: 1497, 1498, and 1499.


The heavy chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1563 or 1564 and/or the light chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1570 or 1571. The heavy chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1455 or 1456 and/or the light chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1462 or 1463. The heavy chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1490 or 1491 and/or the light chain may comprise an amino acid sequence with at least 80% sequence identity to SEQ ID NO:1495 or 1496. The heavy chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO: 1563 or 1564 and/or the light chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:1570 or 1571. The heavy chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:1455 or 1456 and/or the light chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:1462 or 1463. The heavy chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO: 1490 or 1491 and/or the light chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NO:1495 or 1496.


The antibody or antigen binding fragment may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 1563 or 1564 and/or a light chain comprising the amino acid sequence of SEQ ID NO:1570 or 1571. The antibody or antigen binding fragment may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 1455 or 1456 and/or a light chain comprising the amino acid sequence of SEQ ID NO: 1462 or 1463. The antibody or antigen binding fragment may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO: 1490 or 1491 and/or a light chain comprising the amino acid sequence of SEQ ID NO:1495 or 1496.


The antibody or antigen binding fragment may comprise a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4 and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1568, 130, 1569, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1575, 950, 1576, and 69. The antibody or antigen binding fragment may comprise a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1460, 1461, 146, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1467, 1468, 1469, and 53. The antibody or antigen binding fragment may comprise a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 245, 7, 1494, and 44, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1500, 1501, 1502, and 18.


The antibody or antigen binding fragment may comprise a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4 and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 1568, 130, 1569, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 1575, 950, 1576, and 69. The antibody or antigen binding fragment may comprise a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 1460, 1461, 146, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 1467, 1468, 1469, and 53. The antibody or antigen binding fragment may comprise a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 245, 7, 1494, and 44, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to SEQ ID NOs: 1500, 1501, 1502, and 18.


The antibody or antigen binding fragment may comprise a HFR1, HFR2, HFR3, and HFR4 comprising the amino acid sequence of SEQ ID NOs: 1568, 130, 1569, and 60, and a LFR1, LFR2, LFR3, and LFR4 comprising the amino acid sequence of SEQ ID NOs: 1575, 950, 1576, and 69. The antibody or antigen binding fragment may comprise a HFR1, HFR2, HFR3, and HFR4 comprising the amino acid sequence of SEQ ID NOs: 1460, 1461, 146, and 60, and a LFR1, LFR2, LFR3, and LFR4 comprising the amino acid sequence of SEQ ID NOs: 1467, 1468, 1469, and 53. The antibody or antigen binding fragment may comprise a HFR1, HFR2, HFR3, and HFR4 comprising the amino acid sequence of SEQ ID NOs: 245, 7, 1494, and 44, and a LFR1, LFR2, LFR3, and LFR4 comprising the amino acid sequence of SEQ ID NOs: 1500, 1501, 1502, and 18.


The disclosure describes an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 from a heavy chain variable region of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same clone of Table 1. Also described is an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having or having at least 80% sequence identity or having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity with a HCDR1, HCDR2, and HCDR3 from a heavy chain variable region of an antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having or having at least 80% sequence identity or having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity with a LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same clone of Table 1. The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and/or LCDR3 may be determined from the variable region sequences by methods known in the art. The CDR may be a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and/or LCDR3 determined by the Chothia method. The CDR may be a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and/or LCDR3 determined by the Kabat method. The CDR may be a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and/or LCDR3 determined by the IMGT method.


Also described is an antibody or antigen binding fragment in which the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 each comprise an amino acid sequence that has at least 80% sequence identity to an HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 of Table 1, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 are from the same antibody clone. The HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 may each comprise an amino acid sequence that has or has at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to an HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 of Table 1, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 are from the same antibody clone. The HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 may each comprise the amino acid sequence of an HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 of Table 1, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 are from the same antibody clone.


Also described is an antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region of a antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having or having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region of a antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same antibody clone of Table 1. In some aspects, the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of an of a HCDR1, HCDR2, and HCDR3 of a clone of Table 1 and the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same clone of Table 1.


The polypeptides of the disclosure may comprise at least two antigen binding fragments or antibodies, wherein each antigen binding fragment or antibody is independently selected from an antigen binding fragment or antibody of the disclosure, such as those disclosed in Table 1. The polypeptide may be multivalent. The polypeptide may be multispecific. The polypeptide may be bispecific. The polypeptide may comprise, comprise at least, or comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 antigen binding regions or antibodies. Each antigen binding region or antibody may be independently selected from an antigen binding region or antibody of the disclosure, such as those in Table 1. The polypeptide may have repeated units of the same antigen binding region, such as at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeated units.


The heavy chain variable region may comprise an amino acid sequence with at least 80% sequence identity to a heavy chain variable region of an antibody clone of Table 1 and/or the light chain variable region may comprise an amino acid sequence with at least 80% sequence identity to the light chain variable region of the same antibody clone of Table 1. The heavy chain variable region may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to a heavy chain variable region of an antibody clone of Table 1 and/or the light chain variable region may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the light chain variable region of the same antibody clone of Table 1. The heavy chain variable region may comprise the amino acid sequence of a heavy chain variable region of an antibody clone of Table 1 and/or the light chain variable region may comprise the amino acid sequence of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to an HFR1, HFR2, HFR3, and HFR4, respectively, of an antibody clone of Table 1, and the LFR1, LFR2, LFR3, and LFR4 may comprise an amino acid sequence with at least 80% sequence identity to the LFR1, LFR2, LFR3, and LFR4, respectively, of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to an HFR1, HFR2, HFR3, and HFR4, respectively, of an antibody clone of Table 1, and the LFR1, LFR2, LFR3, and LFR4 may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the LFR1, LFR2, LFR3, and LFR4, respectively, of the same antibody clone of Table 1. The HFR1, HFR2, HFR3, and HFR4 may comprise the amino acid sequence of an HFR1, HFR2, HFR3, and HFR4, respectively, of an antibody clone of Table 1, and the LFR1, LFR2, LFR3, and LFR4 may comprise the amino acid sequence of the LFR1, LFR2, LFR3, and LFR4, respectively, of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain and a light chain and wherein the heavy chain may comprise an amino acid sequence with at least 70% sequence identity to a heavy chain of an antibody clone of Table 1 and the light chain may comprise an amino acid sequence with at least 70% sequence identity to the light chain of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain and a light chain and wherein the heavy chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to a heavy chain of an antibody clone of Table 1 and the light chain may comprise an amino acid sequence having or having at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (or any derivable range therein) sequence identity to the light chain of the same antibody clone of Table 1. The antibody or antigen binding fragment may comprise a heavy chain and a light chain and wherein the heavy chain may comprise the amino acid sequence of an antibody clone of Table 1 and the light chain may comprise the amino acid sequence of the same antibody clone of Table 1.


The antibody or antigen binding fragment of the disclosure may be human, chimeric, or humanized. The antibody, or antigen binding fragment may bind a SARS-CoV-2 Spike, NP protein, or ORF8 with a KD of about 10−6 nM to about 10−12 pM. The antibody, or antigen binding fragment may bind a SARS-CoV-2 Spike, NP protein, or ORF8 with a KD of about, a KD of at least, or a KD of at most 10−3, 10−4, 10−5, 10−6, 10−7, 10−8, 10−9, 10−10, 10−11, 10−12, 10−13, 10−14, 10−15, 10−16, 10−17, or 10−18 (or any derivable range therein) μM, nM, or pM. The antibody or antigen binding fragment may specifically bind to a receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The antibody may be further defined as a neutralizing antibody. The antibody or antigen binding fragment may be further defined as a human antibody or antigen binding fragment, humanized antibody or antigen binding fragment, recombinant antibody or antigen binding fragment, chimeric antibody or antigen binding fragment, an antibody or antigen binding fragment derivative, a veneered antibody or antigen binding fragment, a diabody, a monoclonal antibody or antigen binding fragment, a single domain antibody, or a single chain antibody. The antigen binding fragment may be further defined as a single chain variable fragment (scFv), F(ab′)2, Fab′, Fab, Fv, or rIgG. The antibody, antigen binding fragment, or polypeptide may be operatively linked to a detectable label. Detectable labels are described herein.


Also provided are multi-specific and/or multivalent antibodies and polypeptides. The disclosure provides for bivalent or bispecific antibodies that comprise two antigen binding fragments, wherein the antigen binding fragment is two of the same antigen binding fragments or two different antigen binding fragments described herein. The disclosure also provides for multi-specific polypeptides. The polypeptides may comprise at least 2, 3, 4, 5, or 6 antigen binding fragments.


The antigen binding fragment may be at least 2, 3, 4, 5, or 6 scFv, F(ab′)2, Fab′, Fab, Fv, or rIgG, or combinations thereof. The polypeptide and/or antigen binding fragments of the disclosure may comprise a linker between a heavy chain and light chain variable region or between antigen binding fragments. The linker may be a flexible linker. Exemplary flexible linkers include glycine polymers (G) n, glycine-serine polymers (including, for example, (GS)n, (GSGGS-SEQ ID NO: 1875)n, (G4S)n and (GGGS-SEQ ID NO:1876) n, where n is an integer of at least one. n may be at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (or any derivable range therein). Glycine-alanine polymers, alanine-serine polymers, and other flexible linkers known in the art and may be used as a linker in the polypeptides of the disclosure. Exemplary linkers can comprise or consist of GGSG (SEQ ID NO:1877), GGSGG (SEQ ID NO:1878), GSGSG (SEQ ID NO:1879), GSGGG (SEQ ID NO:1880), GGGSG (SEQ ID NO:1881), GSSSG (SEQ ID NO:1882), and the like.


The coronavirus infection may be a SARS-CoV-2 infection. The coronavirus infection may be a SARS-CoV infection. The coronavirus infection may be a MERS-CoV infection. The coronavirus infection may be a HCoV-OC43, HCoV-HKU1, HCOV-229E, or HCoV-NL63 infection.


Compositions of the disclosure, such as pharmaceutical compositions may comprise a pharmaceutical excipient, carrier, or molecule described herein. The composition may further comprises an adjuvant or an immunostimulator. Such adjuvants or immunostimulators may include, but are not limited to stimulators of pattern recognition receptors, such as Toll-like receptors, RIG-1 and NOD-like receptors (NLR), mineral salts, such as alum, alum combined with monphosphoryl lipid (MPL) A of Enterobacteria, such as Escherihia coli, Salmonella minnesota, Salmonella typhimurium, or Shigella flexneri or specifically with MPL (ASO4), MPL A of above-mentioned bacteria separately, saponins, such as QS-21, Quil-A, ISCOMs, ISCOMATRIX, emulsions such as MF59, Montanide, ISA 51 and ISA 720, AS02 (QS21+squalene+MPL), liposomes and liposomal formulations such as AS01, synthesized or specifically prepared microparticles and microcarriers such as bacteria-derived outer membrane vesicles (OMV) of N. gonorrheae, Chlamydia trachomatis and others, or chitosan particles, depot-forming agents, such as Pluronic block co-polymers, specifically modified or prepared peptides, such as muramyl dipeptide, aminoalkyl glucosaminide 4-phosphates, such as RC529, or proteins, such as bacterial toxoids or toxin fragments. Compositions may comprise more than one antibody and/or antigen binding fragment of the disclosure. Accordingly, compositions of the disclosure may comprise, may comprise at least, or may comprise at most 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 antibodies and/or antigen binding fragments of the disclosure, wherein each antibody or antigen binding fragment is independently selected from an antibody or antigen binding fragment of the disclosure, such as those shown in Table 1. The compositions of the disclosure may be formulated for a route of administration described herein. The composition, antibody, antigen binding fragment, or polypeptide may be formulated for parenteral, intravenous, subcutaneous, intramuscular, or intranasal administration. The compositions may be formulated for intranasal administration.


The polypeptides, compositions, antibodies, antigen binding fragments, nucleic acids, or host cells, when administered to a subject, may be provided or may be provided at least, or may be provided at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times (or any derivable range therein) over the course of, over the course of at least, or over the course of at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years (or any range derivable therein).


The host cell may be a human cell, B cell, T cell, Chinese hamster ovary, NS0 murine myeloma cell, or PER.C6 cell. The host cell may be a cell type or cell population described herein.


The subject or patient may be a human subject or a human patient. The subject or patient may be a non-human animal. The non-human animal may be a bat, monkey, camel, rat, mouse, rabbit, goat, chicken, bird, cat, or dog. The subject may further be defined as an at-risk subject. At-risk subjects include health care workers, immunocompromised subjects, people over the age of 65, or those with at least one or at least two underlying conditions. Example of underlying conditions include obesity, high blood pressure, autoimmunity, cancer, and asthma. The subject may be one that has one or more symptoms of a coronavirus infection. Symptoms of a coronavirus infection include, but are not limited to elevated temperature or a fever of 100.0° F. or more, loss of taste or smell, cough, difficulty breathing, shortness of breath, fatigue, headache, chills, sore throat, congestion or runny nose, shaking or exaggerated shivering, significant muscle pain or ache, diarrhea, and/or nausea or vomiting. The subject may be one that does not have any symptoms of a coronavirus infection. The subject may be one that has been diagnosed with a coronavirus infection. The subject may be one that has not been diagnosed with a coronavirus infection. The subject may be one that has been previously treated for a coronavirus infection. The subject may be one that has been previously vaccinated for coronavirus. The subject may be one that has not been previously vaccinated for coronavirus. The previous treatment may comprise a pain reliever, such as acetaminophen or ibuprofen, a steroid such as dexamethasone, prednisolone, beclomethasone, fluticasone, or methylprednisone or an antiviral such as remdesivir. The subject may be administered an additional therapeutic. The additional therapeutic may comprise one or more of a pain reliever, such as acetaminophen or ibuprofen, a steroid such as dexamethasone, prednisolone, beclomethasone, fluticasone, or methylprednisone or an antiviral such as remdesivir. The additional therapeutic may comprise dexamethasone. The additional therapeutic may comprise remdesivir.


The method may comprise or further comprise incubating the antibody, antigen binding fragment, or polypeptide under conditions that allow for the binding of the antibody, antigen binding fragment, or polypeptide to antigens in the biological sample or extract thereof. The method may comprise or further comprise detecting the binding of an antigen to the antibody, antigen binding fragment, or polypeptide. The method may comprise or further comprise contacting the biological sample with at least one capture antibody, antigen, or polypeptide. The at least one capture antibody, antigen binding fragment, or polypeptide may be an antibody, polypeptide, or antigen binding fragment of the disclosure. The capture antibody may be linked or operatively linked to a solid support. The term “operatively linked” refers to a situation where two components are combined or capable of combining to form a complex. For example, the components may be covalently attached and/or on the same polypeptide, such as in a fusion protein or the components may have a certain degree of binding affinity for each other, such as a binding affinity that occurs through van der Waals forces. The biological sample may comprise a blood sample, urine sample, fecal sample, or nasopharyngeal sample. The at least one antibody, antigen binding fragment, or polypeptide may be operatively linked to a detectable label. The method may comprise or further comprise incubating the antibody, antigen binding fragment, or polypeptide under conditions that allow for the binding of the antibody, antigen binding fragment, or polypeptide to antigens in the biological sample or extract thereof. The method may comprise or further comprise detecting the binding of an antigen to the antibody, antigen binding fragment, or polypeptide. The method may comprise or further comprise contacting the biological sample with at least one capture antibody, antigen, or polypeptide. The biological sample may comprise a blood sample, urine sample, fecal sample, or nasopharyngeal sample.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 3, 4, and 5, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 12, 13, and 14, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 21, 22, and 23, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 29, 30, and 31, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 38, 39, and 40, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 47, 48, and 49, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 57, and 58, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 64, and 65, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 72, 73, and 74, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 79, 80, and 81, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 3, 88, and 89, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 94, and 95, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 100, 101, and 102, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 64, and 65, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 111, and 112, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 118, 119, and 120, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 126, 127, and 128, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 134, 135, and 136, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 142, and 143, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 150, 151, and 152, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 156, 157, and 158, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 164, and 165, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 170, 171, and 172, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 178, 179, and 180, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 188, and 189, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 194, 135, and 195, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 199, 200, and 201, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 207, 208, and 209, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 214, 215, and 216, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 223, 224, and 225, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 231, 232, and 233, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 237, 135, and 238, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 242, 243, and 244, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 248, 249, and 250, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 199, 256, and 257, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 262, 263, and 264, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 270, 271, and 272, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 276, 277, and 278, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 284, 285, and 286, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 291, 30, and 292, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 296, 297, and 298, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 302, 135, and 303, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 308, 157, and 309, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 313, 314, and 315, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 321, 322, and 323, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 328, 249, and 329, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 333, and 334, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 303, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 342, 343, and 344, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 349, 350, and 351, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 358, 359, and 360, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 365, 366, and 367, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 358, 373, and 374, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 378, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 242, 243, and 383, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 386, 387, and 388, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 358, 392, and 393, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 276, 396, and 397, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 4, and 400, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 403, 404, and 405, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 126, 409, and 410, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 414, 13, and 415, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 199, 419, and 420, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 207, 208, and 424, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 427, and 428, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 432, 249, and 433, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 437, 142, and 438, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 178, 441, and 442, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 446, 447, and 448, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 386, 387, and 452, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 457, 458, and 459, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 464, 465, and 466, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 472, 473, and 474, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 64, and 480, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 483, and 484, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 489, 490, and 491, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 497, and 498, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 502, 503, and 504, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 142, and 507, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 502, 503, and 510, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 513, 514, and 515, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 521, and 522, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 527, 528, and 529, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 535, 350, and 536, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 542, 543, and 544, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 548, 387, and 549, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 553, and 554, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 262, 263, and 560, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 563, 564, and 565, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 570, 249, and 571, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 576, and 577, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 403, 404, and 581, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 585, and 586, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 591, 592, and 593, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 599, 600, and 601, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 605, 135, and 606, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 610, 611, and 612, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 248, 249, and 617, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 622, 623, and 624, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 630, 631, and 632, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 638, 639, and 640, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 645, 387, and 646, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 650, 88, and 651, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 262, 263, and 654, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 658, 543, and 659, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 387, and 646, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 585, and 667, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 674, and 675, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 679, 680, and 681, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 686, 687, and 688, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 693, 157, and 694, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 698, and 699, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 242, 243, and 704, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 502, 366, and 708, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 527, 543, and 711, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 716, and 717, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 724, and 725, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 728, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 734, 585, and 735, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 740, 119, and 741, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 744, 543, and 745, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 387, and 750, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 754, 755, and 756, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 761, 208, and 762, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 765, 497, and 766, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 769, 770, and 771, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 775, 776, and 777, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 782, 30, and 783, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 786, 787, and 788, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 794, 30, and 795, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 798, 799, and 800, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 804, 30, and 805, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 693, 809, and 810, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 816, 135, and 817, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 821, and 822, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 403, 404, and 826, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 829, 830, and 831, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 837, 64, and 838, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 842, 843, and 844, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 387, and 646, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 850, 851, and 852, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 520, 387, and 856, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 860, 861, and 862, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 867, 868, and 869, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 542, 875, and 876, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 881, 387, and 882, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 888, 889, and 890, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 895, 208, and 303, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 126, 899, and 900, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 904, 905, and 906, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 610, 910, and 911, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 645, 915, and 916, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 919, 920, and 921, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 291, 30, and 924, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 929, 930, and 931, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 935, 151, and 936, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 270, 940, and 941, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 12, 947, and 948, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 953, and 954, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 94, and 959, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 4, and 963, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 432, 249, and 966, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 929, 930, and 931, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 935, 151, and 936, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 953, and 970, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 974, and 975, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 979, 980, and 981, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 151, and 986, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 990, 991, and 992, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 995, 770, and 996, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 308, 1000, and 1001, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 94, and 1005, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1009, 1010, and 1011, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1017, 64, and 1018, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 1023, and 1024, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1028, 94, and 1029, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 56, 333, and 1032, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1036, 249, and 1037, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 953, and 1042, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 64, and 1046, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1049, 1050, and 1051, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1058, 387, and 1059, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1062, 1063, and 1064, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1070, 441, and 1071, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 457, 458, and 1076, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1082, 208, and 1083, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 457, 1087, and 1088, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1091, 208, and 1092, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1062, 1095, and 1096, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1101, 1102, and 1103, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1109, 4, and 1110, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1115, 1116, and 1117, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1123, 1124, and 1125, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1130, 1131, and 1132, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 610, 1137, and 1138, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1142, 1143, and 1144, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 142, and 1149, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1152, 249, and 1153, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1157, 1158, and 1159, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1165, 1166, and 1167, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1171, 1172, and 1173, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 248, 249, and 1179, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1184, 1185, and 1186, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1191, 1192, and 1193, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 126, 127, and 1199, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 1202, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1205, 1206, and 1207, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 1211, and 1212, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1216, 1217, and 1218, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 350, and 1222, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1226, 1227, and 1228, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 1232, and 1222, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1235, 1236, and 1237, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1243, 592, and 1244, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1249, 1250, and 1251, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 570, 249, and 1255, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1258, 1259, and 1260, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 769, 1265, and 1266, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1205, 1206, and 1207, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 1211, and 1212, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1272, 1273, and 1274, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 1280, and 1281, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1184, 1185, and 1186, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1191, 1192, and 1193, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1216, 1217, and 1218, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 350, and 1222, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 72, 1286, and 1287, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1293, 30, and 1294, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1299, 1300, and 1301, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 151, and 1306, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1311, 4, and 1312, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 816, 135, and 1318, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1226, 1227, and 1228, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 673, 1232, and 1222, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1258, 1259, and 1260, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 769, 1265, and 1266, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1321, 1322, and 1323, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1329, 1330, and 1331, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1321, 1322, and 1323, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1329, 1330, and 1331, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1272, 1273, and 1274, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 1280, and 1281, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 72, 1286, and 1287, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1293, 30, and 1294, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1335, 1336, and 1337, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1342, 1343, and 1344, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1350, 1351, and 1352, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1359, 30, and 1360, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 585, and 1363, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 151, and 1366, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1369, 1370, and 1371, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 1375, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 187, 585, and 1363, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 151, and 1366, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1378, 1379, and 1380, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1385, 441, and 1386, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1389, 953, and 1390, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1395, 1396, and 1397, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1369, 1370, and 1371, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 135, and 1375, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 141, 142, and 1149, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1152, 249, and 1153, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1402, 1403, and 1404, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1036, 249, and 1408, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1378, 1379, and 1380, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1385, 441, and 1386, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1184, 1185, and 1186, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1191, 1192, and 1193, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1389, 953, and 1390, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1395, 1396, and 1397, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1412, 1413, and 1414, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1395, 94, and 1419, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 199, 1422, and 1423, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1428, 1429, and 1430, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 798, 1436, and 1437, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1442, 208, and 1443, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1447, 473, and 1448, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 151, and 1454, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1457, 1458, and 1459, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1464, 1465, and 1466, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1472, 1473, and 1474, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1478, 119, and 1479, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1482, 1483, and 1484, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 338, 1143, and 1488, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1492, 243, and 1493, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1497, 1498, and 1499, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1505, 953, and 1506, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 63, 592, and 1511, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1515, 1516, and 1517, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1522, 1523, and 1524, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1235, 1529, and 1530, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1535, 1536, and 1537, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 358, 392, and 1543, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1547, 770, and 1548, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1551, 1552, and 1553, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1558, 249, and 1559, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1565, 1566, and 1567, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1572, 1573, and 1574, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1579, 1580, and 1581, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1585, 135, and 1586, respectively.


The disclosure describes an antibody, antigen binding fragment, or polypeptide comprising a heavy chain variable region having a HCDR1, HCDR2, and HCDR3, and a light chain variable region having a LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 comprises an amino acid sequence of SEQ ID NOS: 1590, 1591, and 1592, respectively and the LCDR1, LCDR2, and LCDR3 comprises an amino acid sequence of SEQ ID NOS: 1599, 135, and 1600, respectively.


The disclosure also describes a heavy and light chain comprising the sequences of SEQ ID NO: 1 and SEQ ID NO: 10; SEQ ID NO:19 and SEQ ID NO:27; SEQ ID NO:36 and SEQ ID NO: 45; SEQ ID NO:54 and SEQ ID NO:61; SEQ ID NO: 70 and SEQ ID NO:77; SEQ ID NO:86 and SEQ ID NO:92; SEQ ID NO:98 and SEQ ID NO: 107; SEQ ID NO: 109 and SEQ ID NO: 116; SEQ ID NO: 124 and SEQ ID NO: 132; SEQ ID NO:139 and SEQ ID NO:148; SEQ ID NO:154 and SEQ ID NO:162; SEQ ID NO:168 and SEQ ID NO:176; SEQ ID NO: 185 and SEQ ID NO: 192; SEQ ID NO: 197 and SEQ ID NO:205; SEQ ID NO:212 and SEQ ID NO:221; SEQ ID NO: 229 and SEQ ID NO:235; SEQ ID NO:240 and SEQ ID NO:246; SEQ ID NO:254 and SEQ ID NO: 260; SEQ ID NO:268 and SEQ ID NO:274; SEQ ID NO:282 and SEQ ID NO:289; SEQ ID NO: 294 and SEQ ID NO:300; SEQ ID NO:306 and SEQ ID NO:311; SEQ ID NO:319 and SEQ ID NO:326; SEQ ID NO:331 and SEQ ID NO:336; SEQ ID NO:340 and SEQ ID NO:347; SEQ ID NO:356 and SEQ ID NO:363; SEQ ID NO:371 and SEQ ID NO:376; SEQ ID NO:381 and SEQ ID NO:384; SEQ ID NO:390 and SEQ ID NO:394; SEQ ID NO:398 and SEQ ID NO: 401; SEQ ID NO:407 and SEQ ID NO:412; SEQ ID NO:417 and SEQ ID NO:422; SEQ ID NO: 425 and SEQ ID NO:430; SEQ ID NO: 435 and SEQ ID NO: 439; SEQ ID NO:444 and SEQ ID NO: 450; SEQ ID NO:455 and SEQ ID NO:462; SEQ ID NO:470 and SEQ ID NO:478; SEQ ID NO: 481 and SEQ ID NO:487; SEQ ID NO:495 and SEQ ID NO:500; SEQ ID NO:505 and SEQ ID NO:508; SEQ ID NO:511 and SEQ ID NO:518; SEQ ID NO:525 and SEQ ID NO:533; SEQ ID NO:540 and SEQ ID NO:546; SEQ ID NO:551 and SEQ ID NO:558; SEQ ID NO:561 and SEQ ID NO:568; SEQ ID NO:574 and SEQ ID NO:579; SEQ ID NO:583 and SEQ ID NO: 589; SEQ ID NO:597 and SEQ ID NO:603; SEQ ID NO:608 and SEQ ID NO:615; SEQ ID NO: 620 and SEQ ID NO: 628; SEQ ID NO:636 and SEQ ID NO:643; SEQ ID NO:648 and SEQ ID NO: 652; SEQ ID NO:656 and SEQ ID NO:662; SEQ ID NO:665 and SEQ ID NO:671; SEQ ID NO: 677 and SEQ ID NO:684; SEQ ID NO:691 and SEQ ID NO:696; SEQ ID NO: 702 and SEQ ID NO:706; SEQ ID NO:709 and SEQ ID NO:714; SEQ ID NO:722 and SEQ ID NO:726; SEQ ID NO: 732 and SEQ ID NO: 738; SEQ ID NO: 742 and SEQ ID NO:748; SEQ ID NO:752 and SEQ ID NO:759; SEQ ID NO:763 and SEQ ID NO:767; SEQ ID NO:773 and SEQ ID NO: 780; SEQ ID NO: 784 and SEQ ID NO: 792; SEQ ID NO: 796 and SEQ ID NO:802; SEQ ID NO: 807 and SEQ ID NO:814; SEQ ID NO:819 and SEQ ID NO: 824; SEQ ID NO:827 and SEQ ID NO: 835; SEQ ID NO:840 and SEQ ID NO:846; SEQ ID NO:848 and SEQ ID NO:854; SEQ ID NO: 858 and SEQ ID NO:865; SEQ ID NO:873 and SEQ ID NO:879; SEQ ID NO:886 and SEQ ID NO:893; SEQ ID NO:897 and SEQ ID NO:902; SEQ ID NO:908 and SEQ ID NO:913; SEQ ID NO:917 and SEQ ID NO:922; SEQ ID NO:927 and SEQ ID NO:933; SEQ ID NO:938 and SEQ ID NO:945; SEQ ID NO:951 and SEQ ID NO:957; SEQ ID NO:961 and SEQ ID NO: 964; SEQ ID NO: 927 and SEQ ID NO:933; SEQ ID NO:968 and SEQ ID NO:972; SEQ ID NO: 977 and SEQ ID NO: 984; SEQ ID NO: 988 and SEQ ID NO: 993; SEQ ID NO:998 and SEQ ID NO: 1003; SEQ ID NO: 1007 and SEQ ID NO:1015; SEQ ID NO:1021 and SEQ ID NO:1026; SEQ ID NO:1030 and SEQ ID NO:1034; SEQ ID NO: 1040 and SEQ ID NO: 1044; SEQ ID NO: 1047 and SEQ ID NO: 1056; SEQ ID NO: 1060 and SEQ ID NO: 1068; SEQ ID NO: 1074 and SEQ ID NO:1080; SEQ ID NO: 1085 and SEQ ID NO: 1089; SEQ ID NO: 1093 and SEQ ID NO: 1099; SEQ ID NO: 1107 and SEQ ID NO: 1113; SEQ ID NO: 1121 and SEQ ID NO:1128; SEQ ID NO:1135 and SEQ ID NO:1140; SEQ ID NO:1147 and SEQ ID NO: 1150; SEQ ID NO: 1155 and SEQ ID NO:1163; SEQ ID NO:1169 and SEQ ID NO: 1177; SEQ ID NO: 1182 and SEQ ID NO: 1189; SEQ ID NO:1197 and SEQ ID NO: 1200; SEQ ID NO:1203 and SEQ ID NO: 1209; SEQ ID NO: 1214 and SEQ ID NO: 1220; SEQ ID NO: 1224 and SEQ ID NO: 1230; SEQ ID NO: 1233 and SEQ ID NO: 1241; SEQ ID NO:1247 and SEQ ID NO: 1253; SEQ ID NO: 1256 and SEQ ID NO: 1263; SEQ ID NO: 1203 and SEQ ID NO: 1209; SEQ ID NO: 1270 and SEQ ID NO:1278; SEQ ID NO: 1182 and SEQ ID NO:1189; SEQ ID NO: 1214 and SEQ ID NO: 1220; SEQ ID NO: 1284 and SEQ ID NO: 1291; SEQ ID NO: 1297 and SEQ ID NO: 1304; SEQ ID NO:1309 and SEQ ID NO:1316; SEQ ID NO:1224 and SEQ ID NO: 1230; SEQ ID NO: 1256 and SEQ ID NO: 1263; SEQ ID NO: 1319 and SEQ ID NO: 1327; SEQ ID NO: 1319 and SEQ ID NO:1327; SEQ ID NO:1270 and SEQ ID NO:1278; SEQ ID NO:1284 and SEQ ID NO: 1291; SEQ ID NO: 1333 and SEQ ID NO: 1340; SEQ ID NO: 1348 and SEQ ID NO: 1357; SEQ ID NO:1361 and SEQ ID NO: 1364; SEQ ID NO:1367 and SEQ ID NO: 1374; SEQ ID NO: 1361 and SEQ ID NO: 1364; SEQ ID NO: 1376 and SEQ ID NO: 1383; SEQ ID NO: 1387 and SEQ ID NO: 1393; SEQ ID NO: 1367 and SEQ ID NO: 1374; SEQ ID NO:1147 and SEQ ID NO: 1150; SEQ ID NO:1400 and SEQ ID NO:1406; SEQ ID NO:1376 and SEQ ID NO:1383; SEQ ID NO:1182 and SEQ ID NO:1189; SEQ ID NO: 1387 and SEQ ID NO: 1393; SEQ ID NO: 1410 and SEQ ID NO: 1417; SEQ ID NO: 1420 and SEQ ID NO: 1426; SEQ ID NO: 1434 and SEQ ID NO: 1440; SEQ ID NO:1445 and SEQ ID NO:1452; SEQ ID NO: 1455 and SEQ ID NO: 1462; SEQ ID NO: 1470 and SEQ ID NO: 1476; SEQ ID NO: 1480 and SEQ ID NO: 1486; SEQ ID NO: 1490 and SEQ ID NO: 1495; SEQ ID NO: 1503 and SEQ ID NO: 1509; SEQ ID NO: 1513 and SEQ ID NO: 1520; SEQ ID NO: 1527 and SEQ ID NO: 1533; SEQ ID NO: 1541 and SEQ ID NO: 1545; SEQ ID NO: 1549 and SEQ ID NO:1556; SEQ ID NO: 1563 and SEQ ID NO: 1570; SEQ ID NO: 1577 and SEQ ID NO: 1583; or SEQ ID NO: 1588 and SEQ ID NO: 1597.


The disclosure also describes a heavy and light chain comprising the sequences of SEQ ID NO: 2 and SEQ ID NO: 11; SEQ ID NO:20 and SEQ ID NO:28; SEQ ID NO:37 and SEQ ID NO: 46; SEQ ID NO:55 and SEQ ID NO:62; SEQ ID NO: 71 and SEQ ID NO: 78; SEQ ID NO:87 and SEQ ID NO: 93; SEQ ID NO:99 and SEQ ID NO: 108; SEQ ID NO: 110 and SEQ ID NO: 117; SEQ ID NO: 125 and SEQ ID NO: 133; SEQ ID NO: 140 and SEQ ID NO:149; SEQ ID NO: 155 and SEQ ID NO:163; SEQ ID NO:169 and SEQ ID NO:177; SEQ ID NO: 186 and SEQ ID NO: 193; SEQ ID NO: 198 and SEQ ID NO:206; SEQ ID NO:213 and SEQ ID NO:222; SEQ ID NO: 230 and SEQ ID NO:236; SEQ ID NO:241 and SEQ ID NO:247; SEQ ID NO:255 and SEQ ID NO: 261; SEQ ID NO:269 and SEQ ID NO:275; SEQ ID NO:283 and SEQ ID NO:290; SEQ ID NO: 295 and SEQ ID NO:301; SEQ ID NO:307 and SEQ ID NO:312; SEQ ID NO:320 and SEQ ID NO:327; SEQ ID NO:332 and SEQ ID NO:337; SEQ ID NO:341 and SEQ ID NO:348; SEQ ID NO:357 and SEQ ID NO:364; SEQ ID NO:372 and SEQ ID NO:377; SEQ ID NO:382 and SEQ ID NO:385; SEQ ID NO:391 and SEQ ID NO:395; SEQ ID NO:399 and SEQ ID NO: 402; SEQ ID NO:408 and SEQ ID NO:413; SEQ ID NO:418 and SEQ ID NO:423; SEQ ID NO: 426 and SEQ ID NO:431; SEQ ID NO:436 and SEQ ID NO:440; SEQ ID NO:445 and SEQ ID NO: 451; SEQ ID NO:456 and SEQ ID NO:463; SEQ ID NO:471 and SEQ ID NO:479; SEQ ID NO: 482 and SEQ ID NO:488; SEQ ID NO:496 and SEQ ID NO:501; SEQ ID NO:506 and SEQ ID NO:509; SEQ ID NO:512 and SEQ ID NO:519; SEQ ID NO:526 and SEQ ID NO:534; SEQ ID NO:541 and SEQ ID NO:547; SEQ ID NO:552 and SEQ ID NO:559; SEQ ID NO:562 and SEQ ID NO:569; SEQ ID NO:575 and SEQ ID NO:580; SEQ ID NO:584 and SEQ ID NO: 590; SEQ ID NO:598 and SEQ ID NO:604; SEQ ID NO:609 and SEQ ID NO:616; SEQ ID NO: 621 and SEQ ID NO: 629; SEQ ID NO: 637 and SEQ ID NO: 644; SEQ ID NO:649 and SEQ ID NO: 653; SEQ ID NO:657 and SEQ ID NO:663; SEQ ID NO:666 and SEQ ID NO:672; SEQ ID NO: 678 and SEQ ID NO:685; SEQ ID NO: 692 and SEQ ID NO:697; SEQ ID NO:703 and SEQ ID NO: 707; SEQ ID NO:710 and SEQ ID NO:715; SEQ ID NO:723 and SEQ ID NO:727; SEQ ID NO: 733 and SEQ ID NO: 739; SEQ ID NO: 743 and SEQ ID NO:749; SEQ ID NO: 753 and SEQ ID NO:760; SEQ ID NO:764 and SEQ ID NO: 768; SEQ ID NO:774 and SEQ ID NO: 781; SEQ ID NO: 785 and SEQ ID NO: 793; SEQ ID NO: 797 and SEQ ID NO:803; SEQ ID NO: 808 and SEQ ID NO:815; SEQ ID NO: 820 and SEQ ID NO:825; SEQ ID NO:828 and SEQ ID NO: 836; SEQ ID NO:841 and SEQ ID NO:847; SEQ ID NO:849 and SEQ ID NO:855; SEQ ID NO: 859 and SEQ ID NO:866; SEQ ID NO:874 and SEQ ID NO:880; SEQ ID NO:887 and SEQ ID NO:894; SEQ ID NO: 898 and SEQ ID NO: 903; SEQ ID NO:909 and SEQ ID NO:914; SEQ ID NO:918 and SEQ ID NO:923; SEQ ID NO: 928 and SEQ ID NO:934; SEQ ID NO:939 and SEQ ID NO:946; SEQ ID NO:952 and SEQ ID NO:958; SEQ ID NO:962 and SEQ ID NO: 965; SEQ ID NO:928 and SEQ ID NO: 934; SEQ ID NO: 969 and SEQ ID NO:973; SEQ ID NO: 978 and SEQ ID NO: 985; SEQ ID NO:989 and SEQ ID NO: 994; SEQ ID NO: 999 and SEQ ID NO: 1004; SEQ ID NO:1008 and SEQ ID NO:1016; SEQ ID NO: 1022 and SEQ ID NO:1027; SEQ ID NO: 1031 and SEQ ID NO: 1035; SEQ ID NO: 1041 and SEQ ID NO: 1045; SEQ ID NO: 1048 and SEQ ID NO: 1057; SEQ ID NO: 1061 and SEQ ID NO: 1069; SEQ ID NO: 1075 and SEQ ID NO:1081; SEQ ID NO:1086 and SEQ ID NO:1090; SEQ ID NO:1094 and SEQ ID NO: 1100; SEQ ID NO: 1108 and SEQ ID NO:1114; SEQ ID NO: 1122 and SEQ ID NO:1129; SEQ ID NO:1136 and SEQ ID NO:1141; SEQ ID NO: 1148 and SEQ ID NO:1151; SEQ ID NO: 1156 and SEQ ID NO: 1164; SEQ ID NO: 1170 and SEQ ID NO: 1178; SEQ ID NO: 1183 and SEQ ID NO:1190; SEQ ID NO:1198 and SEQ ID NO: 1201; SEQ ID NO: 1204 and SEQ ID NO: 1210; SEQ ID NO: 1215 and SEQ ID NO: 1221; SEQ ID NO: 1225 and SEQ ID NO: 1231; SEQ ID NO:1234 and SEQ ID NO: 1242; SEQ ID NO: 1248 and SEQ ID NO: 1254; SEQ ID NO: 1257 and SEQ ID NO: 1264; SEQ ID NO: 1204 and SEQ ID NO: 1210; SEQ ID NO: 1271 and SEQ ID NO:1279; SEQ ID NO:1183 and SEQ ID NO: 1190; SEQ ID NO: 1215 and SEQ ID NO: 1221; SEQ ID NO: 1285 and SEQ ID NO: 1292; SEQ ID NO: 1298 and SEQ ID NO: 1305; SEQ ID NO:1310 and SEQ ID NO:1317; SEQ ID NO:1225 and SEQ ID NO: 1231; SEQ ID NO: 1257 and SEQ ID NO: 1264; SEQ ID NO: 1320 and SEQ ID NO: 1328; SEQ ID NO: 1320 and SEQ ID NO:1328; SEQ ID NO: 1271 and SEQ ID NO: 1279; SEQ ID NO: 1285 and SEQ ID NO: 1292; SEQ ID NO: 1334 and SEQ ID NO: 1341; SEQ ID NO: 1349 and SEQ ID NO: 1358; SEQ ID NO:1362 and SEQ ID NO:1365; SEQ ID NO: 1368 and SEQ ID NO: 1201; SEQ ID NO: 1362 and SEQ ID NO: 1365; SEQ ID NO: 1377 and SEQ ID NO: 1384; SEQ ID NO: 1388 and SEQ ID NO:1394; SEQ ID NO:1368 and SEQ ID NO: 1201; SEQ ID NO: 1148 and SEQ ID NO: 1151; SEQ ID NO:1401 and SEQ ID NO:1407; SEQ ID NO:1377 and SEQ ID NO:1384; SEQ ID NO:1183 and SEQ ID NO:1190; SEQ ID NO: 1388 and SEQ ID NO:1394; SEQ ID NO: 1411 and SEQ ID NO: 1418; SEQ ID NO: 1421 and SEQ ID NO: 1427; SEQ ID NO: 1435 and SEQ ID NO:1441; SEQ ID NO: 1446 and SEQ ID NO:1453; SEQ ID NO: 1456 and SEQ ID NO: 1463; SEQ ID NO: 1471 and SEQ ID NO: 1477; SEQ ID NO: 1481 and SEQ ID NO: 1487; SEQ ID NO:1491 and SEQ ID NO: 1496; SEQ ID NO: 1504 and SEQ ID NO: 1510; SEQ ID NO: 1514 and SEQ ID NO: 1521; SEQ ID NO: 1528 and SEQ ID NO: 1534; SEQ ID NO: 1542 and SEQ ID NO:1546; SEQ ID NO:1550 and SEQ ID NO:1557; SEQ ID NO:1564 and SEQ ID NO: 1571; SEQ ID NO: 1578 and SEQ ID NO: 1584; or SEQ ID NO: 1589 and SEQ ID NO: 1598.


“Treatment” or treating may refer to any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition prior to the induction of the disease; (ii) suppressing the disease, that is, causing the clinical symptoms of the disease not to develop by administration of a protective composition after the inductive event but prior to the clinical appearance or reappearance of the disease; (iii) inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a protective composition after their initial appearance; and/or (iv) relieving the disease, that is, causing the regression of clinical symptoms by administration of a protective composition after their initial appearance. The treatment may exclude prevention of the disease.


Throughout this application, the term “about” is used according to its plain and ordinary meaning in the area of cell and molecular biology to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.


The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”


As used herein, the terms “or” and “and/or” are utilized to describe multiple components in combination or exclusive of one another. For example, “x, y, and/or z” can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.” It is specifically contemplated that x, y, or z may be specifically excluded from an embodiment or aspect.


The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), “characterized by” (and any form of including, such as “characterized as”), or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.


The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of” any of the ingredients or steps disclosed throughout the specification. The phrase “consisting of” excludes any element, step, or ingredient not specified. The phrase “consisting essentially of” limits the scope of described subject matter to the specified materials or steps and those that do not materially affect its basic and novel characteristics. It is contemplated that embodiments and aspects described in the context of the term “comprising” may also be implemented in the context of the term “consisting of” or “consisting essentially of.”


Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “Use of” any compound, composition, or agent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.


Use of the one or more sequences or compositions may be employed based on any of the methods described herein. Other embodiments are discussed throughout this application. Any embodiment or aspect discussed with respect to one aspect of the disclosure applies to other aspects of the disclosure as well and vice versa.


It is specifically contemplated that any limitation discussed with respect to one embodiment or aspect of the invention may apply to any other embodiment or aspect of the invention. Furthermore, any composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any composition of the invention. Aspects of an embodiment set forth in the Examples are also embodiments that may be implemented in the context of embodiments discussed elsewhere in a different Example or elsewhere in the application, such as in the Summary, Detailed Description, Claims, and description of Figure Legends.


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 and aspects 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 DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.



FIGS. 1A-C. Analyses of serum antibody responses in COVID-19 convalescent individuals. a, b, Total IgG endpoint antibody titers from 10 convalescent subjects against SARS-CoV-2 full-length spike variants (a) and RBD recombinant antigens (b). Dashed line is the mean IgG titer. c, Neutralization titers from 10 convalescent donors against WT SARS-CoV-2, B.1.1.7, P.1, B.1.617.2 and B.1.617.1. Dashed line represents the mean neutralization titer. Data in a-c were analyzed using non-parametric Friedman's test with Dunnett's multiple comparison test. Fold-change in relative mAb binding to variants or mutants compared to WT in a and b are indicated above the statistical asterisks.



FIGS. 2A-I. a, b, Uniform manifold approximation and projection (UMAP) of SARS-CoV-2 spike non-RBD binding (a) and spike RBD binding B cells (b) isolated from the PBMCs of 10 convalescent subjects. c, The proportion of spike non-RBD and spike RBD specific binding B cells. The number in center of pie chart indicates the number of antigen-specific binding B cells. d, mAbs generated from selected B cells (n=43) were tested for binding to full-length spike, S1, S2, and RBD and neutralization potential against WT SARS-CoV-2. Binding data are represented as area under the curve (AUC). Neutralizing activity less than 10,000 ng/ml are considered neutralizing. e, f, Pie charts of mAbs domain specificity (e) and neutralizing capability (f). Number in the center of pie graphs indicate the number of antibodies tested. g, Comparison of neutralizing capability of mAbs targeting spike RBD and spike non-RBD. h and i, IC50 of neutralization potency of spike-reactive antibodies against WT virus based on domain specificity (h) and by subject (i). Mean in h indicated as a solid line. Dashed lines shown in h and i indicate limit of detection (10,000 ng/mL). Data in d-i are representative of two independent experiment performed in duplicate. Genetic characterization of each mAb is further detailed in Extended Data Table 2 (Example 1).



FIG. 3A-H. Binding breadth and neutralization of spike non-RBD mAbs. a, Full-length spike protein binding to ACE2 (a; PDB: 7KJ2). b-g, Locations of mutations found on B.1.1.7 (b), B.1.351 (c), P.1 (d), B.1.617.2 (e), B.1.526 (f) and B.1.617.1 (g). (b-g; modified from PDB: 6XM4). h, The binding reactivity and neutralization capabilities of NTA-A, NTD-B and S2 reactive mAbs. The color gradients indicate percentage of relative binding compared to WT spike. The neutralization potency (IC50) of spike-non RBD mAbs against WT, B.1.1.7, P.1, B.1.617.2 and B.1.617.1 variants are indicated as ng/ml. The panel of SARS-CoV-2 viruses are detailed in Extended Data Table 4 (Example 1). Data in h are representative of two independent experiments performed in duplicate. Genetic information for each mAb is in Extended Data Table 2 (Example 1).



FIG. 4A-C. Binding and neutralization profiles of RBD-binding 2 mAbs against a panel of RBD escape mutants and variants. a, Structural model of RBD “up” binding with ACE2 (a; PDB: 7KJ2) and RBD antibody classes and associated escape mutants. b, RBD is colored by antibody classes and associated mutations. c, Heatmap detailing binding reactivity of RBD mAbs (n=29) against single key escape sites for class 1, class 2 and class 3 antibodies, combinations of RBD mutants, and RBD from SARS-CoV-1 and MERS-CoV. Abbreviation of a refers to class-3 like antibodies, which are defined by mAbs that compete with a class 3 mAb (Extended Data FIG. 2c). Abbreviations b-f refer to mutations in the RBD of each full length spike variant, B.1.1.7 with N501Y (b), B.1.351 with K417N:E484K:N501Y (c), P.1 with K417T:E484K:N501Y (d), B.1.617.2 with T478K: L452R (e), B.1.526 with E484K (f) and B.1.617.1 with L452R:E484Q (g). The panel of recombinant antigens in c are detailed in Extended Data Table 3 (Example 1), including mutations found in circulating SARS-CoV-2 variants (bold), the mutations that escape/reduce binding by polyclonal serum/potent neutralizing mAbs (italic), the mutations found in both circulating SARS-CoV-2 variants and in vitro escape-map (bold+italic), and artificial mutants at key contact residues of the RBD-ACE2 interaction (normal typeface). The neutralization potency (IC50) of spike-RBD mAbs against WT, B.1.1.7, P.1, B.1.617.2 and B.1.617.1 variants are indicated as ng/ml. The panel of SARS-CoV-2 viruses are detailed in Extended Data Table 4 (Example 1). Data in c are representative of two independent experiments performed in duplicate. Genetic information for each antibody is in Extended Data Table 2 (Example 1).



FIG. 5A-I. MAb genetic, somatic hypermutation, and CDR3 length features. a-d, The distribution of V gene usage of spike-non RBD and spike RBD antibodies for all paired heavy (a, c) and light (b, d) chains. Percentage shown indicates proportion of the top 3 utilized genes. e, Clonal relationships between heavy and light chain variable gene locus of spike non-RBD and spike RBD-specific antibodies. Connecting lines represent the pairing of heavy and light chain of antibody clones specific to spike non-RBD or RBD and antibody clones shared between both groups (purple). f, g, Comparison of number of somatic hypermutations of heavy (f) and light chains (g) of spike non-RBD and spike RBD-binding B cells. h and i, The complementarity determining region 3 (CDR3) amino acid length for heavy (h) and light chains (i) of spike non-RBD and spike RBD-binding B cells. Median indicated as line in the box and whisker graph. Each dot represents an individual antibody with range from minimum to maximum value. Data in f-i were analyzed using Mann-Whitney non-parametric test.



FIG. 6A-E. MAb binding competition by ELISA and BLI and serum competition by ELISA. a, Competition ELISA of RBD mAbs of spike non-RBD mAbs with NTD-A (S451-11) and NTD-B (S305-1456). b, Competition ELISA of RBD mAbs of undetermined class with class 2 mAbs (S144-1079 and S564-138) and class 3 mAb (S24-821). c, MAb binding competition by BLI of class 2 mAb, S144-1406, with the other class 2 mAbs (n=4) that did not neutralize P.1. d, MAb binding competition by BLI between class 4 mAbs that utilized VH5-51 (S144-466, S144-509, S144 and S144-69) with CR3022. e, EC50 of serum antibodies of 10 convalescent subjects competing with RBD-reactive mAbs for binding to RBD class 2, class 3 and class 3-like epitopes, and NTD-reactive mAbs for binding to NTD-B epitopes. Dashed line represents the limit of detection. Data in a-b and e are representative of two independent experiments performed in duplicate. Data in e were analyzed using nonparametric Friedman's test with Dunn's multiple comparison test.



FIG. 7A-B. Comparison of neutralization potency of SARS-CoV-2 neutralizing mAbs. a, Neutralization potency (IC50) of RBD-binding mAbs, class 2 and class 3, and NTD-B binding mAbs against WT SARS-CoV-2. b, Neutralization potency of each mAb from each subject against WT SARS-CoV-2, B.1.1.7, P.1, B.1.617.1 and B.1.617.2. Each dot indicates one mAb. MAbs that neutralize VOCs are bolded. Data in a-c are representative of two independent experiments performed in duplicate. Data in a were analyzed using Mann-Whitney non-parametric test.



FIG. 8A-K. Proportion of SARS-CoV-2-specific B cells and characterization of RBD-reactive mAbs isolated from COVID-19 convalescent individuals. a-b, Uniform manifold approximation and projection (UMAP) of SARS-CoV-2 (a) spike RBD binding and (b) spike non-RBD binding B cells isolated from convalescent subjects that could be characterized into 3 groups (high, mid and low responder) based on their serological response against SARS-CoV-2 spike. c, Proportion of spike non-RBD- and spike RBD-specific binding B cells representing in each responder group. d-e, Number of somatic hypermutations in the IGHV in antibodies targeting (d) RBD and (e) non-RBD. f, Binding profile of RBD-reactive mAbs against single RBD mutants associated with different antibody classes, a combinatorial RBD mutant, and the RBDs of SARS-CoV-1 and MERS-CoV. Color gradients indicate relative binding percentage compared to spike WT g, Neutralization potency measured by plaque assay (complete inhibitory concentration; IC99) and focus reduction neutralization test (FRNT; half inhibitory concentration; IC50) of RBD-reactive mAbs to SARS-CoV-2 variants and sarbecoviruses. Binding breadth against full-length spike SARS-CoV-2 variants determined by ELISA is shown for (h) S728-1157, (i) S451-1140, and (j) S626-161. k, Heatmap represents area under curve (AUC) fold-change of broadly neutralizing RBD-reactive mAbs against ectodomain spike SARS-CoV-2 variants relative to WT-2P and the differences of AUC fold-change between spike BA.1-2P relative to spike BA.1-6P. The statistical analysis in d-e was determined using Kruskal-Wallis with Dunn's multiple comparison test. Data in f-g and h-j are representative of two independent experiments performed in duplicate. Genetic information for each antibody is in Table S2 (Example 2). The SARS-CoV-2 viruses used in neutralization assay are indicated in Table S4 (Example 2).



FIG. 9A-D: Mechanism of broad neutralization of S728-1157. (a) Epitope binning of broadly neutralizing RBD-reactive mAbs. Heatmap demonstrating the percentage of competition between each RBD-reactive mAb from previous studies with three broadly neutralizing mAbs, S728-1157, S451-1140 and S626-161. Data are representative of two independent experiments performed in triplicate. (b) Surface representation of the model derived from the cryoEM map of spike WT-6P-Mut7 in complex with IgG S728-1157. Although the inventors observe full mAb occupancy in the cryo-EM map, only one Fv is shown here. (c) Structural comparison of S728-1157 to other RBS-A antibodies such as CC12.1 (PDB ID: 6XC2), CC12.3 (PDB ID: 6XC4), B38 (PDB ID: 7BZ5), and C105 (PDB ID: 6XCN). The heavy chains are a darker shade, and the light chains are a lighter shade. Omicron BA.1 mutations near the epitope interface are shown as spheres. (d) CDR-H3 forms distinct interactions with SARS-CoV-2 RBD between S728-1157 and CC12.3. Sequence alignment of CDR-H3 of the two antibodies are shown in the middle with non-conserved residues.



FIG. 10A-G: Protective efficacy of broadly neutralizing antibodies against SARS-CoV-2 infection in hamster. Schematic illustrating the in vivo experiment schedule (a). Lung and nasal turbinate (NT) viral replication SARS-CoV-2 are shown for hamster treated therapeutically with (b-d) S728-1157 (n=3) (e) S451-1140 (n=3) and (f-g) S626-161 (n=4) at day 4 post-challenge with SARS-CoV-2 compared with control mAb, anti-Ebola surface glycoprotein (KZ52) antibody. Dashed horizontal lines represent the limit of detection (LOD) of the experiment. P-values in (b-g) were calculated using Unpaired t-test. The infected SARS-CoV-2 viruses are detailed in Table S4 (Example 2).



FIG. 11A-K: Convalescent serum antibody competition with broadly neutralizing RBD-reactive mAbs and comparison of serum antibody response against spike 6P-versus 2P-stabilized. Schematic diagram for experimental procedure of serum competitive ELISA (a). Half-maximal inhibitory concentration (EC50) of polyclonal antibody serum from convalescent individuals that could compete with broadly neutralizing mAbs (competitor mAb): S728-1157 (b), S451-1140 (c) and S626-161 (d), therapeutic neutralizing mAbs LY-CoV555 (e), REGN-10933 (f), non-neutralizing mAb CR3022 (g) and well-defined class 1 mAb CC12.3 (h). The reciprocal serum dilutions in b-h are showed as Log 1P of the IC50 of serum dilution that can achieve 50% competition with the competitor mAb of interest. The statistical analysis in b-h was determined using Kruskal-Wallis with Dunn's multiple comparison test. Representative three conformations of pre-fusion spike trimer antigen observed in the previous structural characterization of SARS-CoV-2 stabilized by 2P and 6P31,47 (i). Endpoint titer of convalescent sera against SARS-CoV-2 spike wildtype (WT) (j) and Omicron BA.1 (k) in two versions of spike substituted by 2P and 6P. Data in b-h and j-k are representative of two independent experiments performed in duplicate. Wilcoxon matched-pairs signed rank test was used to compare the anti-spike antibody titer against 2P and 6P in j-k. Fold change indicated in j-k is defined as the mean fold change.



FIG. 12: Amino acid and nucleotide sequences of complementarity-determining region (CDR) of heavy chain and light chain of the three bnAbs. Contacting residues within CDR of S728-1157 and SARS-CoV-2 are highlighted as light grey. Genetic information for each antibody is in Table S2 (Example 2). The sequences in the figure correspond to SEQ ID NO: 1883 (S728-1157 heavy chain amino acid sequence), SEQ ID NO:1884 (S728-1157 heavy chain nucleotide sequence), SEQ ID NO:1885 (S728-1157 light chain amino acid sequence), SEQ ID NO:1886 (S728-1157 light chain nucleotide sequence), SEQ ID NO: 1887 (S451-1140 heavy chain amino acid sequence), SEQ ID NO:1888 (S451-1140 heavy chain nucleotide sequence), SEQ ID NO: 1889 (S451-1140 light chain amino acid sequence), SEQ ID NO: 1890 (S451-1140 light chain nucleotide sequence), SEQ ID NO: 1891 (S626-161 heavy chain amino acid sequence), SEQ ID NO: 1892 (S626-161 heavy chain nucleotide sequence), SEQ ID NO: 1893 (S626-161 light chain amino acid sequence), and SEQ ID NO: 1894 (S626-161 light chain nucleotide sequence).



FIG. 13A-D: Broadly neutralizing RBD-reactive mAbs activity against SARS-CoV-2 and emerging variants. a, Structural models for the full-length spike protein variants and amino acid substitutions that encoded in B.1.1.7 Alpha, B.1.351 Beta, P.1 Gamma, B.1.617.2 Delta and Omicron, BA.1, BA.2 and BA.4. The structural models in a are modified from PDB ID: 6XM4. b, The table illustrating the binding rate and equilibrium constants (kon, koff, and affinity binding KD) measured by BLI of S728-1157, S451-1140 and S626-161 IgG in response to the panel of SARS-CoV-2 VOCs (either former or current VOCs). c, The binding rate comparison of Fabs of S728-1157, S451-1140 and S626-161 in responding to spike WT-6P and 2P constructs. The binding traces of IgG and Fab analyzed by BLI were represented by the 1:2 and 1:1 interaction model, respectively. d, The fold-change of binding rate (Kon, Koff) and binding affinity (KD) between spike WT-6P and spike WT-2P bound by broadly neutralizing RBD-reactive mAbs, whole IgG form and Fab. Data in c-d are representative of two independent experiments, the data from experiments that have the best fit (R2>0.90) are selected for analysis.



FIG. 14A-F: Biolayer interferometry analysis demonstrates binding affinity curves of three broadly neutralizing mAbs competing with each other in response to biotinylated spike wildtype (WT)-6P (left panel) and spike BA.1 Omicron-6P (right panel). a-b, S626-161 was firstly bound, followed by S728-1157 mAb as competing mAb. c-d, S451-1140 was firstly bound and competed with S728-1157 and e-f, S626-161. The response curve was normalized in relation to its starting response value.



FIG. 15A-E. Structural analysis of S728-1157 binding to SARS-CoV-2 spike. (a) Three-dimensional (3D) reconstruction of Omicron BA.1-6P in complex with IgG S728-1157 shows binding by negative stain electron microscopy. The binding mode is the same as binding to spike WT-6P-Mut7 shown in FIG. 2b. (b) CDR-H1 of S728-1157 forms similar interactions with SARS-CoV-2 RBD compared to another IGHV3-53 antibody CC12.3 (PDB ID: 6XC4). (c) CDR-H2 of S728-1157 forms similar interactions with the RBD compared to CC12.3 (PDB ID: 6XC4). (d) For spike WT-6P-Mut7 in complex with S728-1157, residues Y505 and VL Q31, and E484 and VL Y99 are predicted to make hydrogen bonds. Hydrophobic residues Y486 and Y489 are shown as well. Since S728-1157 binds spike Omicron BA.1-6P in the same way as to spike WT-6P-Mut7, it may accommodate the E484A and Y505H mutations in Omicron. (e) Local resolution estimates of the cryo-EM map (upper panel) and local refinement on the RBD-Fv after symmetry expansion using RELION (lower panel).





DETAILED DESCRIPTION

Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, the inventors generated monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484 and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, they identified neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and the variants of concern, including B.1.1.7 (alpha), P.1 (gamma) and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to first pandemic wave of prototype SARS-CoV-2 do possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.


I. Antibodies

The disclosure relates to antibodies, antigen binding fragments thereof, or polypeptides capable of specifically binding to a SARS-CoV-2 spike(S) protein, NP protein, or ORF8. Also described are antibodies, or fragments thereof, that specifically bind to a receptor binding domain (RBD) of a SARS-CoV-2 spike protein.


The term “antibody” refers to an intact immunoglobulin of any isotype, or a fragment thereof that can compete with the intact antibody for specific binding to the target antigen, and includes chimeric, humanized, fully human, and bispecific antibodies. As used herein, the terms “antibody” or “immunoglobulin” are used interchangeably and refer to any of several classes of structurally related proteins that function as part of the immune response of an animal, including IgG, IgD, IgE, IgA, IgM, and related proteins, as well as polypeptides comprising antibody CDR domains that retain antigen-binding activity.


The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody. An antigen may possess one or more epitopes that are capable of interacting with different antibodies.


The term “epitope” includes any region or portion of molecule capable eliciting an immune response by binding to an immunoglobulin or to a T-cell receptor. Epitope determinants may include chemically active surface groups such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural characteristics and/or specific charge characteristics. Generally, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen within a complex mixture.


The epitope regions of a given polypeptide can be identified using many different epitope mapping techniques are well known in the art, including: x-ray crystallography, nuclear magnetic resonance spectroscopy, site-directed mutagenesis mapping, protein display arrays, see, e.g., Epitope Mapping Protocols, (Johan Rockberg and Johan Nilvebrant, Ed., 2018) Humana Press, New York, N.Y. Such techniques are known in the art and described in, e.g., U.S. Pat. No. 4,708,871; Geysen et al. Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984); Geysen et al. Proc. Natl. Acad. Sci. USA 82:178-182 (1985); Geysen et al. Molec. Immunol. 23:709-715 (1986). Additionally, antigenic regions of proteins can also be predicted and identified using standard antigenicity and hydropathy plots.


The term “immunogenic sequence” means a molecule that includes an amino acid sequence of at least one epitope such that the molecule is capable of stimulating the production of antibodies in an appropriate host. The term “immunogenic composition” means a composition that comprises at least one immunogenic molecule (e.g., an antigen or carbohydrate).


An intact antibody is generally composed of two full-length heavy chains and two full-length light chains, but in some instances may include fewer chains, such as antibodies naturally occurring in camelids that may comprise only heavy chains. Antibodies as disclosed herein may be derived solely from a single source or may be “chimeric,” that is, different portions of the antibody may be derived from two different antibodies. For example, the variable or CDR regions may be derived from a rat or murine source, while the constant region is derived from a different animal source, such as a human. The antibodies or binding fragments may be produced in hybridomas, by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact antibodies. Unless otherwise indicated, the term “antibody” includes derivatives, variants, fragments, and muteins thereof, examples of which are described below (Sela-Culang et al., Front Immunol. 2013; 4:302; 2013).


The term “light chain” includes a full-length light chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length light chain has a molecular weight of around 25,000 Daltons and includes a variable region domain (abbreviated herein as VL), and a constant region domain (abbreviated herein as CL). There are two classifications of light chains, identified as kappa (κ) and lambda (2). The term “VL fragment” means a fragment of the light chain of a monoclonal antibody that includes all or part of the light chain variable region, including CDRs. A VL fragment can further include light chain constant region sequences. The variable region domain of the light chain is at the amino-terminus of the polypeptide.


The term “heavy chain” includes a full-length heavy chain and fragments thereof having sufficient variable region sequence to confer binding specificity. A full-length heavy chain has a molecular weight of around 50,000 Daltons and includes a variable region domain (abbreviated herein as VH), and three constant region domains (abbreviated herein as CH1, CH2, and CH3). The term “VH fragment” means a fragment of the heavy chain of a monoclonal antibody that includes all or part of the heavy chain variable region, including CDRs. A VH fragment can further include heavy chain constant region sequences. The number of heavy chain constant region domains will depend on the isotype. The VH domain is at the amino-terminus of the polypeptide, and the CH domains are at the carboxy-terminus, with the CH3 being closest to the —COOH end. The isotype of an antibody can be IgM, IgD, IgG, IgA, or IgE and is defined by the heavy chains present of which there are five classifications: mu (μ), delta (δ), gamma (γ), alpha (α), or epsilon (ε) chains, respectively. IgG has several subtypes, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM subtypes include IgM1 and IgM2. IgA subtypes include IgA1 and IgA2.


A. Types of Antibodies

Antibodies can be whole immunoglobulins of any isotype or classification, chimeric antibodies, or hybrid antibodies with specificity to two or more antigens. They may also be fragments (e.g., F(ab′)2, Fab′, Fab, Fv, and the like), including hybrid fragments. An immunoglobulin also includes natural, synthetic, or genetically engineered proteins that act like an antibody by binding to specific antigens to form a complex. The term antibody includes genetically engineered or otherwise modified forms of immunoglobulins.


The term “monomer” means an antibody containing only one Ig unit. Monomers are the basic functional units of antibodies. The term “dimer” means an antibody containing two Ig units attached to one another via constant domains of the antibody heavy chains (the Fc, or fragment crystallizable, region). The complex may be stabilized by a joining (J) chain protein. The term “multimer” means an antibody containing more than two Ig units attached to one another via constant domains of the antibody heavy chains (the Fc region). The complex may be stabilized by a joining (J) chain protein.


The term “bivalent antibody” means an antibody that comprises two antigen-binding sites. The two binding sites may have the same antigen specificities or they may be bi-specific, meaning the two antigen-binding sites have different antigen specificities.


Bispecific antibodies are a class of antibodies that have two paratopes with different binding sites for two or more distinct epitopes. Bispecific antibodies can be biparatopic, wherein a bispecific antibody may specifically recognize a different epitope from the same antigen. Bispecific antibodies can be constructed from a pair of different single domain antibodies termed “nanobodies”. Single domain antibodies are sourced and modified from cartilaginous fish and camelids. Nanobodies can be joined together by a linker using techniques typical to a person skilled in the art; such methods for selection and joining of nanobodies are described in PCT Publication No. WO2015044386A1, No. WO2010037838A2, and Bever et al., Anal Chem. 86:7875-7882 (2014), each of which are specifically incorporated herein by reference in their entirety.


Bispecific antibodies can be constructed as: a whole IgG, Fab′2, Fab′PEG, a diabody, or alternatively as scFv. Diabodies and scFvs can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. Bispecific antibodies may be produced by a variety of methods including, but not limited to, fusion of hybridomas or linking of Fab′ fragments. See, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol. 79:315-321 (1990); Kostelny et al., J. Immunol. 148:1547-1553 (1992), each of which are specifically incorporated by reference in their entirety.


The antigen-binding domain may be multispecific or heterospecific by multimerizing with VH and VL region pairs that bind a different antigen. For example, the antibody may bind to, or interact with, (a) a cell surface antigen, (b) an Fc receptor on the surface of an effector cell, or (c) at least one other component. Accordingly, included are bispecific, trispecific, tetraspecific, and other multispecific antibodies or antigen-binding fragments thereof that are directed to epitopes and to other targets, such as Fc receptors on effector cells.


Multispecific antibodies can be used and directly linked via a short flexible polypeptide chain, using routine methods known in the art. One such example is diabodies that are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, and utilize a linker that is too short to allow for pairing between domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain creating two antigen binding sites. The linker functionality is applicable for triabodies, tetrabodies, and higher order antibody multimers. (see, e.g., Hollinger et al., Proc Natl. Acad. Sci. USA 90:6444-6448 (1993); Polijak et al., Structure 2:1121-1123 (1994); Todorovska et al., J. Immunol. Methods 248:47-66 (2001)).


Bispecific diabodies, as opposed to bispecific whole antibodies, may also be advantageous because they can be readily constructed and expressed in E. coli. Diabodies (and other polypeptides such as antibody fragments) of appropriate binding specificities can be readily selected using phage display (WO94/13804) from libraries. If one arm of the diabody is kept constant, for instance, with a specificity directed against a protein, then a library can be made where the other arm is varied and an antibody of appropriate specificity selected. Bispecific whole antibodies may be made by alternative engineering methods as described in Ridgeway et al., (Protein Eng., 9:616-621, 1996) and Krah et al., (N Biotechnol. 39:167-173, 2017), each of which is hereby incorporated by reference in their entirety.


Heteroconjugate antibodies are composed of two covalently linked monoclonal antibodies with different specificities. See, e.g., U.S. Pat. No. 6,010,902, incorporated herein by reference in its entirety.


The part of the Fv fragment of an antibody molecule that binds with high specificity to the epitope of the antigen is referred to herein as the “paratope.” The paratope consists of the amino acid residues that make contact with the epitope of an antigen to facilitate antigen recognition. Each of the two Fv fragments of an antibody is composed of the two variable domains, VH and VL, in dimerized configuration. The primary structure of each of the variable domains includes three hypervariable loops separated by, and flanked by, Framework Regions (FR). The hypervariable loops are the regions of highest primary sequences variability among the antibody molecules from any mammal. The term hypervariable loop is sometimes used interchangeably with the term “Complementarity Determining Region (CDR).” The length of the hypervariable loops (or CDRs) varies between antibody molecules. The framework regions of all antibody molecules from a given mammal have high primary sequence similarity/consensus. The consensus of framework regions can be used by one skilled in the art to identify both the framework regions and the hypervariable loops (or CDRs) which are interspersed among the framework regions. The hypervariable loops are given identifying names which distinguish their position within the polypeptide, and on which domain they occur. CDRs in the VL domain are identified as L1, L2, and L3, with L1 occurring at the most distal end and L3 occurring closest to the CL domain. The CDRs may also be given the names CDR-L1, CDR-L2, and CDR-L3. The L3 (CDR-L3) is generally the region of highest variability among all antibody molecules produced by a given organism. The CDRs are regions of the polypeptide chain arranged linearly in the primary structure, and separated from each other by Framework Regions. The amino terminal (N-terminal) end of the VL chain is named FR1. The region identified as FR2 occurs between L1 and L2 hypervariable loops. FR3 occurs between L2 and L3 hypervariable loops, and the FR4 region is closest to the CL domain. This structure and nomenclature is repeated for the VH chain, which includes three CDRs identified as CDR-H1, CDR-H2 and CDR-H3. The majority of amino acid residues in the variable domains, or Fv fragments (VH and VL), are part of the framework regions (approximately 85%). The three dimensional, or tertiary, structure of an antibody molecule is such that the framework regions are more internal to the molecule and provide the majority of the structure, with the CDRs on the external surface of the molecule.


Several methods have been developed and can be used by one skilled in the art to identify the exact amino acids that constitute each of these regions. This can be done using any of a number of multiple sequence alignment methods and algorithms, which identify the conserved amino acid residues that make up the framework regions, therefore identifying the CDRs that may vary in length but are located between framework regions. Three commonly used methods have been developed for identification of the CDRs of antibodies: Kabat (as described in T. T. Wu and E. A. Kabat, “AN ANALYSIS OF THE SEQUENCES OF THE VARIABLE REGIONS OF BENCE JONES PROTEINS AND MYELOMA LIGHT CHAINS AND THEIR IMPLICATIONS FOR ANTIBODY COMPLEMENTARITY,” J Exp Med, vol. 132, no. 2, pp. 211-250, August 1970); Chothia (as described in C. Chothia et al., “Conformations of immunoglobulin hypervariable regions,” Nature, vol. 342, no. 6252, pp. 877-883, December 1989); and IMGT (as described in M.-P. Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Developmental & Comparative Immunology, vol. 27, no. 1, pp. 55-77, January 2003). These methods each include unique numbering systems for the identification of the amino acid residues that constitute the variable regions. In most antibody molecules, the amino acid residues that actually contact the epitope of the antigen occur in the CDRs, although in some cases, residues within the framework regions contribute to antigen binding.


One skilled in the art can use any of several methods to determine the paratope of an antibody. These methods include:

    • 1) Computational predictions of the tertiary structure of the antibody/epitope binding interactions based on the chemical nature of the amino acid sequence of the antibody variable region and composition of the epitope.
    • 2) Hydrogen-deuterium exchange and mass spectroscopy
    • 3) Polypeptide fragmentation and peptide mapping approaches in which one generates multiple overlapping peptide fragments from the full length of the polypeptide and evaluates the binding affinity of these peptides for the epitope.
    • 4) Antibody Phage Display Library analysis in which the antibody Fab fragment encoding genes of the mammal are expressed by bacteriophage in such a way as to be incorporated into the coat of the phage. This population of Fab expressing phage are then allowed to interact with the antigen which has been immobilized or may be expressed in by a different exogenous expression system. Non-binding Fab fragments are washed away, thereby leaving only the specific binding Fab fragments attached to the antigen. The binding Fab fragments can be readily isolated and the genes which encode them determined. This approach can also be used for smaller regions of the Fab fragment including Fv fragments or specific VH and VL domains as appropriate.


Affinity matured antibodies may be enhanced with one or more modifications in one or more CDRs thereof that result in an improvement in the affinity of the antibody for a target antigen as compared to a parent antibody that does not possess those alteration(s). Certain affinity matured antibodies will have nanomolar or picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art, e.g., Marks et al., Bio/Technology 10:779 (1992) describes affinity maturation by VH and VL domain shuffling, random mutagenesis of CDR and/or framework residues employed in phage display is described by Rajpal et al., PNAS. 24:8466-8471 (2005) and Thie et al., Methods Mol Biol. 525:309-22 (2009) in conjugation with computation methods as demonstrated in Tiller et al., Front. Immunol. 8:986 (2017).


Chimeric immunoglobulins are the products of fused genes derived from different species; “humanized” chimeras generally have the framework region (FR) from human immunoglobulins and one or more CDRs are from a non-human source.


Portions of the heavy and/or light chain may be identical or homologous to corresponding sequences from another particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical 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, so long as they exhibit the desired biological activity. U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851 (1984). For methods relating to chimeric antibodies, see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1985), each of which are specifically incorporated herein by reference in their entirety. CDR grafting is described, for example, in U.S. Pat. Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101, which are all hereby incorporated by reference for all purposes.


Minimizing the antibody polypeptide sequence from the non-human species may optimize chimeric antibody function and reduce immunogenicity. Specific amino acid residues from non-antigen recognizing regions of the non-human antibody are modified to be homologous to corresponding residues in a human antibody or isotype. One example is the “CDR-grafted” antibody, in which an antibody comprises one or more CDRs from a particular species or belonging to a specific antibody class or subclass, while the remainder of the antibody chain(s) is identical or homologous to a corresponding sequence in antibodies derived from another species or belonging to another antibody class or subclass. For use in humans, the V region composed of CDR1, CDR2, and partial CDR3 for both the light and heavy chain variance region from a non-human immunoglobulin, are grafted with a human antibody framework region, replacing the naturally occurring antigen receptors of the human antibody with the non-human CDRs. In some instances, corresponding non-human residues replace framework region residues of the human immunoglobulin. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody to further refine performance. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. See, e.g., Jones et al., Nature 321:522 (1986); Riechmann et al., Nature 332:323 (1988); Presta, Curr. Op. Struct. Biol. 2:593 (1992); Vaswani and Hamilton, Ann. Allergy, Asthma and Immunol. 1:105 (1998); Harris, Biochem. Soc. Transactions 23; 1035 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428 (1994); Verhoeyen et al., Science 239:1534-36 (1988).


Intrabodies are intracellularly localized immunoglobulins that bind to intracellular antigens as opposed to secreted antibodies, which bind antigens in the extracellular space.


Polyclonal antibody preparations typically include different antibodies against different determinants (epitopes). In order to produce polyclonal antibodies, a host, such as a rabbit or goat, is immunized with the antigen or antigen fragment, generally with an adjuvant and, if necessary, coupled to a carrier. Antibodies to the antigen are subsequently collected from the sera of the host. The polyclonal antibody can be affinity purified against the antigen rendering it monospecific.


Monoclonal antibodies or “mAb” refer to an antibody obtained from a population of homogeneous antibodies from an exclusive parental cell, e.g., the population is identical except for naturally occurring mutations that may be present in minor amounts. Each monoclonal antibody is directed against a single antigenic determinant.


B. Functional Antibody Fragments and Antigen-Binding Fragments
1. Antigen-Binding Fragments

The disclosure provides for antibody fragments, such as antibody fragments that bind to a SARS-CoV-2 spike protein. The term functional antibody fragment includes antigen-binding fragments of an antibody that retain the ability to specifically bind to an antigen. These fragments are constituted of various arrangements of the variable region heavy chain (VH) and/or light chain (VL); and may include constant region heavy chain 1 (CH1) and light chain (CL). They may also lack the Fc region constituted of heavy chain 2 (CH2) and 3 (CH3) domains. Antigen binding fragments and the modifications thereof may include: (i) the Fab fragment type constituted with the VL, VH, CL, and CH1 domains; (ii) the Fd fragment type constituted with the VH and CH1 domains; (iii) the Fv fragment type constituted with the VH and VL domains; (iv) the single domain fragment type, dAb, (Ward, 1989; McCafferty et al., 1990; Holt et al., 2003) constituted with a single VH or VL domain; (v) isolated complementarity determining region (CDR) regions. Such terms are described, for example, in Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, NY (1989); Molec. Biology and Biotechnology: A Comprehensive Desk Reference (Myers, R. A. (ed.), New York: VCH Publisher, Inc.); Huston et al., Cell Biophysics, 22:189-224 (1993); Pluckthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E. D., Advanced Immunochemistry, 2d ed., Wiley-Liss, Inc. New York, N.Y. (1990); Antibodies, 4:259-277 (2015), each of which are incorporated by reference.


Antigen-binding fragments also include fragments of an antibody that retain exactly, at least, or at most 1, 2, or 3 complementarity determining regions (CDRs) from a light chain variable region. Fusions of CDR-containing sequences to an Fc region (or a CH2 or CH3 region thereof) are included within the scope of this definition including, for example, scFv fused, directly or indirectly, to an Fc region are included herein.


The term Fab fragment (also “Fab”) means a monovalent antigen-binding fragment of an antibody containing the VL, VH, CL and CH1 domains. The term Fab′ fragment means a monovalent antigen-binding fragment of a monoclonal antibody that is larger than a Fab fragment. For example, a Fab′ fragment includes the VL, VH, CL and CH1 domains and all or part of the hinge region. The term F(ab′)2 fragment means a bivalent antigen-binding fragment of a monoclonal antibody comprising two Fab′ fragments linked by a disulfide bridge at the hinge region. An F(ab′)2 fragment includes, for example, all or part of the two VH and VL domains, and can further include all or part of the two CL and CH1 domains.


The term Fd fragment means a fragment of the heavy chain of a monoclonal antibody, which includes all or part of the VH, including the CDRs. An Fd fragment can further include CH1 region sequences.


The term Fv fragment means a monovalent antigen-binding fragment of a monoclonal antibody, including all or part of the VL and VH, and absent of the CL and CH1 domains. The VL and VH include, for example, the CDRs. Single-chain antibodies (sFv or scFv) are Fv molecules in which the VL and VH regions have been connected by a flexible linker to form a single polypeptide chain, which forms an antigen-binding fragment. Single chain antibodies are discussed in detail in International Patent Application Publication No. WO 88/01649 and U.S. Pat. Nos. 4,946,778 and 5,260,203, the disclosures of which are herein incorporated by reference. The term (scFv) 2 means bivalent or bispecific sFv polypeptide chains that include oligomerization domains at their C-termini, separated from the sFv by a hinge region (Pack et al. 1992). The oligomerization domain comprises self-associating a-helices, e.g., leucine zippers, which can be further stabilized by additional disulfide bonds. (scFv) 2 fragments are also known as “miniantibodies” or “minibodies.”


A single domain antibody is an antigen-binding fragment containing only a VH or the VL domain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.


2. Fragment Antigen Binding Region, Fab

Fab polypeptides of the disclosure include the Fab antigen binding fragment of an antibody. Unless specifically stated otherwise, the term “Fab” relates to a polypeptide excluding the Fc portion of the antibody. The Fab may be conjugated to a polypeptide comprising other components, such as further antigen binding domains, costimulatory domains, linkers, peptide spacers, transmembrane domains, endodomains, and accessory proteins. Fab polypeptides can be generated using conventional techniques known in the art and are well-described in the literature.


3. Fragment Crystallizable Region, Fc

An Fc region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains. The term “Fc polypeptide” as used herein includes native and mutein forms of polypeptides derived from the Fc region of an antibody. Truncated forms of such polypeptides containing the hinge region that promotes dimerization are included.


C. Polypeptides with antibody CDRs & Scaffolding Domains that Display the CDRs


Antigen-binding peptide scaffolds, such as complementarity-determining regions (CDRs), may be used to generate protein-binding molecules. Generally, a person skilled in the art can determine the type of protein scaffold on which to graft at least one of the CDRs. It is known that scaffolds, optimally, must meet a number of criteria such as: good phylogenetic conservation; known three-dimensional structure; small size; few or no post-transcriptional modifications; and/or be easy to produce, express, and purify. Skerra, J Mol Recognit, 13:167-87 (2000).


The protein scaffolds can be sourced from, but not limited to: fibronectin type III FN3 domain (known as “monobodies”), fibronectin type III domain 10, lipocalin, anticalin, Z-domain of protein A of Staphylococcus aureus, thioredoxin A or proteins with a repeated motif such as the “ankyrin repeat”, the “armadillo repeat”, the “leucine-rich repeat” and the “tetratricopeptide repeat”. Such proteins are described in US Patent Publication Nos. 2010/0285564, 2006/0058510, 2006/0088908, 2005/0106660, and PCT Publication No. WO2006/056464, each of which are specifically incorporated herein by reference in their entirety. Scaffolds derived from toxins from scorpions, insects, plants, mollusks, etc., and the protein inhibiters of neuronal NO synthase (PIN) may also be used.


D. Antibody Binding

The term “selective binding agent” refers to a molecule that binds to an antigen. Non-limiting examples include antibodies, antigen-binding fragments, scFv, Fab, Fab′, F(ab′)2, single chain antibodies, peptides, peptide fragments and proteins.


The term “binding” refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges. “Immunologically reactive” means that the selective binding agent or antibody of interest will bind with antigens present in a biological sample. The term “immune complex” refers the combination formed when an antibody or selective binding agent binds to an epitope on an antigen.


1. Affinity/Avidity

The term “affinity” refers the strength with which an antibody or selective binding agent binds an epitope. In antibody binding reactions, this is expressed as the affinity constant (Ka or ka sometimes referred to as the association constant) for any given antibody or selective binding agent. Affinity is measured as a comparison of the binding strength of the antibody to its antigen relative to the binding strength of the antibody to an unrelated amino acid sequence. Affinity can be expressed as, for example, 20-fold greater binding ability of the antibody to its antigen then to an unrelated amino acid sequence. As used herein, the term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution. The terms “immunoreactive” and “preferentially binds” are used interchangeably herein with respect to antibodies and/or selective binding agent.


There are several experimental methods that can be used by one skilled in the art to evaluate the binding affinity of any given antibody or selective binding agent for its antigen. This is generally done by measuring the equilibrium dissociation constant (KD or Kd), using the equation KD=koff/kon=[A][B]/[AB]. The term koff is the rate of dissociation between the antibody and antigen per unit time, and is related to the concentration of antibody and antigen present in solution in the unbound form at equilibrium. The term kon is the rate of antibody and antigen association per unit time, and is related to the concentration of the bound antigen-antibody complex at equilibrium. The units used for measuring the KD are mol/L (molarity, or M), or concentration. The Ka of an antibody is the opposite of the KD, and is determined by the equation Ka=1/KD. Examples of some experimental methods that can be used to determine the KD value are: enzyme-linked immunosorbent assays (ELISA), isothermal titration calorimetry (ITC), fluorescence anisotropy, surface plasmon resonance (SPR), and affinity capillary electrophoresis (ACE). The affinity constant (Ka) of an antibody is the opposite of the KD, and is determined by the equation Ka=1/KD.


Antibodies deemed useful may have an affinity constant (Ka) of about, at least about, or at most about 106, 107, 108, 109, or 1010 M or any range derivable therein. Similarly, antibodies may have a dissociation constant of about, at least about or at most about 10−6, 10−7, 10−8, 10−9, 10−10 M, or any range derivable therein. These values are reported for antibodies discussed herein and the same assay may be used to evaluate the binding properties of such antibodies. An antibody of the invention is said to “specifically bind” its target antigen when the dissociation constant (KD) is ≤10−8 M. The antibody specifically binds antigen with “high affinity” when the KD is ≤5×10−9 M, and with “very high affinity” when the KD is ≤5×10−10 M.


2. Epitope Specificity

The epitope of an antigen is the specific region of the antigen for which an antibody has binding affinity. In the case of protein or polypeptide antigens, the epitope is the specific residues (or specified amino acids or protein segment) that the antibody binds with high affinity. An antibody does not necessarily contact every residue within the protein. Nor does every single amino acid substitution or deletion within a protein necessarily affect binding affinity. For purposes of this specification and the accompanying claims, the terms “epitope” and “antigenic determinant” are used interchangeably to refer to the site on an antigen to which B and/or T cells respond or recognize. Polypeptide epitopes can be formed from both contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of a polypeptide. An epitope typically includes at least 3, and typically 5-10 amino acids in a unique spatial conformation.


Epitope specificity of an antibody can be determined in a variety of ways. One approach, for example, involves testing a collection of overlapping peptides of 15 amino acids spanning the full sequence of the protein and differing in increments of a small number of amino acids (e.g., 3 to 30 amino acids). The peptides are immobilized in separate wells of a microtiter dish. Immobilization can be accomplished, for example, by biotinylating one terminus of the peptides. This process may affect the antibody affinity for the epitope, therefore different samples of the same peptide can be biotinylated at the N and C terminus and immobilized in separate wells for the purposes of comparison. This is useful for identifying end-specific antibodies. Optionally, additional peptides can be included terminating at a particular amino acid of interest. This approach is useful for identifying end-specific antibodies to internal fragments. An antibody or antigen-binding fragment is screened for binding to each of the various peptides. The epitope is defined as a segment of amino acids that is common to all peptides to which the antibody shows high affinity binding.


3. Modification of Antibody Antigen-Binding Domains

It is understood that the antibodies of the present invention may be modified, such that they are substantially identical to the antibody polypeptide sequences, or fragments thereof, and still bind the epitopes of the present invention. Polypeptide sequences are “substantially identical” when optimally aligned using such programs as Clustal Omega, IGBLAST, GAP or BESTFIT using default gap weights, they share at least 80% sequence identity, at least 90% sequence identity, at least 95% sequence identity, at least 96% sequence identity, at least 97% sequence identity, at least 98% sequence identity, or at least 99% sequence identity or any range therein.


As discussed herein, minor variations in the amino acid sequences of antibodies or antigen-binding regions thereof are contemplated as being encompassed by the present invention, providing that the variations in the amino acid sequence maintain at least 75%, more preferably at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% and most preferably at least 99% sequence identity. In particular, conservative amino acid replacements are contemplated.


Conservative replacements are those that take place within a family of amino acids that are related in their side chains. Genetically encoded amino acids are generally divided into families based on the chemical nature of the side chain; e.g., acidic (aspartate, glutamate), basic (lysine, arginine, histidine), nonpolar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine). For example, it is reasonable to expect that an isolated replacement of a leucine moiety with an isoleucine or valine moiety, or a similar replacement of an amino acid with a structurally related amino acid in the same family, will not have a major effect on the binding or properties of the resulting molecule, especially if the replacement does not involve an amino acid within a framework site. Whether an amino acid change results in a functional peptide can readily be determined by assaying the specific activity of the polypeptide derivative. Standard ELISA, Surface Plasmon Resonance (SPR), or other antibody binding assays can be performed by one skilled in the art to make a quantitative comparison of antigen binging affinity between the unmodified antibody and any polypeptide derivatives with conservative substitutions generated through any of several methods available to one skilled in the art.


Fragments or analogs of antibodies or immunoglobulin molecules can be readily prepared by those skilled in the art. Preferred amino- and carboxy-termini of fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and/or amino acid sequence data to public or proprietary sequence databases. Preferably, computerized comparison methods are used to identify sequence motifs or predicted protein conformation domains that occur in other proteins of known structure and/or function. Standard methods to identify protein sequences that fold into a known three-dimensional structure are available to those skilled in the art; Dill and McCallum., Science 338:1042-1046 (2012). Several algorithms for predicting protein structures and the gene sequences that encode these have been developed, and many of these algorithms can be found at the National Center for Biotechnology Information (on the World Wide Web at ncbi.nlm.nih.gov/guide/proteins/) and at the Bioinformatics Resource Portal (on the World Wide Web at expasy.org/proteomics). Thus, the foregoing examples demonstrate that those of skill in the art can recognize sequence motifs and structural conformations that may be used to define structural and functional domains in accordance with the invention.


Framework modifications can be made to antibodies to decrease immunogenicity, for example, by “backmutating” one or more framework residues to a corresponding germline sequence.


It is also contemplated that the antigen-binding domain may be multi-specific or multivalent by multimerizing the antigen-binding domain with VH and VL region pairs that bind either the same antigen (multi-valent) or a different antigen (multi-specific).


E. Chemical Modification of Antibodies

Also contemplated are glycosylation variants of antibodies, wherein the number and/or type of glycosylation site(s) has been altered compared to the amino acid sequences of the parent polypeptide. Glycosylation of the polypeptides can be altered, for example, by modifying one or more sites of glycosylation within the polypeptide sequence to increase the affinity of the polypeptide for antigen (U.S. Pat. Nos. 5,714,350 and 6,350,861). Antibody protein variants may comprise a greater or a lesser number of N-linked glycosylation sites than the native antibody. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate or alter this sequence will prevent addition of an N-linked carbohydrate chain present in the native polypeptide. For example, the glycosylation can be reduced by the deletion of an Asn or by substituting the Asn with a different amino acid. One or more new N-linked glycosylation sites may be created. Antibodies typically have an N-linked glycosylation site in the Fc region.


Additional antibody variants include cysteine variants, wherein one or more cysteine residues in the parent or native amino acid sequence are deleted from or substituted with another amino acid (e.g., serine). Cysteine variants are useful, inter alia, when antibodies must be refolded into a biologically active conformation. Cysteine variants may have fewer cysteine residues than the native antibody and typically have an even number to minimize interactions resulting from unpaired cysteines.


The polypeptides can be pegylated to increase biological half-life by reacting the polypeptide with polyethylene glycol (PEG) or a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the polypeptide. Polypeptide pegylation may be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). Methods for pegylating proteins are known in the art and can be applied to the polypeptides of the invention to obtain PEGylated derivatives of antibodies. See, e.g., EP 0 154 316 and EP 0 401 384. The antibody can be conjugated or otherwise linked to transthyretin (TTR) or a TTR variant. The TTR or TTR variant can be chemically modified with, for example, a chemical selected from the group consisting of dextran, poly(n-vinyl pyrrolidone), polyethylene glycols, propropylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, and polyvinyl alcohols. As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins.


1. Conjugation

Derivatives of the antibodies and antigen binding fragments that are described herein are also provided. The derivatized antibody or fragment thereof may comprise any molecule or substance that imparts a desired property to the antibody or fragment. The derivatized antibody can comprise, for example, a detectable (or labeling) moiety (e.g., a radioactive, colorimetric, antigenic, or enzymatic molecule, or a detectable bead), a molecule that binds to another molecule (e.g., biotin or streptavidin), a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, or pharmaceutically active moiety), or a molecule that increases the suitability of the antibody for a particular use (e.g., administration to a subject, such as a human subject, or other in vivo or in vitro uses).


Optionally, an antibody or an immunological portion of an antibody can be chemically conjugated to, or expressed as, a fusion protein with other proteins. Polypeptides may be chemically modified by conjugating or fusing the polypeptide to serum protein, such as human serum albumin, to increase half-life of the resulting molecule. See, e.g., EP 0322094 and EP 0 486 525. The polypeptides may be conjugated to a diagnostic agent and used diagnostically, for example, to monitor the development or progression of a disease and determine the efficacy of a given treatment regimen. The polypeptides may also be conjugated to a therapeutic agent to provide a therapy in combination with the therapeutic effect of the polypeptide. Additional suitable conjugated molecules include ribonuclease (RNase), DNase I, an antisense nucleic acid, an inhibitory RNA molecule such as a siRNA molecule, an immunostimulatory nucleic acid, aptamers, ribozymes, triplex forming molecules, and external guide sequences. The functional nucleic acid molecules may act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional nucleic acid molecules may possess a de novo activity independent of any other molecules.


Disclosed are antibodies and antibody-like molecules that are linked to at least one agent to form an antibody conjugate or payload. In order to increase the efficacy of antibody molecules as diagnostic or therapeutic agents, it is conventional to link or covalently bind or complex at least one desired molecule or moiety. Such a molecule or moiety may be, but is not limited to, at least one effector or reporter molecule. Effector molecules comprise molecules having a desired activity, e.g., cytotoxic activity. Non-limiting examples of effector molecules include toxins, therapeutic enzymes, antibiotics, radiolabeled nucleotides and the like. By contrast, a reporter molecule is defined as any moiety that may be detected using an assay. Non-limiting examples of reporter molecules that have been conjugated to antibodies include enzymes, radiolabels, haptens, fluorescent labels, phosphorescent molecules, chemiluminescent molecules, chromophores, luminescent molecules, photoaffinity molecules, colored particles, or ligands.


a. Conjugate Types


Certain examples of antibody conjugates are those conjugates in which the antibody is linked to a detectable label. “Detectable labels” are compounds and/or elements that can be detected due to their specific functional properties, and/or chemical characteristics, the use of which allows the antibody to be detected, and/or further quantified if desired. Examples of detectable labels include, but not limited to, radioactive isotopes, fluorescers, semiconductor nanocrystals, chemiluminescers, chromophores, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metal ions, metal sols, ligands (e.g., biotin, streptavidin or haptens) and the like. Particular examples of labels are, but not limited to, horseradish peroxidase (HRP), fluorescein, FITC, rhodamine, dansyl, umbelliferone, dimethyl acridinium ester (DMAE), Texas red, luminol, NADPH and α- or β-galactosidase. Antibody conjugates include those intended primarily for use in vitro, where the antibody is linked to a secondary binding ligand and/or to an enzyme to generate a colored product upon contact with a chromogenic substrate. Examples of suitable enzymes include, but are not limited to, urease, alkaline phosphatase, (horseradish) hydrogen peroxidase, or glucose oxidase. Preferred secondary binding ligands are biotin and/or avidin and streptavidin compounds. The uses of such labels is well known to those of skill in the art and are described, for example, in U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149 and 4,366,241; each incorporated herein by reference. Molecules containing azido groups may also be used to form covalent bonds to proteins through reactive nitrene intermediates that are generated by low intensity ultraviolet light (Potter & Haley, 1983).


Also contemplated are immunoconjugates comprising an antibody or antigen-binding fragment thereof conjugated to a cytotoxic agent such as a chemotherapeutic agent, a drug, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). In this way, the agent of interest can be targeted directly to cells bearing cell surface antigen. The antibody and agent may be associated through non-covalent interactions such as through electrostatic forces, or by covalent bonds. Various linkers, known in the art, can be employed in order to form the immunoconjugate. Additionally, the immunoconjugate can be provided in the form of a fusion protein. An antibody may be conjugated to various therapeutic substances in order to target the cell surface antigen. Examples of conjugated agents include, but are not limited to, metal chelate complexes, drugs, toxins and other effector molecules, such as cytokines, lymphokines, chemokines, immunomodulators, radiosensitizers, asparaginase, carboranes, and radioactive halogens.


In antibody drug conjugates (ADC), an antibody (Ab) is conjugated to one or more drug moieties (D) through a linker (L). The ADC may be prepared by several routes, employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of an antibody with a bivalent linker reagent, to form Ab-L, via a covalent bond, followed by reaction with a drug moiety D; and (2) reaction of a nucleophilic group of a drug moiety with a bivalent linker reagent, to form D-L, via a covalent bond, followed by reaction with the nucleophilic group of an antibody. Antibody drug conjugates may also be produced by modification of the antibody to introduce electrophilic moieties, which can react with nucleophilic substituents on the linker reagent or drug. Alternatively, a fusion protein comprising the antibody and cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.


ADC can include covalent or aggregative conjugates of antibodies, or antigen-binding fragments thereof, with other proteins or polypeptides, such as by expression of recombinant fusion proteins comprising heterologous polypeptides fused to the N-terminus or C-terminus of an antibody polypeptide. For example, the conjugated peptide may be a heterologous signal (or leader) polypeptide, e.g., the yeast alpha-factor leader, or a peptide such as an epitope tag (e.g., V5-His). Antibody-containing fusion proteins may comprise peptides added to facilitate purification or identification of the antibody (e.g., poly-His). An antibody polypeptide also can be linked to the FLAG® (Sigma-Aldrich, St. Louis, Mo.) peptide as described in Hopp et al., Bio/Technology 6:1204 (1988), and U.S. Pat. No. 5,011,912. Oligomers that contain one or more antibody polypeptides may be employed as antagonists. Oligomers may be in the form of covalently linked or non-covalently linked dimers, trimers, or higher oligomers. Oligomers comprising two or more antibody polypeptides are contemplated for use. Other oligomers include heterodimers, homotrimers, heterotrimers, homotetramers, heterotetramers, etc. Oligomers may comprise multiple antibody polypeptides joined via covalent or non-covalent interactions between peptide moieties fused to the antibody polypeptides. Such peptides may be peptide linkers (spacers), or peptides that have the property of promoting oligomerization. Leucine zippers and certain polypeptides derived from antibodies are among the peptides that can promote oligomerization of antibody polypeptides attached thereto, as described in more detail below.


b. Conjugation Methodology


Several methods are known in the art for the attachment or conjugation of an antibody to its conjugate moiety. Some attachment methods involve the use of a metal chelate complex employing, for example, an organic chelating agent such a diethylenetriaminepentaacetic acid anhydride (DTPA); ethylenetriaminetetraacetic acid; N-chloro-p-toluenesulfonamide; and/or tetrachloro-3-6-diphenylglycouril-3 attached to the antibody (U.S. Pat. Nos. 4,472,509 and 4,938,948, each incorporated herein by reference). Monoclonal antibodies may also be reacted with an enzyme in the presence of a coupling agent such as glutaraldehyde or periodate. Conjugates may also be made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bos(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Also contemplated are derivatization of immunoglobulins by selectively introducing sulfhydryl groups in the Fc region of an immunoglobulin, using reaction conditions that do not alter the antibody combining site. Antibody conjugates produced according to this methodology are disclosed to exhibit improved longevity, specificity, and sensitivity (U.S. Pat. No. 5,196,066, incorporated herein by reference). Site-specific attachment of effector or reporter molecules, wherein the reporter or effector molecule is conjugated to a carbohydrate residue in the Fc region has also been disclosed in the literature (O'Shannessy et al., 1987).


II. Antibody Production
A. Antibody Production

Methods for preparing and characterizing antibodies for use in diagnostic and detection assays, for purification, and for use as therapeutics are well known in the art as disclosed in, for example, U.S. Pat. Nos. 4,011,308; 4,722,890; 4,016,043; 3,876,504; 3,770,380; and 4,372,745 (see, e.g., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988; incorporated herein by reference). These antibodies may be polyclonal or monoclonal antibody preparations, monospecific antisera, human antibodies, hybrid or chimeric antibodies, such as humanized antibodies, altered antibodies, F(ab′)2 fragments, Fab fragments, Fv fragments, single-domain antibodies, dimeric or trimeric antibody fragment constructs, minibodies, or functional fragments thereof which bind to the antigen in question. Polypeptides, peptides, and proteins and immunogenic fragments thereof for use in methods and compositions of the disclosure can also be synthesized in solution or on a solid support in accordance with conventional techniques. See, for example, Stewart and Young, (1984); Tarn et al, (1983); Merrifield, (1986); and Barany and Merrifield (1979), each incorporated herein by reference.


Briefly, a polyclonal antibody is prepared by immunizing an animal with an antigen or a portion thereof and collecting antisera from that immunized animal. The antigen may be altered compared to an antigen sequence found in nature. A variant or altered antigenic peptide or polypeptide may be employed to generate antibodies. Inocula are typically prepared by dispersing the antigenic composition in a physiologically tolerable diluent to form an aqueous composition. Antisera is subsequently collected by methods known in the arts, and the serum may be used as-is for various applications or else the desired antibody fraction may be purified by well-known methods, such as affinity chromatography (Harlow and Lane, Antibodies: A Laboratory Manual 1988).


Methods of making monoclonal antibodies are also well known in the art (Kohler and Milstein, 1975; Harlow and Lane, 1988, U.S. Pat. No. 4,196,265, herein incorporated by reference in its entirety for all purposes). Typically, this technique involves immunizing a suitable animal with a selected immunogenic composition, e.g., a purified or partially purified protein, polypeptide, peptide or domain. Resulting antibody-producing B-cells from the immunized animal, or all dissociated splenocytes, are then induced to fuse with cells from an immortalized cell line to form hybridomas. Myeloma cell lines suited for use in hybridoma-producing fusion procedures preferably are non-antibody-producing and have high fusion efficiency and enzyme deficiencies that render then incapable of growing in certain selective media that support the growth of only the desired fused cells (hybridomas). Typically, the fusion partner includes a property that allows selection of the resulting hybridomas using specific media. For example, fusion partners can be hypoxanthine/aminopterin/thymidine (HAT)-sensitive. Methods for generating hybrids of antibody-producing spleen or lymph node cells and myeloma cells usually comprise mixing somatic cells with myeloma cells in the presence of an agent or agents (chemical or electrical) that promote the fusion of cell membranes. Next, selection of hybridomas can be performed by culturing the cells by single-clone dilution in microtiter plates, followed by testing the individual clonal supernatants (after two to three weeks) for the desired reactivity. Fusion procedures for making hybridomas, immunization protocols, and techniques for isolation of immunized splenocytes for fusion are known in the art.


Other techniques for producing monoclonal antibodies include the viral or oncogenic transformation of B-lymphocytes, a molecular cloning approach may be used to generate a nucleic acid or polypeptide, the selected lymphocyte antibody method (SLAM) (see, e.g., Babcook et al., Proc. Natl. Acad. Sci. USA 93:7843-7848 (1996), the preparation of combinatorial immunoglobulin phagemid libraries from RNA isolated from the spleen of the immunized animal and selection of phagemids expressing appropriate antibodies, or producing a cell expressing an antibody from a genomic sequence of the cell comprising a modified immunoglobulin locus using Cre-mediated site-specific recombination (see, e.g., U.S. Pat. No. 6,091,001).


Monoclonal antibodies may be further purified using filtration, centrifugation, and various chromatographic methods such as HPLC or affinity chromatography. Monoclonal antibodies may be further screened or optimized for properties relating to specificity, avidity, half-life, immunogenicity, binding association, binding disassociation, or overall functional properties relative to being a treatment for infection. Thus, monoclonal antibodies may have alterations in the amino acid sequence of CDRs, including insertions, deletions, or substitutions with a conserved or non-conserved amino acid.


The immunogenicity of a particular immunogen composition can be enhanced by the use of non-specific stimulators of the immune response, known as adjuvants. Adjuvants that may be used include, but are not limited to, IL-1, IL-2, IL-4, IL-7, IL-12, -interferon, GMCSP, BCG, aluminum hydroxide, MDP compounds, such as thur-MDP and nor-MDP, CGP (MTP-PE), lipid A, and monophosphoryl lipid A (MPL). Exemplary adjuvants may include complete Freund's adjuvant (a non-specific stimulator of the immune response containing killed Mycobacterium tuberculosis), incomplete Freund's adjuvants, and/or aluminum hydroxide adjuvant. In addition to adjuvants, it may be desirable to co-administer biologic response modifiers (BRM), such as but not limited to, Cimetidine (CIM; 1200 mg/d) (Smith/Kline, PA); low-dose Cyclophosphamide (CYP; 300 mg/m2) (Johnson/Mead, NJ), cytokines such as B-interferon, IL-2, or IL-12, or genes encoding proteins involved in immune helper functions, such as B-7.A phage-display system can be used to expand antibody molecule populations in vitro. Saiki, et al., Nature 324:163 (1986); Scharf et al., Science 233:1076 (1986); U.S. Pat. Nos. 4,683,195 and 4,683,202; Yang et al., J Mol Biol. 254:392 (1995); Barbas, III et al., Methods: Comp. Meth Enzymol. (1995) 8:94; Barbas, III et al., Proc Natl Acad Sci USA 88:7978 (1991).


B. Fully Human Antibody Production

Methods are available for making fully human antibodies. Using fully human antibodies can minimize the immunogenic and allergic responses that may be caused by administering non-human monoclonal antibodies to humans as therapeutic agents. Human antibodies may be produced in a non-human transgenic animal, e.g., a transgenic mouse capable of producing multiple isotypes of human antibodies to protein (e.g., IgG, IgA, and/or IgE) by undergoing V-D-J recombination and isotype switching. This may apply to antibodies, antibody fragments, and pharmaceutical compositions thereof, but also non-human transgenic animals, B-cells, host cells, and hybridomas that produce monoclonal antibodies. Applications of human antibodies include, but are not limited to, detect a cell expressing an anticipated protein, either in vivo or in vitro, pharmaceutical preparations containing the antibodies of the present invention, and methods of treating disorders by administering the antibodies.


Fully human antibodies can be produced by immunizing transgenic animals (usually mice) that are capable of producing a repertoire of human antibodies in the absence of endogenous immunoglobulin production. Antigens for this purpose typically have six or more contiguous amino acids, and optionally are conjugated to a carrier, such as a hapten. See, for example, Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551-2555 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggermann et al., Year in Immunol. 7:33 (1993). In one example, transgenic animals are produced by incapacitating the endogenous mouse immunoglobulin loci encoding the mouse heavy and light immunoglobulin chains therein, and inserting into the mouse genome large fragments of human genome DNA containing loci that encode human heavy and light chain proteins. Partially modified animals, which have less than the full complement of human immunoglobulin loci, are then crossbred to obtain an animal having all of the desired immune system modifications. When administered an immunogen, these transgenic animals produce antibodies that are immunospecific for the immunogen but have human rather than murine amino acid sequences, including the variable regions. For further details of such methods, see, for example, International Patent Application Publication Nos. WO 96/33735 and WO 94/02602, which are hereby incorporated by reference in their entirety. Additional methods relating to transgenic mice for making human antibodies are described in U.S. Pat. Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 6,300,129; 6,255,458; 5,877,397; 5,874,299 and 5,545,806; in International Patent Application Publication Nos. WO 91/10741 and WO 90/04036; and in European Patent Nos. EP 546073B1 and EP 546073A1, all of which are hereby incorporated by reference in their entirety for all purposes.


The transgenic mice described above, referred to herein as “HuMAb” mice, contain a human immunoglobulin gene minilocus that encodes unrearranged human heavy (μ and γ) and κ light chain immunoglobulin sequences, together with targeted mutations that inactivate the endogenous μ and κ chain loci (Lonberg et al., Nature 368:856-859 (1994)). Accordingly, the mice exhibit reduced expression of mouse IgM or κ chains and in response to immunization, the introduced human heavy and light chain transgenes undergo class switching and somatic mutation to generate high affinity human IgG K monoclonal antibodies (Lonberg et al., supra; Lonberg and Huszar, Intern. Ref. Immunol. 13:65-93 (1995); Harding and Lonberg, Ann. N.Y. Acad. Sci. 764:536-546 (1995)). The preparation of HuMAb mice is described in detail in Taylor et al., Nucl. Acids Res. 20:6287-6295 (1992); Chen et al., Int. Immunol. 5:647-656 (1993); Tuaillon et al., J. Immunol. 152:2912-2920 (1994); Lonberg et al., supra; Lonberg, Handbook of Exp. Pharmacol. 113:49-101 (1994); Taylor et al., Int. Immunol. 6:579-591 (1994); Lonberg and Huszar, Intern. Ref. Immunol. 13:65-93 (1995); Harding and Lonberg, Ann. N. Y. Acad. Sci. 764:536-546 (1995); Fishwild et al., Nat. Biotechnol. 14:845-851 (1996); the foregoing references are herein incorporated by reference in their entirety for all purposes. See further, U.S. Pat. Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; 5,770,429; and 5,545,807; as well as International Patent Application Publication Nos. WO 93/1227; WO 92/22646; and WO 92/03918, the disclosures of all of which are hereby incorporated by reference in their entirety for all purposes. Technologies utilized for producing human antibodies in these transgenic mice are disclosed also in WO 98/24893, and Mendez et al., Nat. Genetics 15:146-156 (1997), which are herein incorporated by reference. For example, the HCo7 and HCo12 transgenic mice strains can be used to generate human antibodies.


Using hybridoma technology, antigen-specific humanized monoclonal antibodies with the desired specificity can be produced and selected from the transgenic mice such as those described above. Such antibodies may be cloned and expressed using a suitable vector and host cell, or the antibodies can be harvested from cultured hybridoma cells. Fully human antibodies can also be derived from phage-display libraries (as disclosed in Hoogenboom et al., J. Mol. Biol. 227:381 (1991); and Marks et al., J. Mol. Biol. 222:581 (1991)). One such technique is described in International Patent Application Publication No. WO 99/10494 (herein incorporated by reference), which describes the isolation of high affinity and functional agonistic antibodies for MPL- and msk-receptors using such an approach.


C. Antibody Fragments Production

Antibody fragments that retain the ability to recognize the antigen of interest will also find use herein. A number of antibody fragments are known in the art that comprise antigen-binding sites capable of exhibiting immunological binding properties of an intact antibody molecule and can be subsequently modified by methods known in the arts. Functional fragments, including only the variable regions of the heavy and light chains, can also be produced using standard techniques such as recombinant production or preferential proteolytic cleavage of immunoglobulin molecules. These fragments are known as Fv. See, e.g., Inbar et al., Proc. Nat. Acad. Sci. USA 69:2659-2662 (1972); Hochman et al., Biochem. 15:2706-2710 (1976); and Ehrlich et al., Biochem. 19:4091-4096 (1980).


Single-chain variable fragments (scFvs) may be prepared by fusing DNA encoding a peptide linker between DNAs encoding the two variable domain polypeptides (VL and VH). scFvs can form antigen-binding monomers, or they can form multimers (e.g., dimers, trimers, or tetramers), depending on the length of a flexible linker between the two variable domains (Kortt et al., Prot. Eng. 10:423 (1997); Kort et al., Biomol. Eng. 18:95-108 (2001)). By combining different VL- and VH-comprising polypeptides, one can form multimeric scFvs that bind to different epitopes (Kriangkum et al., Biomol. Eng. 18:31-40 (2001)). Antigen-binding fragments are typically produced by recombinant DNA methods known to those skilled in the art. Although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined using recombinant methods by a synthetic linker that enables them to be made as a single chain polypeptide (known as single chain Fv (sFv or scFv); see e.g., Bird et al., Science 242:423-426 (1988); and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988). Design criteria include determining the appropriate length to span the distance between the C-terminus of one chain and the N-terminus of the other, wherein the linker is generally formed from small hydrophilic amino acid residues that do not tend to coil or form secondary structures. Suitable linkers generally comprise polypeptide chains of alternating sets of glycine and serine residues, and may include glutamic acid and lysine residues inserted to enhance solubility. Antigen-binding fragments are screened for utility in the same manner as intact antibodies. Such fragments include those obtained by amino-terminal and/or carboxy-terminal deletions, where the remaining amino acid sequence is substantially identical to the corresponding positions in the naturally occurring sequence deduced, for example, from a full-length cDNA sequence.


Antibodies may also be generated using peptide analogs of the epitopic determinants disclosed herein, which may consist of non-peptide compounds having properties analogous to those of the template peptide. These types of non-peptide compound are termed “peptide mimetics” or “peptidomimetics”. Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p. 392 (1985); and Evans et al., J. Med. Chem. 30:1229 (1987). Liu et al. (2003) also describe “antibody like binding peptidomimetics” (ABiPs), which are peptides that act as pared-down antibodies and have certain advantages of longer serum half-life as well as less cumbersome synthesis methods. These analogs can be peptides, non-peptides or combinations of peptide and non-peptide regions. Fauchere, Adv. Drug Res. 15:29 (1986); Veber and Freidiner, TINS p. 392 (1985); and Evans et al., J. Med. Chem. 30:1229 (1987), which are incorporated herein by reference in their entirety for any purpose. Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce a similar therapeutic or prophylactic effect. Such compounds are often developed with the aid of computerized molecular modeling. Generally, peptidomimetics of the invention are proteins that are structurally similar to an antibody displaying a desired biological activity, such as the ability to bind a protein, but have one or more peptide linkages optionally replaced by a linkage selected from: —CH2NH—, —CH2S—, —CH2-CH2-, —CH═CH-(cis and trans), —COCH2-, —CH(OH)CH2-, and —CH2SO— by methods well known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may be used to generate more stable proteins. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo and Gierasch, Ann. Rev. Biochem. 61:387 (1992), incorporated herein by reference), for example, by adding internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.


Once generated, a phage display library can be used to improve the immunological binding affinity of the Fab molecules using known techniques. See, e.g., Figini et al., J. Mol. Biol. 239:68 (1994). The coding sequences for the heavy and light chain portions of the Fab molecules selected from the phage display library can be isolated or synthesized and cloned into any suitable vector or replicon for expression. Any suitable expression system can be used.


III. Obtaining Encoded Antibodies

Also provided are nucleic acid molecule encoding antibody polypeptides (e.g., heavy or light chain, variable domain only, or full-length). These may be generated by methods known in the art, e.g., isolated from B cells of mice that have been immunized and isolated, phage display, expressed in any suitable recombinant expression system and allowed to assemble to form antibody molecules.


A. Expression

The nucleic acid molecules may be used to express large quantities of recombinant antibodies or to produce chimeric antibodies, single chain antibodies, immunoadhesins, diabodies, mutated antibodies, and other antibody derivatives. If the nucleic acid molecules are derived from a non-human, non-transgenic animal, the nucleic acid molecules may be used for antibody humanization.


1. Vectors

Also contemplated are expression vectors comprising a nucleic acid molecule encoding a polypeptide of the desired sequence or a portion thereof (e.g., a fragment containing one or more CDRs or one or more variable region domains). Expression vectors comprising the nucleic acid molecules may encode the heavy chain, light chain, or the antigen-binding portion thereof. Expression vectors comprising nucleic acid molecules may encode fusion proteins, modified antibodies, antibody fragments, and probes thereof. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well.


To express the antibodies, or antigen-binding fragments thereof, DNAs encoding partial or full-length light and heavy chains are inserted into expression vectors such that the gene area is operatively linked to transcriptional and translational control sequences. A vector that encodes a functionally complete human CH or CL immunoglobulin sequence with appropriate restriction sites engineered so that any VH or VL sequence can be easily inserted and expressed. Typically, expression vectors used in any of the host cells contain sequences for plasmid or virus maintenance and for cloning and expression of exogenous nucleotide sequences. Such sequences, collectively referred to as “flanking sequences” typically include one or more of the following operatively linked nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcriptional termination sequence, a complete intron sequence containing a donor and acceptor splice site, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element. Such sequences and methods of using the same are well known in the art.


2. Expression Systems

Numerous expression systems exist that comprise at least a part or all of the expression vectors discussed above. Prokaryote- and/or eukaryote-based systems can be employed for use to produce nucleic acid sequences, or their cognate polypeptides, proteins and peptides. Commercially and widely available systems include in but are not limited to bacterial, mammalian, yeast, and insect cell systems. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. Those skilled in the art are able to express a vector to produce a nucleic acid sequence or its cognate polypeptide, protein, or peptide using an appropriate expression system.


3. Methods of Gene Transfer

Suitable methods for nucleic acid delivery to effect expression of compositions are anticipated to include virtually any method by which a nucleic acid (e.g., DNA, including viral and nonviral vectors) can be introduced into a cell, a tissue or an organism, as described herein or as would be known to one of ordinary skill in the art. Such methods include, but are not limited to, direct delivery of DNA such as by injection (U.S. Pat. No. 5,994,624, 5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610, 5,589,466 and 5,580,859, each incorporated herein by reference), including microinjection (Harland and Weintraub, 1985; U.S. Pat. No. 5,789,215, incorporated herein by reference); by electroporation (U.S. Pat. No. 5,384,253, incorporated herein by reference); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); by using DEAE dextran followed by polyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimer et al., 1987); by liposome mediated transfection (Nicolau and Sene, 1982; Fraley et al., 1979; Nicolau et al., 1987; Wong et al., 1980; Kaneda et al., 1989; Kato et al., 1991); by microprojectile bombardment (PCT Application Nos. WO 94/09699 and 95/06128; U.S. Pat. Nos. 5,610,042; 5,322,783, 5,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporated herein by reference); by agitation with silicon carbide fibers (Kaeppler et al., 1990; U.S. Pat. Nos. 5,302,523 and 5,464,765, each incorporated herein by reference); by Agrobacterium mediated transformation (U.S. Pat. Nos. 5,591,616 and 5,563,055, each incorporated herein by reference); or by PEG mediated transformation of protoplasts (Omirulleh et al., 1993; U.S. Pat. Nos. 4,684,611 and 4,952,500, each incorporated herein by reference); by desiccation/inhibition mediated DNA uptake (Potrykus et al., 1985). Other methods include viral transduction, such as gene transfer by lentiviral or retroviral transduction.


4. Host Cells

Also contemplated are the use of host cells into which a recombinant expression vector has been introduced. Antibodies can be expressed in a variety of cell types. An expression construct encoding an antibody can be transfected into cells according to a variety of methods known in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. Some vectors may employ control sequences that allow it to be replicated and/or expressed in both prokaryotic and eukaryotic cells. The antibody expression construct can be placed under control of a promoter that is linked to T-cell activation, such as one that is controlled by NFAT-1 or NF-κB, both of which are transcription factors that can be activated upon T-cell activation. One of skill in the art would understand the conditions under which to incubate host cells to maintain them and to permit replication of a vector. Also understood and known are techniques and conditions that would allow large-scale production of vectors, as well as production of the nucleic acids encoded by vectors and their cognate polypeptides, proteins, or peptides.


For stable transfection of mammalian cells, it is known, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die), among other methods known in the arts.


B. Isolation

The nucleic acid molecule encoding either or both of the entire heavy and light chains of an antibody or the variable regions thereof may be obtained from any source that produces antibodies. Methods of isolating mRNA encoding an antibody are well known in the art. See e.g., Sambrook et al., supra. The sequences of human heavy and light chain constant region genes are also known in the art. See, e.g., Kabat et al., 1991, supra. Nucleic acid molecules encoding the full-length heavy and/or light chains may then be expressed in a cell into which they have been introduced and the antibody isolated.


IV. Viruses

The disclosure relates to treatment, analysis, or use of a virus. Disclosed are methods for treatment or prevention of a viral infection. Also disclosed are compositions comprising one or more anti-viral agents. Also disclosed are methods for diagnosis of a viral infection. Also disclosed are methods for detection of a virus in a sample.


A. Coronaviruses

The virus may be from the family Coronaviridae. Coronaviridae is a family of enveloped, positive-sense, single-stranded RNA viruses. Coronavirus is the common name for Coronaviridae and Orthocoronavirinae (also referred to as Coronavirinae). The family Coronaviridae is organized in 2 sub-families, 5 genera, 23 sub-genera and approximately 40 species. They are enveloped viruses having a positive-sense single-stranded RNA genome and a nucleocapsid having helical symmetry. The genome size of coronaviruses ranges from approximately 26-32 kilobases.


The present disclosure encompasses treatment or prevention of infection of any virus in the Coronaviridae family. The disclosure may encompass treatment or prevention of infection of any virus in the subfamily Coronavirinae and including the four genera, Alpha-, Beta-, Gamma-, and Deltacoronavirus. The disclosure may include treatment or prevention of infection of any virus in the genus of Betacoronavirus, including the subgenus Sarbecovirus and including the species of severe acute respiratory syndrome-related coronavirus. The disclosure may encompass treatment or prevention of infection of any virus in the species of severe acute respiratory syndrome-related coronavirus, including the strains severe acute respiratory syndrome coronavirus (SARS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes COVID-19). The disclosure encompasses treatment or prevention of infection any isolate, strain, type (including Type A, Type B and Type C; Forster et al., 2020, PNAS, available on the World Wide Web at doi.org/10.1073/pnas.2004999117), cluster, or sub-cluster of the species of severe acute respiratory syndrome-related coronavirus, including at least SARS-CoV-2. The virus may have a genome length between 29000 to 30000, between 29100 and 29900, between 29200 and 29900, between 29300 and 29900, between 29400 and 29900, between 29500 and 29900, between 29600 and 29900, between 29700 and 29900, between 29800 and 29900, or between 29780 and 29900 base pairs in length.


Examples of specific SARS-CoV-2 viruses include the following listed in the NCBI GenBank® Database, and these GenBank® Accession sequences are incorporated by reference herein in their entirety: (a) LC534419 and LC534418 and LC528233 and LC529905 (examples of different strains from Japan); (b) MT281577 and MT226610 and NC_045512 and MN996531 and MN908947 (examples of different strains from China); (c) MT281530 (Iran); (d) MT126808 (Brazil); (e) MT020781 (Finland); (f) MT093571 (Sweden); (g) MT263074 (Peru); (h) MT292582 and MT292581 and MT292580 and MT292579 (examples of different strains from Spain); (i) examples from the United States, such as MT276331 (TX); MT276330 (FL); MT276328 (OR) MT276327 (GA); MT276325 (WA); MT276324 (CA); MT276323 (RI); MT188341 (MN); and (j) MT276598 (Israel). The disclosure may include treatment or prevention of infection of any of these or similar viruses, including viruses whose genome has at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to any of these viruses. The disclosure includes treatment or prevention of infection of any of these or similar viruses, including viruses whose genome has its entire sequence that is greater than 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to any of these viruses. As one specific example, the present disclosure includes methods of treatment or prevention of infection of a virus having a genome sequence of SEQ ID NO:110 (represented by GenBank® Accession No. NC_045512; origin Wuhan, China) and any virus having a genome sequence with at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% identity to SEQ ID NO: 110.


SARS-CoV-2 proteins are described in detail in, for example, Yoshimoto F. K. (2020). The protein journal, 39 (3), 198-216, incorporated herein by reference in its entirety.


V. Antibodies, Antigen Binding Fragments, and Polypeptides

As used herein, a “protein” or “polypeptide” refers to a molecule comprising at least five amino acid residues. As used herein, the term “wild-type” refers to the endogenous version of a molecule that occurs naturally in an organism. Wild-type versions of a protein or polypeptide are employed, however, a modified protein or polypeptide may be employed to generate an immune response. The terms described above may be used interchangeably. A “modified protein” or “modified polypeptide” or a “variant” refers to a protein or polypeptide whose chemical structure, particularly its amino acid sequence, is altered with respect to the wild-type protein or polypeptide. A modified/variant protein or polypeptide may have at least one modified activity or function (recognizing that proteins or polypeptides may have multiple activities or functions). It is specifically contemplated that a modified/variant protein or polypeptide may be altered with respect to one activity or function yet retain a wild-type activity or function in other respects, such as immunogenicity. The term polypeptide also includes and antibody fragment described herein as well as antibody domains, such as HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, HFRW1, HFRW2, HFRW3, HFRW4, LFRW1, LFRW2, LFRW3, LFRW4, VH, VL, CH, or CL.


Where a protein is specifically mentioned herein, it is in general a reference to a native (wild-type) or recombinant (modified) protein or, optionally, a protein in which any signal sequence has been removed. The protein may be isolated directly from the organism of which it is native, produced by recombinant DNA/exogenous expression methods, or produced by solid-phase peptide synthesis (SPPS) or other in vitro methods. Also described are isolated nucleic acid segments and recombinant vectors incorporating nucleic acid sequences that encode a polypeptide (e.g., an antibody or fragment thereof). The term “recombinant” may be used in conjunction with a polypeptide or the name of a specific polypeptide, and this generally refers to a polypeptide produced from a nucleic acid molecule that has been manipulated in vitro or that is a replication product of such a molecule.


The size of an antibody, antigen binding fragment, protein or polypeptide (wild-type or modified) may comprise, but is not limited to, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 1500, 1750, 2000, 2250, 2500 amino acid residues or greater, and any range derivable therein, or derivative of a corresponding amino sequence described or referenced herein. It is contemplated that polypeptides may be mutated by truncation, rendering them shorter than their corresponding wild-type form, also, they might be altered by fusing or conjugating a heterologous protein or polypeptide sequence with a particular function (e.g., for targeting or localization, for enhanced immunogenicity, for purification purposes, etc.). As used herein, the term “domain” refers to any distinct functional or structural unit of a protein or polypeptide, and generally refers to a sequence of amino acids with a structure or function recognizable by one skilled in the art.


The antibody, antigen binding fragment, polypeptides, proteins, or polynucleotides encoding such polypeptides or proteins of the disclosure may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (or any derivable range therein) or more variant amino acids or nucleic acid substitutions or be at least 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with at least, or at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 300, 400, 500, 550, 1000 or more contiguous amino acids or nucleic acids, or any range derivable therein, of SEQ ID NO: 1-3028.


The antibody, antigen binding fragment, protein, or polypeptide may comprise amino acids 1 to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, or 1000, (or any derivable range therein) of SEQ ID NOS: 1-3028.


The antibody, antigen binding fragment, or polypeptide may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, or 1000, (or any derivable range therein) contiguous amino acids of SEQ ID NOs: 1-2706.


The antibody, antigen binding fragment, protein, or polypeptide may comprise at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, or 1000 (or any derivable range therein) contiguous amino acids of SEQ ID NOS: 1-3028 that are at least, at most, or exactly 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% (or any derivable range therein) similar, identical, or homologous with one of SEQ ID NOS: 1-3028.


Also provided is a nucleic acid molecule, antibody, antigen binding fragment, protein, or polypeptide starting at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, or 1000 of any of SEQ ID NOS: 1-3028 and comprising at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, or 1000 (or any derivable range therein) contiguous amino acids or nucleotides of any of SEQ ID NOS: 1-3028.


The amino acid at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, or 400 of the heavy chain, light chain, VH, VL, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3, HFRW1, HFRW2, HFRW3, HFRW4, LFRW1, LFRW2, LFRW3, or LFRW4 identified in Table 1 is substituted with an alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.


A polypeptide (e.g., antibody, antibody fragment, Fab, etc.) of the disclosure comprises a CDR that is at least 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% identical (or any range derivable therein) in sequence to a HCDR or LCDR identified in Table 1. A polypeptide may comprise 1, 2, and/or 3 CDRs from a heavy chain or light chain variable region identified in Table 1. The CDR may be one that has been determined by Kabat, IMGT, or Chothia. A polypeptide may have CDRs that have 1, 2, and/or 3 amino acid changes (e.g., addition of 1 or 2 amino acids, deletions of 1 or 2 amino acids, substitution) with respect to these 1, 2, or 3 CDRs. A polypeptide may comprise additionally or alternatively, an amino acid sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical or homologous to the amino acid sequence of the variable region that is not a CDR sequence, i.e., the variable region framework.


From amino to carboxy terminus the CDRs are CDR1, CDR2, and CDR3. A polypeptide may have CDRs that have 1, 2, and/or 3 amino acid changes (e.g., addition of 1 or 2 amino acids, deletions of 1 or 2 amino acids, substitution) with respect to CDR1, CDR2, or CDR3. The CDRs identified in Table 1 may further comprise 1, 2, 3, 4, 5, or 6 additional amino acids at the amino or carboxy terminus of the CDR, The additional amino acids may be from the heavy and/or light chain framework regions of SEQ ID NOS: 44-76, that are shown as immediately adjacent to the CDRs. Accordingly, also described are polypeptides comprising an HCDR1 (i.e., CDR-H1), HCDR2 (i.e., CDR-H2), HCDR3 (i.e., CDR-H3), LCDR1 (i.e., CDR-L1), LCDR2 (i.e., CDR-L2), and/or LCDR3 (i.e., CDR-L3) with at least or at most or exactly 1, 2, 3, 4, 5, 6 or 7 amino acids at the amino end of the CDR or at the carboxy end of the CDR, wherein the additional amino acids are the 1, 2, 3, 4, 5, 6, or 7 amino acids that are shown as immediately adjacent to the CDRs in a variable region of Table 1. Also included are antibodies comprising one or more CDRs, wherein the CDR is a fragment of a CDR identified in Table 1 and wherein the fragment lacks 1, 2, 3, 4, or 5 amino acids from the amino or carboxy end of the CDR. The CDR may lack one, 2, 3, 4, 5, 6, or 7 amino acids from the carboxy end and may further comprise 1, 2, 3, 4, 5, 6, 7, or 8 amino acids from the framework region of the amino end of the CDR. The CDR may lack one, 2, 3, 4, 5, 6, or 7 amino acids from the amino end and may further comprise 1, 2, 3, 4, 5, 6, 7, or 8 amino acids from the framework region of the carboxy end of the CDR. An antibody may be alternatively or additionally humanized in regions outside the CDR(s) and/or variable region(s). A polypeptide may comprise, additionally or alternatively, an amino acid sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, or 100% identical or homologous to the amino acid sequence of the variable region that is not a CDR sequence, i.e., the variable region framework.


A polypeptide or protein may comprise 1, 2, 3, 4, 5, or 6 CDRs from either or both of the light and heavy variable regions of an antibody clone identified in Table, and 1, 2, 3, 4, 5, or 6 CDRs may have 1, 2, and/or 3 amino acid changes with respect to these CDRs. Parts or all of the antibody sequence outside the variable region may have been humanized. A protein may comprise one or more polypeptides. A protein may contain one or two polypeptides similar to a heavy chain polypeptide and/or 1 or 2 polypeptides similar to a light chain polypeptide.


The nucleotide as well as the protein, polypeptide, and peptide sequences for various genes have been previously disclosed, and may be found in the recognized computerized databases. Two commonly used databases are the National Center for Biotechnology Information's Genbank and GenPept databases (on the World Wide Web at ncbi.nlm.nih.gov/) and The Universal Protein Resource (UniProt; on the World Wide Web at uniprot.org). The coding regions for these genes may be amplified and/or expressed using the techniques disclosed herein or as would be known to those of ordinary skill in the art.


It is contemplated that in compositions of the disclosure, there is between about 0.001 mg and about 10 mg of total polypeptide, peptide, and/or protein per ml. The concentration of protein in a composition can be about, at least about or at most about 0.001, 0.010, 0.050, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 mg/ml or more (or any range derivable therein).


VI. Sequences

Polypeptide, antibody, and antigen binding fragments are shown below in the following tables. In the table below, HC refers to heavy chain (including the heavy chain variable and constant regions), and LC refers to light chain (including the light chain variable and constant regions). HCDR1, HCDR2, and HCDR3 are the heavy chain complementarity-determining regions, and LCDR1, LCDR2, and LCDR3 are the light chain complementarity-determining regions. HFR1, HFR2, HFR3, and HFR4 are the framework regions of the heavy chain variable region, and LFR1, LFR2, LFR3, and LFR4 are the framework regions of the light chain variable region. HC variable refers to the heavy chain variable region, and LC variable refers to the light chain variable region.









TABLE 1







Antibody and antigen binding embodiments













SEQ



Descrip-

ID


Clone
tion
Sequence
NO:













S20-15
HC
QVQLQESGPGLVRPSETLSLTCTVS
1




GGSISSHYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLISVTAADTAVYYCARAGG





VFGVVLDFDHWGRGTLVTVSSASTK





GPSVFPLAPSSKSTSGGTAALGCLV





KDYFPEPVTVSWNSGALTSGVHTFP





AVLQSSG







HC
QVQLQESGPGLVRPSETLSLTCTVS
2



variable
GGSISSHYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLISVTAADTAVYYCARAGG





VFGVVLDFDHWGRGTLVTVSS







HCDR1
SHYWS
3






HCDR2
YIYYSGSTNYNPSLKS
4






HCDR3
AGGVFGVVLDFDH
5






HFR1
QVQLQESGPGLVRPSETLSLTCTVS
6




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLISVTAADT
8




AVYYCAR







HFR4
WGRGTLVTVSS
9






LC
SYVLTQPPSVSVAPGQTARITCGGN
10




NIGSKSVHWYQQKPGQAPVLVVYDD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSEHYVFG





TGTKVTVLGQPKANPTVTLFPPSSE





ELQANKATLVCLISDFYPGAVTVAW





KADGSPVKAGVETTKPSKQSNNKYA





ASS







LC
SYVLTQPPSVSVAPGQTARITCGGN
11



variable
NIGSKSVHWYQQKPGQAPVLVVYDD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSEHYVFG





TGTKVTVL







LCDR1
GGNNIGSKSVH
12






LCDR2
DDSDRPS
13






LCDR3
QVWDSSSEHYV
14






LFR1
SYVLTQPPSVSVAPGQTARITC
15






LFR2
WYQQKPGQAPVLVVY
16






LFR3
GIPERFSGSNSGNTATLTISRVEAG
17




DEADYYC







LFR4
FGTGTKVTVL
18





S20-22
HC
QVQLQESGPGLVKPSETLSLTCTVS
19




GGSISSFYWGWIRQPAGKGLEWIGR





FHTSGSTNYNPSFKSRVTMSVDTSK





NQFSLKLTSVTAADTAVYYCASGRG





SSWYVGWFFDLWGRGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
20



variable
GGSISSFYWGWIRQPAGKGLEWIGR





FHTSGSTNYNPSFKSRVTMSVDTSK





NQFSLKLTSVTAADTAVYYCASGRG





SSWYVGWFFDLWGRGTLVTVSS







HCDR1
SFYWG
21






HCDR2
RFHTSGSTNYNPSFKS
22






HCDR3
GRGSSWYVGWFFDL
23






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPAGKGLEWIG
25






HFR3
RVTMSVDTSKNQFSLKLTSVTAADT
26




AVYYCAS







HFR4
WGRGTLVTVSS
9






LC
DIVMTQSPDSLAVSLGERATINCKS
27




SQTVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAGDVAVYYCQQYYNT





PDTFGGGTKVEINRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDN







LC
DIVMTQSPDSLAVSLGERATINCKS
28



variable
SQTVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAGDVAVYYCQQYYNT





PDTFGGGTKVEI







LCDR1
KSSQTVLYSSNNKNYLA
29






LCDR2
WASTRES
30






LCDR3
QQYYNTPDT
31






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTISSLQAG
34




DVAVYYC







LFR4
FGGGTKVEI
35





S20-31
HC
QVQLIQSGAEVKKPGASVKVSCTAS
36




GYSLNELPIQWVRQAPGKGLEWMGE





FDPEDGETIYAEKFQGRVTLTEETS





TNTAYMELSSLKSEDTAAYFCSTGS





TIGVVIYAFAIWGQGTMVTVSSAST





KGPSVFPLAPCSRSTSESTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLIQSGAEVKKPGASVKVSCTAS
37



variable
GYSLNELPIQWVRQAPGKGLEWMGE





FDPEDGETIYAEKFQGRVTLTEETS





TNTAYMELSSLKSEDTAAYFCSTGS





TIGVVIYAFAIWGQGTMVTVSS







HCDR1
ELPIQ
38






HCDR2
EFDPEDGETIYAEKFQG
39






HCDR3
GSTIGVVIYAFAI
40






HFR1
QVQLIQSGAEVKKPGASVKVSCTAS
41




GYSLN







HFR2
WVRQAPGKGLEWMG
42






HFR3
RVTLTEETSTNTAYMELSSLKSEDT
43




AAYFCST







HFR4
WGQGTMVTVSS
44






LC
EIVLTQSPGTLSLSPGERATLSCRA
45




SQDITNNFLAWYQQKAGQAPKLFIY





GASRRAPGIPHRFSGSGSGTDFTLT





ISSLEPEDFAVYYCQQYGPSPTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
46



variable
SQDITNNFLAWYQQKAGQAPKLFIY





GASRRAPGIPHRFSGSGSGTDFTLT





ISSLEPEDFAVYYCQQYGPSPTFGQ





GTKVEIK







LCDR1
RASQDITNNFLA
47






LCDR2
GASRRAP
48






LCDR3
QQYGPSPT
49






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKAGQAPKLFIY
51






LFR3
GIPHRFSGSGSGTDFTLTISSLEPE
52




DFAVYYC







LFR4
FGQGTKVEIK
53





S20-40
HC
QVQLQESGPGLVKPSETLSLTCTVS
54




GGSISSYYWSWIRQPAGKGLEWIGR





IYTSGSTNYNPSLKSRVTMSVDTSK





NQFSLKLSSVTAADTAVYYCARGGS





GWRFDYWGQGTLVTVSSGSASAPTL





FPLVSCENSPSDTSSV







HC
QVQLQESGPGLVKPSETLSLTCTVS
55



variable
GGSISSYYWSWIRQPAGKGLEWIGR





IYTSGSTNYNPSLKSRVTMSVDTSK





NQFSLKLSSVTAADTAVYYCARGGS





GWRFDYWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
RIYTSGSTNYNPSLKS
57






HCDR3
GGSGWRFDY
58






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPAGKGLEWIG
25






HFR3
RVTMSVDTSKNQFSLKLSSVTAADT
59




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
61




SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLG





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QSALTQPASVSGSPGQSITISCTGT
62



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLG





VFGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
DVSNRPS
64






LCDR3
SSYTSSSTLGV
65






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S20-58
HC
QVQLQESGPGLVKPSQTLSLTCTVS
70




GGSINSGDYYWSWIRQPPGKGLEWI





GYIYFSGSTYYNPSLKSRVTISLDR





SKNQFSLKLSSVTAADTAVYYCARE





ESMITLGGVIVDWGQGTLVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
QVQLQESGPGLVKPSQTLSLTCTVS
71



variable
GGSINSGDYYWSWIRQPPGKGLEWI





GYIYFSGSTYYNPSLKSRVTISLDR





SKNQFSLKLSSVTAADTAVYYCARE





ESMITLGGVIVDWGQGTLVTVSS







HCDR1
SGDYYWS
72






HCDR2
YIYFSGSTYYNPSLKS
73






HCDR3
EESMITLGGVIVD
74






HFR1
QVQLQESGPGLVKPSQTLSLTCTVS
75




GGSIN







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISLDRSKNQFSLKLSSVTAADT
76




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQTPLSSPVTLGQPASISCRS
77




SQSLVHSDGDTYLSWLQQRPGQPPR





LLIYKISNRFSGVPDRFSGSGAGTD





FTLKISRVEAEDVGVYYCMQATQFP





LTFGGGTKVEIKRTVAAPSVFIFPP





SDEQLKSGTASVVCLLNNFYPREAK





VQWKVDNALQSGNSQESVTEQDSKD





STYSLSSTLTLSKADYE







LC
DIVMTQTPLSSPVTLGQPASISCRS
78



variable
SQSLVHSDGDTYLSWLQQRPGQPPR





LLIYKISNRFSGVPDRFSGSGAGTD





FTLKISRVEAEDVGVYYCMQATQFP





LTFGGGTKVEIK







LCDR1
RSSQSLVHSDGDTYLS
79






LCDR2
KISNRFS
80






LCDR3
MQATQFPLT
81






LFR1
DIVMTQTPLSSPVTLGQPASISC
82






LFR2
WLQQRPGQPPRLLIY
83






LFR3
GVPDRFSGSGAGTDFTLKISRVEAE
84




DVGVYYC







LFR4
FGGGTKVEIK
85





S20-74
HC
QVQLQESGPGLVKPSETLSLTCTVS
86




GGSISSHYWSWIRQPPGKGLEQIGY





MYYSGSTNYNPSLKSRVIISVDTSK





NQFSLKLSSVTAADTAVYYCAGRDQ





LLYGADGFDIWGQGTMVTVSSASTK





GPSVFPLAPSSKSTSGGTAALGCLV





KDYFPEPVTVSWNSGALTSGVHTFP





AVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
87



variable
GGSISSHYWSWIRQPPGKGLEQIGY





MYYSGSTNYNPSLKSRVIISVDTSK





NQFSLKLSSVTAADTAVYYCAGRDQ





LLYGADGFDIWGQGTMVTVSS







HCDR1
SHYWS
3






HCDR2
YMYYSGSTNYNPSLKS
88






HCDR3
RDQLLYGADGFDI
89






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEQIG
90






HFR3
RVIISVDTSKNQFSLKLSSVTAADT
91




AVYYCAG







HFR4
WGQGTMVTVSS
44






LC
QSALTQPPSASGSPGQSVTISCTGT
92




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRYSGSKSGNTASL





TVSGLQAEDEADYYCSSYAGSSNHV





IFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QSALTQPPSASGSPGQSVTISCTGT
93



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRYSGSKSGNTASL





TVSGLQAEDEADYYCSSYAGSSNHV





IFGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSKRPS
94






LCDR3
SSYAGSSNHVI
95






LFR1
QSALTQPPSASGSPGQSVTISC
96






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRYSGSKSGNTASLTVSGLQAE
97




DEADYYC







LFR4
FGGGTKLTVL
69





S20-86
HC
EVQLVESGGGLVQPGRSLRLSCAAS
98




GFTFGDYAMYWVRQPPGKGLEWVSG





ISWNRGTIGYADSVKGRFTISRDNA





KNSLYLQMNSLTPEDTALYYCAKDM





LPASRFFYYMDVWGKGTTVIVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
EVQLVESGGGLVQPGRSLRLSCAAS
99



variable
GFTFGDYAMYWVRQPPGKGLEWVSG





ISWNRGTIGYADSVKGRFTISRDNA





KNSLYLQMNSLTPEDTALYYCAKDM





LPASRFFYYMDVWGKGTTVIVSS







HCDR1
DYAMY
100






HCDR2
GISWNRGTIGYADSVKG
101






HCDR3
DMLPASRFFYYMDV
102






HFR1
EVQLVESGGGLVQPGRSLRLSCAAS
103




GFTFG







HFR2
WVRQPPGKGLEWVS
104






HFR3
RFTISRDNAKNSLYLQMNSLTPEDT
105




ALYYCAK







HFR4
WGKGTTVIVSS
106






LC
QSALTQPASVSGSPGQSITISCTGT
107




SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLG





VFGTGTKVTVLGQPKANPTVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADGSPVKAGVETTKPSKQSNN





KYAASS







LC
QSALTQPASVSGSPGQSITISCTGT
108



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLG





VFGTGTKVTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
DVSNRPS
64






LCDR3
SSYTSSSTLGV
65






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGTGTKVTVL
18





S24-68
HC
QVQLQESGPGLVKPSETLSLTCTVS
109




GGSITSYYWSWIRQPPGKGLEWIEY





IHYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARLLK





YSRGGCYFDHWGQGTLVTVSSASTK





GPSVFPLAPSSKSTSGGTAALGCLV





KDYFPEPVTVSWNSGALTSGVHTFP





AVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
110



variable
GGSITSYYWSWIRQPPGKGLEWIEY





IHYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARLLK





YSRGGCYFDHWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
YIHYSGSTNYNPSLKS
111






HCDR3
LLKYSRGGCYFDH
112






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
113




GGSIT







HFR2
WIRQPPGKGLEWIE
114






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSASGTPGQRVTISCSGS
116




SSNIGGNPVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLKGPV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASSYLSLTPEQWKSH







LC
QSVLTQPPSASGTPGQRVTISCSGS
117



variable
SSNIGGNPVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLKGPV





FGGGTKLTVL







LCDR1
SGSSSNIGGNPVN
118






LCDR2
SNNQRPS
119






LCDR3
AAWDDSLKGPV
120






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLQSE
123




DEADYYC







LFR4
FGGGTKLTVL
69





S24-105
HC
EVQLVESGGGLVQPGGSLRLSCAAS
124




GFTLSSYSMNWVRQAPGKGLEWVSY





ISSSSSTIYYADSVKGRFTISKDNA





KNSLYLQMNSLRAEDTAVYYCAVGR





GYFVYWGQGTLVTVSSASTKGPSVF





PLAPSSKSTSGGTAALGCLVKDYFP





EPVTVSWNSGALTSGVHTFPAVLQS





SG







HC
EVQLVESGGGLVQPGGSLRLSCAAS
125



variable
GFTLSSYSMNWVRQAPGKGLEWVSY





ISSSSSTIYYADSVKGRFTISKDNA





KNSLYLQMNSLRAEDTAVYYCAVGR





GYFVYWGQGTLVTVSS







HCDR1
SYSMN
126






HCDR2
YISSSSSTIYYADSVKG
127






HCDR3
GRGYFVY
128






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
129




GFTLS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISKDNAKNSLYLQMNSLRAEDT
131




AVYYCAV







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
132




SQSVSSGYLAWYQQKPGQAPRLLIF





GASSRATGIPDRFSGSGSGTDFTLT





INRLEPEDFAVYYCQQYGSSRTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
133



variable
SQSVSSGYLAWYQQKPGQAPRLLIF





GASSRATGIPDRFSGSGSGTDFTLT





INRLEPEDFAVYYCQQYGSSRTFGQ





GTKVEIK







LCDR1
RASQSVSSGYLA
134






LCDR2
GASSRAT
135






LCDR3
QQYGSSRT
136






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIF
137






LFR3
GIPDRFSGSGSGTDFTLTINRLEPE
138




DFAVYYC







LFR4
FGQGTKVEIK
53





S24-178
HC
QVQLVESGGGVVQPGRSLRLSCAAS
139




GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARIE





GYSYGDVRVYYYYGMDVWGQGTTVT





VSSASTKGPSVFPLAPSSKSTSGGT





AALGCLVKDYFPEPVTVSWNSGALT





SGVHTFPAVLQSSG







HC
QVQLVESGGGVVQPGRSLRLSCAAS
140



variable
GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARIE





GYSYGDVRVYYYYGMDVWGQGTTVT





VSS







HCDR1
SYGMH
141






HCDR2
VIWYDGSNKYYADSVKG
142






HCDR3
IEGYSYGDVRVYYYYGMDV
143






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
QSALTQPASVSGSPGQSITISCTGT
148




TSDVGGYDYVSWYQQHPGKAPKLIL





SEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYPSSSTLV





FGTGTKVTVLGQPKANPTVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADGSPVKAGVETTTPSKQSNNK





YAASS







LC
QSALTQPASVSGSPGQSITISCTGT
149



variable
TSDVGGYDYVSWYQQHPGKAPKLIL





SEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYPSSSTLV





FGTGTKVTVL







LCDR1
TGTTSDVGGYDYVS
150






LCDR2
EVSNRPS
151






LCDR3
SSYPSSSTLV
152






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLILS
153






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGTGTKVTVL
18





S24-188
HC
QVHLVQSGAEVKKPGSSVKVSCKAS
154




GGTFSSCAISWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARGW





EFGSGSYYRTDYYYYAMDVWGQGTT





VTVSSASTKGPSVFPLAPCSRSTSG





GTAALGCLVKDYFPEPVTVSWNSGA





LTSGVHTFPAVLQSSG







HC
QVHLVQSGAEVKKPGSSVKVSCKAS
155



variable
GGTFSSCAISWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARGW





EFGSGSYYRTDYYYYAMDVWGQGTT





VTVSS







HCDR1
SCAIS
156






HCDR2
RIIPILGIANYAQKFQG
157






HCDR3
GWEFGSGSYYRTDYYYYAMDV
158






HFR1
QVHLVQSGAEVKKPGSSVKVSCKAS
159




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
QSALTQPASVSGSPGQSITISCTGT
162




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVTNRPSGVSNRFSGSRSGNTASL





TISGLQAEDEADYYCSSYTSSSLYV





FGTGTKVAVLGQPKANPTVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTKPSKQSNNK





YAASS







LC
QSALTQPASVSGSPGQSITISCTGT
163



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVTNRPSGVSNRFSGSRSGNTASL





TISGLQAEDEADYYCSSYTSSSLYV





FGTGTKVAVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVTNRPS
164






LCDR3
SSYTSSSLYV
165






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSRSGNTASLTISGLQAE
166




DEADYYC







LFR4
FGTGTKVAVL
167





S24-202
HC
EVQLVQSGAEVKKPGESLRISCKGS
168




GYSFSSYWISWVRQMPGKGLEWMGR





IDPSDSNTNYSPSFQGHVTISADKS





ISTAYLQWSSLKASDTAMYYCARLS





VRVWFGELPHYGMDVWGQGTTVTVS





SASTKGPSVFPLAPSSKSTSGGTAA





LGCLVKDYFPEPVTVSWNSGALTSG





VHTFPAVLQSSG







HC
EVQLVQSGAEVKKPGESLRISCKGS
169



variable
GYSFSSYWISWVRQMPGKGLEWMGR





IDPSDSNTNYSPSFQGHVTISADKS





ISTAYLQWSSLKASDTAMYYCARLS





VRVWFGELPHYGMDVWGQGTTVTVS





S







HCDR1
SYWIS
170






HCDR2
RIDPSDSNTNYSPSFQG
171






HCDR3
LSVRVWFGELPHYGMDV
172






HFR1
EVQLVQSGAEVKKPGESLRISCKGS
173




GYSFS







HFR2
WVRQMPGKGLEWMG
174






HFR3
HVTISADKSISTAYLQWSSLKASDT
175




AMYYCAR







HFR4
WGQGTTVTVSS
147






LC
EIVLTQSPATLSLSPGERATLSCRA
176




SQSVSSYLAWYQQKPGQAPRLLIYD





ASNRASGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRRNWPLTFGG





GTKVETKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DN







LC
EIVLTQSPATLSLSPGERATLSCRA
177



variable
SQSVSSYLAWYQQKPGQAPRLLIYD





ASNRASGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRRNWPLTFGG





GTKVETK







LCDR1
RASQSVSSYLA
178






LCDR2
DASNRAS
179






LCDR3
QQRRNWPLT
180






LFR1
EIVLTQSPATLSLSPGERATLSC
181






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTDFTLTISSLEPE
183




DFAVYYC







LFR4
FGGGTKVETK
184





S24-278
HC
QVQLVQSGAEVKKPGASVKVSCKAS
185




GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGDTNYAQKFQGWVTMTRDTS





LSTAYMELSRLKSDDTAVYYCARVG





VGEYSGRHYYYYGMDVWGQGTTVTV





SSASTKGPSVFPLAPSSKSTSGGTA





ALGCLVKDYFPEPVTVSWNSGALTS





GVHTFPAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
186



variable
GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGDTNYAQKFQGWVTMTRDTS





LSTAYMELSRLKSDDTAVYYCARVG





VGEYSGRHYYYYGMDVWGQGTTVTV





SS







HCDR1
GYYMH
187






HCDR2
WINPNSGDTNYAQKFQG
188






HCDR3
VGVGEYSGRHYYYYGMDV
189






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
WVTMTRDTSLSTAYMELSRLKSDDT
191




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
EIVLTQSPGTLSLSPGERATLSCRA
192




SQSISSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSLTFGG





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DN







LC
EIVLTQSPGTLSLSPGERATLSCRA
193



variable
SQSISSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSLTFGG





GTKVEIK







LCDR1
RASQSISSSYLA
194






LCDR2
GASSRAT
135






LCDR3
QQYGSSLT
195






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGGGTKVEIK
85





S24-339
HC
EVQLVESGGGLVQPGRSLRLSCTAS
197




GFTFGDYAMSWFRQAPGKGLEWVGF





IRSKAYGGTTQHAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYHCAR





DGYDCSGGRCYSHIFDYWGQGTLVT





VSSGESSPPPLVHLGRLSLPGSQGQ





SLV







HC
EVQLVESGGGLVQPGRSLRLSCTAS
198



variable
GFTFGDYAMSWFRQAPGKGLEWVGF





IRSKAYGGTTQHAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYHCAR





DGYDCSGGRCYSHIFDYWGQGTLVT





VSS







HCDR1
DYAMS
199






HCDR2
FIRSKAYGGTTQHAASVKG
200






HCDR3
DGYDCSGGRCYSHIFDY
201






HFR1
EVQLVESGGGLVQPGRSLRLSCTAS
202




GFTFG







HFR2
WFRQAPGKGLEWVG
203






HFR3
RFTISRDDSKSIAYLQMNSLKTEDT
204




AVYHCAR







HFR4
WGQGTLVTVSS
60






LC
EIVMTQSPATLSVSPGERATLSCRA
205




SQSVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYDNWWTFGQG





TKVEIKRTVAAPSVFIFPPSDEQLK





SGTASVVCLLNNFYPREAKVQWKVD





N







LC
EIVMTQSPATLSVSPGERATLSCRA
206



variable
SQSVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYDNWWTFGQG





TKVEIK







LCDR1
RASQSVSSNLA
207






LCDR2
GASTRAT
208






LCDR3
QQYDNWWT
209






LFR1
EIVMTQSPATLSVSPGERATLSC
210






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTEFTLTISSLQSE
211




DFAVYYC







LFR4
FGQGTKVEIK
53





S24-472
HC
QVQLQESGPGLVKPSGTLSLTCAVS
212




GGSISSINWWSWVRQPPGKGLEWIG





EIYHSGNTNYNPSLKSRVTISGDKS





KNQFSLKLSSVTAADTAVYYCARGY





YDSSPYYEPQGIDYWGQGILVTVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSG







HC
QVQLQESGPGLVKPSGTLSLTCAVS
213



variable
GGSISSINWWSWVRQPPGKGLEWIG





EIYHSGNTNYNPSLKSRVTISGDKS





KNQFSLKLSSVTAADTAVYYCARGY





YDSSPYYEPQGIDYWGQGILVTVSS







HCDR1
SINWWS
214






HCDR2
EIYHSGNTNYNPSLKS
215






HCDR3
GYYDSSPYYEPQGIDY
216






HFR1
QVQLQESGPGLVKPSGTLSLTCAVS
217




GGSIS







HFR2
WVRQPPGKGLEWIG
218






HFR3
RVTISGDKSKNQFSLKLSSVTAADT
219




AVYYCAR







HFR4
WGQGILVTVSS
220






LC
QLVLTQSPSASASLGASVKLTCTLS
221




SGHSSYTIAWHQQQPEKGPRYLMKV





NSDGSHTKGDGIPDRFSGSSSGAER





YLTISSLQSEDEADYYCQTWGTGIR





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QLVLTQSPSASASLGASVKLTCTLS
222



variable
SGHSSYTIAWHQQQPEKGPRYLMKV





NSDGSHTKGDGIPDRFSGSSSGAER





YLTISSLQSEDEADYYCQTWGTGIR





VFGGGTKLTVL







LCDR1
TLSSGHSSYTIA
223






LCDR2
VNSDGSHTKGD
224






LCDR3
QTWGTGIRV
225






LFR1
QLVLTQSPSASASLGASVKLTC
226






LFR2
WHQQQPEKGPRYLMK
227






LFR3
GIPDRFSGSSSGAERYLTISSLQSE
228




DEADYYC







LFR4
FGGGTKLTVL
69





S24-490
HC
QVQLVQSGAEVKKPGASVKVSCKAS
229




GYTFTSYFIHWVRQAPGQGLEWMGI





INPSGGSTSYAQKFQGRVTMTRDTS





TSTVYMELSSLRSEDTAVYYCARHT





TPTRYFDYWGQGTLVTVSSGSASAP





TLFPLVSCENSPSDTSSV







HC
QVQLVQSGAEVKKPGASVKVSCKAS
230



variable
GYTFTSYFIHWVRQAPGQGLEWMGI





INPSGGSTSYAQKFQGRVTMTRDTS





TSTVYMELSSLRSEDTAVYYCARHT





TPTRYFDYWGQGTLVTVSS







HCDR1
SYFIH
231






HCDR2
IINPSGGSTSYAQKFQG
232






HCDR3
HTTPTRYFDY
233






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSTSTVYMELSSLRSEDT
234




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
235




SQSVTSSYLAWYQQRRGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPLTFG





GGTKVEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDN







LC
EIVLTQSPGTLSLSPGERATLSCRA
236



variable
SQSVTSSYLAWYQQRRGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPLTFG





GGTKVEIK







LCDR1
RASQSVTSSYLA
237






LCDR2
GASSRAT
135






LCDR3
QQYGSSPLT
238






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQRRGQAPRLLIY
239






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGGGTKVEIK
85





S24-494
HC
QLQLQESGPGLVKPSETLSLTCTVS
240




GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARK





PRSDYGYFDLWGRGTLVTVSSASTK





GPSV







HC
QLQLQESGPGLVKPSETLSLTCTVS
241



variable
GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARK





PRSDYGYFDLWGRGTLVTVSS







HCDR1
SSSYYWG
242






HCDR2
SIYYSGSTYYNPSLKS
243






HCDR3
KPRSDYGYFDL
244






HFR1
QLQLQESGPGLVKPSETLSLTCTVS
245




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGRGTLVTVSS
9






LC
DIQMTQSPSSLSASVGDRVTITCRA
246




SQSISSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYSTPQLTFG





GGTKVEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDN







LC
DIQMTQSPSSLSASVGDRVTITCRA
247



variable
SQSISSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYSTPQLTFG





GGTKVEIK







LCDR1
RASQSISSYLN
248






LCDR2
AASSLQS
249






LCDR3
QQSYSTPQLT
250






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGGGTKVEIK
85





S24-566
HC
EVQLVESGGGLVKPGRSLRLSCTAS
254




GFTFGDYAMSWFRQAPGKGLEWVGF





TRRKAYGGTTEYAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYYCTR





IKVGRFDLTDSGSYRYFDYWGQGTL





VTVSSASTKGPSVFPLAPSSKSTSG





GTAALGCLVKDYFPEPVTVSWNSGA





LTSGVHTFPAVLQSSG







HC
EVQLVESGGGLVKPGRSLRLSCTAS
255



variable
GFTFGDYAMSWFRQAPGKGLEWVGF





TRRKAYGGTTEYAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYYCTR





IKVGRFDLTDSGSYRYFDYWGQGTL





VTVSS







HCDR1
DYAMS
199






HCDR2
FTRRKAYGGTTEYAASVKG
256






HCDR3
IKVGRFDLTDSGSYRYFDY
257






HFR1
EVQLVESGGGLVKPGRSLRLSCTAS
258




GFTFG







HFR2
WFRQAPGKGLEWVG
203






HFR3
RFTISRDDSKSIAYLQMNSLKTEDT
259




AVYYCTR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPLSLPVTPGEPASISCRS
260




SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSGSGTD





FTLKISRVEAEDVGVYYCMQPLQTP





WTFGQGTKVEIKRTVAAPSVFIFPP





SDEQLKSGTASVVCLLNNFYPREAK





VQWKVDN







LC
DIVMTQSPLSLPVTPGEPASISCRS
261



variable
SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSGSGTD





FTLKISRVEAEDVGVYYCMQPLQTP





WTFGQGTKVEIK







LCDR1
RSSQSLLHSNGYNYLD
262






LCDR2
LGSNRAS
263






LCDR3
MQPLQTPWT
264






LFR1
DIVMTQSPLSLPVTPGEPASISC
265






LFR2
WYLQKPGQSPQLLIY
266






LFR3
GVPDRFSGSGSGTDFTLKISRVEAE
267




DVGVYYC







LFR4
FGQGTKVEIK
53





S24-636
HC
EVQLVESGGGLVQPGGSLRLSCAAS
268




GFTLSSYWMSWVRQAPGKGLEWVAN





IKQDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDL





TATWFDPWGQGTLVTVSSAPTKAPD





VFPIISGCRHPKDNSPVVLACLITG





YH







HC
EVQLVESGGGLVQPGGSLRLSCAAS
269



variable
GFTLSSYWMSWVRQAPGKGLEWVAN





IKQDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDL





TATWFDPWGQGTLVTVSS







HCDR1
SYWMS
270






HCDR2
NIKQDGSEKYYVDSVKG
271






HCDR3
DLTATWFDP
272






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
129




GFTLS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QTVVTQEPSFSVSPGGTVTLTCGLS
274




SGSVSTSYYPSWYQQTPGQAPRTLI





YSTNKRSSGVPDRFSGSILGNKAAL





TITGAQADDESDYYCVLYMGSGMSV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASS







LC
QTVVTQEPSFSVSPGGTVTLTCGLS
275



variable
SGSVSTSYYPSWYQQTPGQAPRTLI





YSTNKRSSGVPDRFSGSILGNKAAL





TITGAQADDESDYYCVLYMGSGMSV





FGGGTKLTVL







LCDR1
GLSSGSVSTSYYPS
276






LCDR2
STNKRSS
277






LCDR3
VLYMGSGMSV
278






LFR1
QTVVTQEPSFSVSPGGTVTLTC
279






LFR2
WYQQTPGQAPRTLIY
280






LFR3
GVPDRFSGSILGNKAALTITGAQAD
281




DESDYYC







LFR4
FGGGTKLTVL
69





S24-740
HC
QVQLVQSGAEVKKPGASVKVSCKAS
282




GYTFTSYALHWVRQAPGQRLEWMGW





INAGNGNTKYSQRFQGRVTIIRDTS





ASTTYMELSSLRSEDTAVYYCARGY





ARAGVITIKESLHHWGQGTLVTVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
283



variable
GYTFTSYALHWVRQAPGQRLEWMGW





INAGNGNTKYSQRFQGRVTIIRDTS





ASTTYMELSSLRSEDTAVYYCARGY





ARAGVITIKESLHHWGQGTLVTVSS







HCDR1
SYALH
284






HCDR2
WINAGNGNTKYSQRFQG
285






HCDR3
GYARAGVITIKESLHH
286






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQRLEWMG
287






HFR3
RVTIIRDTSASTTYMELSSLRSEDT
288




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCKS
289




SQSVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYST





PPLTFGGGTKVEIKRTVAAPSVFIF





PPSDEQLKSGTASVVCLLNNFYPRE





AKVQWKVDN







LC
DIVMTQSPDSLAVSLGERATINCKS
290



variable
SQSVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYST





PPLTFGGGTKVEIK







LCDR1
KSSQSVLYSSNNKNYLA
291






LCDR2
WASTRES
30






LCDR3
QQYYSTPPLT
292






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTISSLQAE
293




DVAVYYC







LFR4
FGGGTKVEIK
85





S24-791
HC
QVQLQESGPGLVKPSETLSLTCTVS
294




GGSISSSYWSWIRQPPGKGLEWIGY





IYYSGNTNYNPSLKSRVTLSIDTSK





NQFSLKLSSVTAADTAVYYCACSVT





IFGVVTPAFDIWGQGTMVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
295



variable
GGSISSSYWSWIRQPPGKGLEWIGY





IYYSGNTNYNPSLKSRVTLSIDTSK





NQFSLKLSSVTAADTAVYYCACSVT





IFGVVTPAFDIWGQGTMVTVSS







HCDR1
SSYWS
296






HCDR2
YIYYSGNTNYNPSLKS
297






HCDR3
SVTIFGVVTPAFDI
298






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTLSIDTSKNQFSLKLSSVTAADT
299




AVYYCAC







HFR4
WGQGTMVTVSS
44






LC
EIVLTHSPGTLSLSPGERATLSCRA
300




SQSVRSYLAWYQQKPGQAPRLLIYG





ASSRATGIPDRFSGSGSGTDFTLTI





SRLEPDDFAVYYCQQYGSSPWTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
EIVLTHSPGTLSLSPGERATLSCRA
301



variable
SQSVRSYLAWYQQKPGQAPRLLIYG





ASSRATGIPDRFSGSGSGTDFTLTI





SRLEPDDFAVYYCQQYGSSPWTFGQ





GTKVEIK







LCDR1
RASQSVRSYLA
302






LCDR2
GASSRAT
135






LCDR3
QQYGSSPWT
303






LFR1
EIVLTHSPGTLSLSPGERATLSC
304






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPD
305




DFAVYYC







LFR4
FGQGTKVEIK
53





S24-902
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
306




GGTFSSYAISWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARWD





FGVVIQYGMDVWGQGTTVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSGLYSLSSVVTVPSSSL







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
307



variable
GGTFSSYAISWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARWD





FGVVIQYGMDVWGQGTTVTVSS







HCDR1
SYAIS
308






HCDR2
RIIPILGIANYAQKFQG
157






HCDR3
WDFGVVIQYGMDV
309






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
QAVVTQEPSLTVSPGGTVTLTCGSS
311




TGAVTSGHYPYWFQQKPGQAPRTLI





YDTSNKHSWTPARFSGSLLGGKAAL





TLSGAQPEDEAEYYCLLSYSGWVFG





GGTKLTVLGQPKAAPSVTLFPPSSE





ELQANKATLVCLISDFYPGAVTVAW





KADSSPVKAGVETTTPSKQSNNKYA





ASS







LC
QAVVTQEPSLTVSPGGTVTLTCGSS
312



variable
TGAVTSGHYPYWFQQKPGQAPRTLI





YDTSNKHSWTPARFSGSLLGGKAAL





TLSGAQPEDEAEYYCLLSYSGWVFG





GGTKLTVL







LCDR1
GSSTGAVTSGHYPY
313






LCDR2
DTSNKHS
314






LCDR3
LLSYSGWV
315






LFR1
QAVVTQEPSLTVSPGGTVTLTC
316






LFR2
WFQQKPGQAPRTLIY
317






LFR3
WTPARFSGSLLGGKAALTLSGAQPE
318




DEAEYYC







LFR4
FGGGTKLTVL
69





S24-921
HC
QVQLQESGPGLVKPSETLSLTCTVS
319




GGSINSFYWNWIRQPPGKGLEWIGY





IYYSGNTKYNPSLKSRVTISVDTSN





SQFSLKLSSVTAADTAVYYCAALKK





QELVSLQAFDIWGQGTMVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
320



variable
GGSINSFYWNWIRQPPGKGLEWIGY





IYYSGNTKYNPSLKSRVTISVDTSN





SQFSLKLSSVTAADTAVYYCAALKK





QELVSLQAFDIWGQGTMVTVSS







HCDR1
SFYWN
321






HCDR2
YIYYSGNTKYNPSLKS
322






HCDR3
LKKQELVSLQAFDI
323






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
324




GGSIN







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSNSQFSLKLSSVTAADT
325




AVYYCAA







HFR4
WGQGTMVTVSS
44






LC
DIQMTQSPSSLSASLGDGVTITCRA
326




SQSISSYLSWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYNTPVTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNADRKS







LC
DIQMTQSPSSLSASLGDGVTITCRA
327



variable
SQSISSYLSWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYNTPVTFGQ





GTKVEIK




LCDR1
RASQSISSYLS
328






LCDR2
AASSLQS
249






LCDR3
QQSYNTPVT
329






LFR1
DIQMTQSPSSLSASLGDGVTITC
330






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKVEIK
53





S24-1063
HC
QVQLQESGPGLVKPSETLSLTCTVS
331




GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTKYNPSLKSRVTISVDTSK





NQFSLKLTSVTAADTAVYYCARIYD





SSGYYHPVFDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
332



variable
GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTKYNPSLKSRVTISVDTSK





NQFSLKLTSVTAADTAVYYCARIYD





SSGYYHPVFDYWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
YIYYSGSTKYNPSLKS
333






HCDR3
IYDSSGYYHPVFDY
334






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLTSVTAADT
335




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
336




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATDIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPWTFG





QGTKVEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDN







LC
EIVLTQSPGTLSLSPGERATLSCRA
337



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATDIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPWTFG





QGTKVEIK







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQYGSSPWT
303






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
DIPDRFSGSGSGTDFTLTISRLEPE
339




DFAVYYC







LFR4
FGQGTKVEIK
53





S24-1224
HC
QVQLVQSGAEVKKPGASVRVSCKAS
340




GYTFTSYYIYWVRQAPGQGLEWMGV





INPSGGSTSYAQKFQGRVTLTRDTS





TSTVYMDLSSLRSEDTAVYYCARDP





IMWEVVTRGRGNWFDPWGQGTLVTV





SSASTKGPSVFPLAPSSKSTSGGTA





ALGCLVKDYFPEPVTVSWNSGALTS





GVHTFPAVLQSSG







HC
QVQLVQSGAEVKKPGASVRVSCKAS
341



variable
GYTFTSYYIYWVRQAPGQGLEWMGV





INPSGGSTSYAQKFQGRVTLTRDTS





TSTVYMDLSSLRSEDTAVYYCARDP





IMWEVVTRGRGNWFDPWGQGTLVTV





SS







HCDR1
SYYIY
342






HCDR2
VINPSGGSTSYAQKFQG
343






HCDR3
DPIMWEVVTRGRGNWFDP
344






HFR1
QVQLVQSGAEVKKPGASVRVSCKAS
345




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTLTRDTSTSTVYMDLSSLRSEDT
346




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSVSGAPGQRVTIPCTGS
347




SFNIGAGYDVHWYQQLPGTAPKLLI





FGNSNRPSGVPDRFSGSRSGTSASL





AITGLQAEDEADYYCQSYDSSLSGV





VFGGGTTLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASSYLSLTPEQWKSH







LC
QSVLTQPPSVSGAPGQRVTIPCTGS
348



variable
SFNIGAGYDVHWYQQLPGTAPKLLI





FGNSNRPSGVPDRFSGSRSGTSASL





AITGLQAEDEADYYCQSYDSSLSGV





VFGGGTTLTVL







LCDR1
TGSSFNIGAGYDVH
349






LCDR2
GNSNRPS
350






LCDR3
QSYDSSLSGVV
351






LFR1
QSVLTQPPSVSGAPGQRVTIPC
352






LFR2
WYQQLPGTAPKLLIF
353






LFR3
GVPDRFSGSRSGTSASLAITGLQAE
354




DEADYYC







LFR4
FGGGTTLTVL
355





S24-1271
HC
EVQLVESGGGLVQPGGSLRLSCAAS
356




GFTVSSNYMSWVRQAPGKGLEWVSV





IYSDGNTYYADSVKGRFTISRDNSK





NMLYLQMNSLRAEDTAVYYCARDPG





QGYCSGGSCAPSYSLDYWGQGTLVT





VSSGSASAPTLFPLVSCENSPSDTS





SV







HC
EVQLVESGGGLVQPGGSLRLSCAAS
357



variable
GFTVSSNYMSWVRQAPGKGLEWVSV





IYSDGNTYYADSVKGRFTISRDNSK





NMLYLQMNSLRAEDTAVYYCARDPG





QGYCSGGSCAPSYSLDYWGQGTLVT





VSS







HCDR1
SNYMS
358






HCDR2
VIYSDGNTYYADSVKG
359






HCDR3
DPGQGYCSGGSCAPSYSLDY
360






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
361




GFTVS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNMLYLQMNSLRAEDT
362




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
SYELTQPPSVSVSPGQTASITCSGD
363




KLGDRYVCWYQQKPGQSPVLVIYQD





TKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTWVFGGG





TKLTVLGQPKAAPSVTLFPPSSEEL





QANKATLVCLISDFYPGAVTVAWKA





DSSPVKAGVETTTPSKQSNNKYAAS





S







LC
SYELTQPPSVSVSPGQTASITCSGD
364



variable
KLGDRYVCWYQQKPGQSPVLVIYQD





TKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTWVFGGG





TKLTVL







LCDR1
SGDKLGDRYVC
365






LCDR2
QDTKRPS
366






LCDR3
QAWDSSTWV
367






LFR1
SYELTQPPSVSVSPGQTASITC
368






LFR2
WYQQKPGQSPVLVIY
369






LFR3
GIPERFSGSNSGNTATLTISGTQAM
370




DEADYYC







LFR4
FGGGTKLTVL
69





S24-1339
HC
EVQLVESGGGLVQPGGSLRLSCAAS
371




GFTVSSNYMSWVRQAPGKGLEWVSD





IYSGGSTYYADSVKGRFTISRHNSK





NTLYLQMNSLRAEDTAVYYCARDRR





GYSYGLHHGMDVWGQGTTVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
EVQLVESGGGLVQPGGSLRLSCAAS
372



variable
GFTVSSNYMSWVRQAPGKGLEWVSD





IYSGGSTYYADSVKGRFTISRHNSK





NTLYLQMNSLRAEDTAVYYCARDRR





GYSYGLHHGMDVWGQGTTVTVSS







HCDR1
SNYMS
358






HCDR2
DIYSGGSTYYADSVKG
373






HCDR3
DRRGYSYGLHHGMDV
374






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
361




GFTVS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRHNSKNTLYLQMNSLRAEDT
375




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
EIVLTQSPGTLSLSPGERATLSCRA
376




SQSVSSSYLAWYQQKPDQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPNTFG





QGTKLEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDN







LC
EIVLTQSPGTLSLSPGERATLSCRA
377



variable
SQSVSSSYLAWYQQKPDQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPNTFG





QGTKLEIK







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQYGSSPNT
378






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPDQAPRLLIY
379






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTKLEIK
380





S24-1345
HC
QLQLQESGPGLVKPSETLSLTCTVS
381




GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARR





IRRPTSEVVITYVFDYWGQGTLVTV





SSAPTKAPDVFPIISGCRHPKDNSP





VVLACLITGYH







HC
QLQLQESGPGLVKPSETLSLTCTVS
382



variable
GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARR





IRRPTSEVVITYVFDYWGQGTLVTV





SS







HCDR1
SSSYYWG
242






HCDR2
SIYYSGSTYYNPSLKS
243






HCDR3
RIRRPTSEVVITYVFDY
383






HFR1
QLQLQESGPGLVKPSETLSLTCTVS
245




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
AIQLTQSPSSLSASVGDRVTITCRA
384




SQGISSALAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQFNSYLTFGGG





TKVEIKRTVAAPSVFIFPPSDEQLK





SGTASVVCLLNNFYPREAKVQWKVD





NALQSGNSQESVTEQDSKDSTYSLS







LC
AIQLTQSPSSLSASVGDRVTITCRA
385



variable
SQGISSALAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQFNSYLTFGGG





TKVEIK







LCDR1
RASQGISSALA
386






LCDR2
DASSLES
387






LCDR3
QQFNSYLT
388






LFR1
AIQLTQSPSSLSASVGDRVTITC
389






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGGGTKVEIK
85





S24-1378
HC
EVQLVESGGGLVQPGGSLRLSCAAS
390




GFTVSSNYMSWVRQAPGKGLEWVSV





IYSGGSTYYADSVKGRFTISRHNSK





NTLYLQMNSLRAEDTAVYYCAREGY





CTNGVCYRHAFDIWGQGTMVTVSSG





SASAPTLFPLVSCENSPSDTSSV







HC
EVQLVESGGGLVQPGGSLRLSCAAS
391



variable
GFTVSSNYMSWVRQAPGKGLEWVSV





IYSGGSTYYADSVKGRFTISRHNSK





NTLYLQMNSLRAEDTAVYYCAREGY





CTNGVCYRHAFDIWGQGTMVTVSS







HCDR1
SNYMS
358






HCDR2
VIYSGGSTYYADSVKG
392






HCDR3
EGYCTNGVCYRHAFDI
393






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
361




GFTVS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRHNSKNTLYLQMNSLRAEDT
375




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
QTVVTQEPSFSVSPGGTVTLTCGLS
394




SGSVSTSYYPSWYQQTPGQAPRTLI





YSTNTRSSGVPDRFSGSILGNKAAL





TITGAQADDESDYYCVLYMGSGISV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASS







LC
QTVVTQEPSFSVSPGGTVTLTCGLS
395



variable
SGSVSTSYYPSWYQQTPGQAPRTLI





YSTNTRSSGVPDRFSGSILGNKAAL





TITGAQADDESDYYCVLYMGSGISV





FGGGTKLTVL







LCDR1
GLSSGSVSTSYYPS
276






LCDR2
STNTRSS
396






LCDR3
VLYMGSGISV
397






LFR1
QTVVTQEPSFSVSPGGTVTLTC
279






LFR2
WYQQTPGQAPRTLIY
280






LFR3
GVPDRFSGSILGNKAALTITGAQAD
281




DESDYYC







LFR4
FGGGTKLTVL
69





S24-1379
HC
QVQLQESGPGLVKPSETLSLTCTVS
398




GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARDYY





QLPMDVWGQGTTVTVSSASTKGPSV





FPLAPSSKSTSGGTAALGCLVKDYF





PEPVTVSWNSGALTSGVHTFPAVLQ





SSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
399



variable
GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARDYY





QLPMDVWGQGTTVTVSS







HCDR1
SYYWS
56






HCDR2
YIYYSGSTNYNPSLKS
4






HCDR3
DYYQLPMDV
400






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
QSVLTQPPSASGTPGQRVTISCSGS
401




SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDSLSGRV





FGGGT





KLTVLGQPKAAPSVTLFPPSSEELQ





ANKATLVCLISDFYPGAVTVAWKAD





SSPVKAGVETTTPSKQSNNKYAASS







LC
QSVLTQPPSASGTPGQRVTISCSGS
402



variable
SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDSLSGRV





FGGGTKLTVL







LCDR1
SGSSSNIGSNYVY
403






LCDR2
RNNQRPS
404






LCDR3
AAWDDSLSGRV
405






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLRSE
406




DEADYYC







LFR4
FGGGTKLTVL
69





S24-1384
HC
EVQLVESGGGLVQPGGSLRLSCAVS
407




GFTFSSYSMNWVRQAPGKGLEWVSY





ISSSSSIIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDF





LDYSRSYSYGMDVWGQGTTVTVSSA





STKGPSVFPLAPSSKSTSGGTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSG







HC
EVQLVESGGGLVQPGGSLRLSCAVS
408



variable
GFTFSSYSMNWVRQAPGKGLEWVSY





ISSSSSIIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDF





LDYSRSYSYGMDVWGQGTTVTVSS







HCDR1
SYSMN
126






HCDR2
YISSSSSIIYYADSVKG
409






HCDR3
DFLDYSRSYSYGMDV
410






HFR1
EVQLVESGGGLVQPGGSLRLSCAVS
411




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
SYVLTQPPSVSVAPGQTARITCGGD
412




NIGSKNVHWYQQKPGQAPVLVVFDD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSDHYVVF





GGGTKLTVLGQPKAAPSVTLFPPSS





EELQANKATLVCLISDFYPGAVTVA





WKADSSPVKAGVETTTPSKQSNNKY





AASSY







LC
SYVLTQPPSVSVAPGQTARITCGGD
413



variable
NIGSKNVHWYQQKPGQAPVLVVFDD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSDHYVVF





GGGTKLTVL







LCDR1
GGDNIGSKNVH
414






LCDR2
DDSDRPS
13






LCDR3
QVWDSSSDHYVV
415






LFR1
SYVLTQPPSVSVAPGQTARITC
15






LFR2
WYQQKPGQAPVLVVF
416






LFR3
GIPERFSGSNSGNTATLTISRVEAG
17




DEADYYC







LFR4
FGGGTKLTVL
69





S24-1476
HC
EVQLVESGGGLVQPGRSLRLSCTAS
417




GFTFGDYAMSWFRQAPGKGLEWVGF





IRSKAYGGTTQYAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYYCTR





VRYCTNGVCYGYHFDYWGQGTVVTV





SSAST







HC
EVQLVESGGGLVQPGRSLRLSCTAS
418



variable
GFTFGDYAMSWFRQAPGKGLEWVGF





IRSKAYGGTTQYAASVKGRFTISRD





DSKSIAYLQMNSLKTEDTAVYYCTR





VRYCTNGVCYGYHFDYWGQGTVVTV





SS







HCDR1
DYAMS
199






HCDR2
FIRSKAYGGTTQYAASVKG
419






HCDR3
VRYCTNGVCYGYHFDY
420






HFR1
EVQLVESGGGLVQPGRSLRLSCTAS
202




GFTFG







HFR2
WFRQAPGKGLEWVG
203






HFR3
RFTISRDDSKSIAYLQMNSLKTEDT
259




AVYYCTR







HFR4
WGQGTVVTVSS
421






LC
EIVMTQSPATLSVSPGERATLSCRA
422




SQSVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYNNWWTFGQG





TKVEIKRTVAAPSVFIFPPSDEQLK





SGTASVVCLLNNFYPREAKVQWKVD





N







LC
EIVMTQSPATLSVSPGERATLSCRA
423



variable
SQSVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYNNWWTFGQG





TKVEIK







LCDR1
RASQSVSSNLA
207






LCDR2
GASTRAT
208






LCDR3
QQYNNWWT
424






LFR1
EIVMTQSPATLSVSPGERATLSC
210






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTEFTLTISSLQSE
211




DFAVYYC







LFR4
FGQGTKVEIK
53





S24-1564
HC
QVQLQESGPGLVKPSETLSLTCTVS
425




GGSISSYYWSWIRQPPGKGLEWIGY





VYYSGNTKYNPSLKSRVTISVDTSK





NQFSLKLGSVTAADTAVYYCARHSR





IEVAGTLDFDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
426



variable
GGSISSYYWSWIRQPPGKGLEWIGY





VYYSGNTKYNPSLKSRVTISVDTSK





NQFSLKLGSVTAADTAVYYCARHSR





IEVAGTLDFDYWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
YVYYSGNTKYNPSLKS
427






HCDR3
HSRIEVAGTLDFDY
428






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLGSVTAADT
429




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
430




SQSIRSYLNWYQQKRGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYSTPPTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DN







LC
DIQMTQSPSSLSASVGDRVTITCRA
431



variable
SQSIRSYLNWYQQKRGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYSTPPTFGQ





GTKVEIK







LCDR1
RASQSIRSYLN
432






LCDR2
AASSLQS
249






LCDR3
QQSYSTPPT
433






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKRGKAPKLLIY
434






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKVEIK
53





S24-1636
HC
QVQLVESGGGVVQPGRSLRLSCAAS
435




GFTFSNYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARGD





CTNGVCHPLLIYYDSSGLDYWGQGT





LVTVSSASTKGPSVFPLAPSSKSTS





GGTAALGCLVKDYFPEPVTVSWNSG





ALTSGVHTFPAVLQSSG







HC
QVQLVESGGGVVQPGRSLRLSCAAS
436



variable
GFTFSNYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARGD





CTNGVCHPLLIYYDSSGLDYWGQGT





LVTVSS







HCDR1
NYGMH
437






HCDR2
VIWYDGSNKYYADSVKG
142






HCDR3
GDCTNGVCHPLLIYYDSSGLDY
438






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPATLSLSPGERATLSCRA
439




SQSVSSYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPPITFG





PGTKVDIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





L







LC
EIVLTQSPATLSLSPGERATLSCRA
440



variable
SQSVSSYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPPITFG





PGTKVDIK







LCDR1
RASQSVSSYLA
178






LCDR2
DASNRAT
441






LCDR3
QQRSNWPPIT
442






LFR1
EIVLTQSPATLSLSPGERATLSC
181






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTDFTLTISSLEPE
183




DFAVYYC







LFR4
FGPGTKVDIK
443





S24-1002
HC
QVQLVESGGGVVQPGRSLRLSCAAS
444




GFTFTSYAMHWVRQAPGKGLEWVAV





ISYDGGSKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARTT





PGITAAGTGTLGRYYYYGMDVWGQG





TTVTVSSGSASAPTLFPLVSCENSP





SDTSSV







HC
QVQLVESGGGVVQPGRSLRLSCAAS
445



variable
GFTFTSYAMHWVRQAPGKGLEWVAV





ISYDGGSKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARTT





PGITAAGTGTLGRYYYYGMDVWGQG





TTVTVSS







HCDR1
SYAMH
446






HCDR2
VISYDGGSKYYADSVKG
447






HCDR3
TTPGITAAGTGTLGRYYYYGMDV
448






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
449




GFTFT







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
AIQLTQSPSSLSASVGDRVTITCRA
450




SQGISSALAWYQQTPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTDFSLTI





GSLQPEDFASYYCQQFNSYPLTFGG





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
AIQLTQSPSSLSASVGDRVTITCRA
451



variable
SQGISSALAWYQQTPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTDFSLTI





GSLQPEDFASYYCQQFNSYPLTFGG





GTKVEIK







LCDR1
RASQGISSALA
386






LCDR2
DASSLES
387






LCDR3
QQFNSYPLT
452






LFR1
AIQLTQSPSSLSASVGDRVTITC
389






LFR2
WYQQTPGKAPKLLIY
453






LFR3
GVPSRFSGSGSGTDFSLTIGSLQPE
454




DFASYYC







LFR4
FGGGTKVEIK
85





S24-1301
HC
QVQLVQSGAEVKKPGASVKVSCKVS
455




GYTLIELSMHWVRQAPGKGLEWMGG





FDPEDGETIYAQKFQGRVTMTEDTS





TDTAYMALSSLTSEDTAVYYCATAY





AYYYASGGYYTLDYWGQGTLVTVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKVS
456



variable
GYTLIELSMHWVRQAPGKGLEWMGG





FDPEDGETIYAQKFQGRVTMTEDTS





TDTAYMALSSLTSEDTAVYYCATAY





AYYYASGGYYTLDYWGQGTLVTVSS







HCDR1
ELSMH
457






HCDR2
GFDPEDGETIYAQKFQG
458






HCDR3
AYAYYYASGGYYTLDY
459






HFR1
QVQLVQSGAEVKKPGASVKVSCKVS
460




GYTLI







HFR2
WVRQAPGKGLEWMG
42






HFR3
RVTMTEDTSTDTAYMALSSLTSEDT
461




AVYYCAT







HFR4
WGQGTLVTVSS
60






LC
QAGLTQPPSVSKGLRQTATLTCTGS
462




SNNVGNQGAAWLQQHQGHPPKLLSY





RNNNRPSGISERFSASRSGNTASLT





ITGLQPEDEADYYCSAWDSSLSNWV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASS







LC
QAGLTQPPSVSKGLRQTATLTCTGS
463



variable
SNNVGNQGAAWLQQHQGHPPKLLSY





RNNNRPSGISERFSASRSGNTASLT





ITGLQPEDEADYYCSAWDSSLSNWV





FGGGTKLTVL







LCDR1
TGSSNNVGNQGAA
464






LCDR2
RNNNRPS
465






LCDR3
SAWDSSLSNWV
466






LFR1
QAGLTQPPSVSKGLRQTATLTC
467






LFR2
WLQQHQGHPPKLLSY
468






LFR3
GISERFSASRSGNTASLTITGLQPE
469




DEADYYC







LFR4
FGGGTKLTVL
69





S24-223
HC
QITLKESGPTLVKPTQTLTLTCTFS
470




GFSLNTSGVGVGWIRQPPGKALEWL





ALIYWDDDKRYSPSLKSRLTITKDT





SKNQVVLTMTNMDPVDTATYYCAHH





TIVPIFDYWGQGTLVTVSSGSASAP





TLFPLVSCENSPSDTSSV







HC
QITLKESGPTLVKPTQTLTLTCTFS
471



variable
GFSLNTSGVGVGWIRQPPGKALEWL





ALIYWDDDKRYSPSLKSRLTITKDT





SKNQVVLTMTNMDPVDTATYYCAHH





TIVPIFDYWGQGTLVTVSS







HCDR1
TSGVGVG
472






HCDR2
LIYWDDDKRYSPSLKS
473






HCDR3
HTIVPIFDY
474






HFR1
QITLKESGPTLVKPTQTLTLTCTFS
475




GFSLN







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTITKDTSKNQVVLTMTNMDPVDT
477




ATYYCAH







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
478




SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCNSYTSSSTLV





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASSYLSLT







LC
QSALTQPASVSGSPGQSITISCTGT
479



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCNSYTSSSTLV





VFGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
DVSNRPS
64






LCDR3
NSYTSSSTLVV
480






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S24-461
HC
QVQLQESGPGLVKPSETLSLTCTVS
481




GGSISSYYWSWIRQPPGKGLEWIGN





IYNSGSTNYNPSLKSRLTISVDTSK





NHFSLKLSSVTAADTAVYYCARGGL





EHDGDYVYYYGMDVWGQGTTITVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
482



variable
GGSISSYYWSWIRQPPGKGLEWIGN





IYNSGSTNYNPSLKSRLTISVDTSK





NHFSLKLSSVTAADTAVYYCARGGL





EHDGDYVYYYGMDVWGQGTTITVSS







HCDR1
SYYWS
56






HCDR2
NIYNSGSTNYNPSLKS
483






HCDR3
GGLEHDGDYVYYYGMDV
484






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RLTISVDTSKNHFSLKLSSVTAADT
485




AVYYCAR







HFR4
WGQGTTITVSS
486






LC
SYELTQPPSVSVSLGQMARITCSGE
487




ALPKKYAYWYQQKPGQFPILVIYKD





SERPSGIPERFSGSSSGTIVTLTIS





GVQAEDEADYYCLSEDSSGTWVFGG





GTKLTVLGQPKAAPSVTLFPPSSEE





LQANKATLVCLISDFYPGAVTVAWK





ADSSPVKAGVETTTPSKQSNNKYAA





SS







LC
SYELTQPPSVSVSLGQMARITCSGE
488



variable
ALPKKYAYWYQQKPGQFPILVIYKD





SERPSGIPERFSGSSSGTIVTLTIS





GVQAEDEADYYCLSEDSSGTWVFGG





GTKLTVL







LCDR1
SGEALPKKYAY
489






LCDR2
KDSERPS
490






LCDR3
LSEDSSGTWV
491






LFR1
SYELTQPPSVSVSLGQMARITC
492






LFR2
WYQQKPGQFPILVIY
493






LFR3
GIPERFSGSSSGTIVTLTISGVQAE
494




DEADYYC







LFR4
FGGGTKLTVL
69





S24-511
HC
QVQLVESGGGVVQPGRSLRLSCAAS
495




GFTFSSYGMHWVRQAPGKGLEWVAV





ISYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKYT





STVTTNYYYGMDVWGQGTTVTVSSA





PTKAPDVFPIISGCRHPKDNSPVVL





ACLITGYH







HC
QVQLVESGGGVVQPGRSLRLSCAAS
496



variable
GFTFSSYGMHWVRQAPGKGLEWVAV





ISYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKYT





STVTTNYYYGMDVWGQGTTVTVSS







HCDR1
SYGMH
141






HCDR2
VISYDGSNKYYADSVKG
497






HCDR3
YTSTVTTNYYYGMDV
498






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
499




AVYYCAK







HFR4
WGQGTTVTVSS
147






LC
SYELTQPPSVSVSPGQTASITCSGD
500




KLGDKYACWYQQKPGQSPVLVIYQD





SKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTVVFGGG





TKLTVLGQPKAAPSVTLFPPSSEEL





QANKATLVCLISDFYPGAVTVAWKA





DSSPVKAGVETTTPSKQSNNKYAAS





SY







LC
SYELTQPPSVSVSPGQTASITCSGD
501



variable
KLGDKYACWYQQKPGQSPVLVIYQD





SKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTVVFGGG





TKLTVL







LCDR1
SGDKLGDKYAC
502






LCDR2
QDSKRPS
503






LCDR3
QAWDSSTVV
504






LFR1
SYELTQPPSVSVSPGQTASITC
368






LFR2
WYQQKPGQSPVLVIY
369






LFR3
GIPERFSGSNSGNTATLTISGTQAM
370




DEADYYC







LFR4
FGGGTKLTVL
69





S24-788
HC
QVQLVESGGGVVQPGRSLRLSCAAS
505




GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARGR





SPGGGHYYGMDVWGQGTTVTVSSGS





ASAPTLFPLVSCENSPSDTSSV







HC
QVQLVESGGGVVQPGRSLRLSCAAS
506



variable
GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARGR





SPGGGHYYGMDVWGQGTTVTVSS







HCDR1
SYGMH
141






HCDR2
VIWYDGSNKYYADSVKG
142






HCDR3
GRSPGGGHYYGMDV
507






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
SYELTQPPSVSVSPGQTASITCSGD
508




KLGDKYACWYQQKPGQSPVLVIYQD





SKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSSVVFGGG





TKLTVLGQPKAAPSVTLFPPSSEEL





QANKATLVCLISDFYPGAVTVAWKA





DSSPVKAGVETTTPSKQSNNKYAAS





S







LC
SYELTQPPSVSVSPGQTASITCSGD
509



variable
KLGDKYACWYQQKPGQSPVLVIYQD





SKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSSVVFGGG





TKLTVL




LCDR1
SGDKLGDKYAC
502






LCDR2
QDSKRPS
503






LCDR3
QAWDSSSVV
510






LFR1
SYELTQPPSVSVSPGQTASITC
368






LFR2
WYQQKPGQSPVLVIY
369






LFR3
GIPERFSGSNSGNTATLTISGTQAM
370




DEADYYC







LFR4
FGGGTKLTVL
69





S24-821
HC
QVTLRESGPALVKPTQTLTLTCTFS
511




GLSLSSSGMCVSWIRQPPGKALEWL





ARIDWDDDKYYSTSLKTRLTISKDT





SKNQVVLTMTNMDPVDTATYYCARI





CTMVRGLHDAFDIWGQGTMVTVSSG





SASAPTLFPLVSCENSPSDTSSV







HC
QVTLRESGPALVKPTQTLTLTCTFS
512



variable
GLSLSSSGMCVSWIRQPPGKALEWL





ARIDWDDDKYYSTSLKTRLTISKDT





SKNQVVLTMTNMDPVDTATYYCARI





CTMVRGLHDAFDIWGQGTMVTVSS







HCDR1
SSGMCVS
513






HCDR2
RIDWDDDKYYSTSLKT
514






HCDR3
ICTMVRGLHDAFDI
515






HFR1
QVTLRESGPALVKPTQTLTLTCTFS
516




GLSLS







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTISKDTSKNQVVLTMTNMDPVDT
517




ATYYCAR







HFR4
WGQGTMVTVSS
44






LC
DIQMTQSPSTLSASVGDRVTITCRA
518




SQSISSWLAWYQQKPGKAPKLLIYK





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYSWTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DN







LC
DIQMTQSPSTLSASVGDRVTITCRA
519



variable
SQSISSWLAWYQQKPGKAPKLLIYK





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYSWTFGQ





GTKVEIK







LCDR1
RASQSISSWLA
520






LCDR2
KASSLES
521






LCDR3
QQYNSYSWT
522






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S144-67
HC
EVQLVQSGAEVKKPGESLKISCKGS
525




GYSFTTYWIAWVRQMPGKGLEWVGI





IYPDDSDTRYSPSFQGQVTISADKS





IGTAYLQWSSLKASDTAMYYCARGQ





YYDFWSGAGGVDVWGQGTTVTVSSA





STKGPSVFPLAPSSKSTSGGTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSG







HC
EVQLVQSGAEVKKPGESLKISCKGS
526



variable
GYSFTTYWIAWVRQMPGKGLEWVGI





IYPDDSDTRYSPSFQGQVTISADKS





IGTAYLQWSSLKASDTAMYYCARGQ





YYDFWSGAGGVDVWGQGTTVTVSS







HCDR1
TYWIA
527






HCDR2
IIYPDDSDTRYSPSFQG
528






HCDR3
GQYYDFWSGAGGVDV
529






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
530




GYSFT







HFR2
WVRQMPGKGLEWVG
531






HFR3
QVTISADKSIGTAYLQWSSLKASDT
532




AMYYCAR




HFR4
WGQGTTVTVSS
147






LC
QSVLTQPPSVSGAPGQRVTISCTGS
533




RSNIGAGYDVQWYQQVPGTAPKLLI





SGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGL





RVFGGGTKLTVLGQPKAAPSVTLFP





PSSEELQANKATLVCLISDFYPGAV





TVAWKADSSPVKAGVETTTPSKQSN





NKYAASSYLSLTPEQWKSH







LC
QSVLTQPPSVSGAPGQRVTISCTGS
534



variable
RSNIGAGYDVQWYQQVPGTAPKLLI





SGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGL





RVFGGGTKLTVL







LCDR1
TGSRSNIGAGYDVQ
535






LCDR2
GNSNRPS
350






LCDR3
QSYDSSLSGLRV
536






LFR1
QSVLTQPPSVSGAPGQRVTISC
537






LFR2
WYQQVPGTAPKLLIS
538






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGGGTKLTVL
69





S144-69
HC
EVQLVQSGAEVKKPGESLKISCKGS
540




GYSFTSYWIGWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVTISADKS





ITTAYLQWSSLKASDTAMYYCARTQ





TTNWFDSWGQGTLVTVSSASTKGPS





VFPLAPSSKSTSGGTAALGCLVKDY





FPEPVTVSWNSGALTSGVHTFPAVL





QSSG







HC
EVQLVQSGAEVKKPGESLKISCKGS
541



variable
GYSFTSYWIGWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVTISADKS





ITTAYLQWSSLKASDTAMYYCARTQ





TTNWFDSWGQGTLVTVSS







HCDR1
SYWIG
542






HCDR2
IIYPGDSDTRYSPSFQG
543






HCDR3
TQTTNWFDS
544






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
530




GYSFT







HFR2
WVRQMPGKGLEWMG
174






HFR3
QVTISADKSITTAYLQWSSLKASDT
545




AMYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSVSVGDRVTITCRA
546




SQSVSSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSFYTFGQG





TKLEIKRTVAAPSVFIFPPSDEQLK





SGTASVVCLLNNFYPREAKVQWKVD





NALQSGNSQESVTEQDSKDSTYSLS





STLTLSKADYE







LC
DIQMTQSPSTLSVSVGDRVTITCRA
547



variable
SQSVSSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSFYTFGQG





TKLEIK







LCDR1
RASQSVSSWLA
548






LCDR2
DASSLES
387






LCDR3
QQYNSFYT
549






LFR1
DIQMTQSPSTLSVSVGDRVTITC
550






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKLEIK
380





S144-94
HC
QVQLVESGGGVVQPGGSLRLSCAAS
551




GFTFSSYGMHWVRQAPGKGLEWVTF





TRYDGSNKFYADSVKGRFSISRDNS





KNTLYLQMNSLRAEDTAVYYCAKES





RVAFGGAIAIYYFGMDVWGQGTTVT





VSSASTKGPSVFPLAPCSRSTSGGT





AALGCLVKDYFPEPVTVSWNSGALT





SGVHTFPAVLQSSG







HC
QVQLVESGGGVVQPGGSLRLSCAAS
552



variable
GFTFSSYGMHWVRQAPGKGLEWVTF





TRYDGSNKFYADSVKGRFSISRDNS





KNTLYLQMNSLRAEDTAVYYCAKES





RVAFGGAIAIYYFGMDVWGQGTTVT





VSS







HCDR1
SYGMH
141






HCDR2
FTRYDGSNKFYADSVKG
553






HCDR3
ESRVAFGGAIAIYYFGMDV
554






HFR1
QVQLVESGGGVVQPGGSLRLSCAAS
555




GFTFS







HFR2
WVRQAPGKGLEWVT
556






HFR3
RFSISRDNSKNTLYLQMNSLRAEDT
557




AVYYCAK







HFR4
WGQGTTVTVSS
147






LC
DIVMTQSPLSLPVTPGEPASISCRS
558




SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSGSGTD





FTLKISRVEAEDVGVYYCMQALQTP





QYTFGQGTKLEIKRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDNALQSGNSQESVTEQDSK





DSTYSLSSTLTLSKADYE







LC
DIVMTQSPLSLPVTPGEPASISCRS
559



variable
SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSGSGTD





FTLKISRVEAEDVGVYYCMQALQTP





QYTFGQGTKLEIK







LCDR1
RSSQSLLHSNGYNYLD
262






LCDR2
LGSNRAS
263






LCDR3
MQALQTPQYT
560






LFR1
DIVMTQSPLSLPVTPGEPASISC
265






LFR2
WYLQKPGQSPQLLIY
266






LFR3
GVPDRFSGSGSGTDFTLKISRVEAE
267




DVGVYYC







LFR4
FGQGTKLEIK
380





S144-113
HC
EVQLLESGGGLVQPGGSLRLSCAAS
561




GFTFSNYAMSWVRQAPGKGLEWVSA





IRNSGSSTYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDSAVYYCAKVG





GTAAGHPFYDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSGL







HC
EVQLLESGGGLVQPGGSLRLSCAAS
562



variable
GFTFSNYAMSWVRQAPGKGLEWVSA





IRNSGSSTYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDSAVYYCAKVG





GTAAGHPFYDYWGQGTLVTVSS







HCDR1
NYAMS
563






HCDR2
AIRNSGSSTYYADSVKG
564






HCDR3
VGGTAAGHPFYDY
565






HFR1
EVQLLESGGGLVQPGGSLRLSCAAS
566




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNTLYLQMNSLRAEDS
567




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
568




SQSISNYLNWYQQKPGKAPDLLIYA





ASSLQSGVPLRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQTYSAPTFGGG





TKVEIKRTVAAPSVFIFPPSDEQLK





SGTASVVCLLNNFYPREAKVQWKVD





NALQSGNSQESVTEQDSKDSTYSLS





STLTLSKADYE







LC
DIQMTQSPSSLSASVGDRVTITCRA
569



variable
SQSISNYLNWYQQKPGKAPDLLIYA





ASSLQSGVPLRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQTYSAPTFGGG





TKVEIK







LCDR1
RASQSISNYLN
570






LCDR2
AASSLQS
249






LCDR3
QQTYSAPT
571






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPDLLIY
572






LFR3
GVPLRFSGSGSGTDFTLTISSLQPE
573




DFATYYC







LFR4
FGGGTKVEIK
85





S144-175
HC
QVQLVQSGAEVKKPGASVKVSCKAS
574




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNFAQRFQGRVSMTRDTS





ISTAYMELSSLRSDDTAVYYCARGA





KFEHLPFDIWGQGTMVTVSSASTKG





PSVFPLAPSSKSTSGGTAALGCLVK





DYFPEPVTVSWNSGALTSGVHTFPA





VLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
575



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNFAQRFQGRVSMTRDTS





ISTAYMELSSLRSDDTAVYYCARGA





KFEHLPFDIWGQGTMVTVSS







HCDR1
GYYMH
187






HCDR2
RINPNSGGTNFAQRFQG
576






HCDR3
GAKFEHLPFDI
577






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVSMTRDTSISTAYMELSSLRSDDT
578




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
QSMLTQPPSASGTPGQRVTISCSGS
579




SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDRRWVFG





GGTKLTVLGQPKAAPSVTLFPPSSE





ELQANKATLVCLISDFYPGAVTVAW





KADSSPVKAGVETTTPSKQSNNKYA





ASS







LC
QSMLTQPPSASGTPGQRVTISCSGS
580



variable
SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDRRWVFG





GGTKLTVL







LCDR1
SGSSSNIGSNYVY
403






LCDR2
RNNQRPS
404






LCDR3
AAWDDRRWV
581






LFR1
QSMLTQPPSASGTPGQRVTISC
582






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLRSE
406




DEADYYC







LFR4
FGGGTKLTVL
69





S144-208
HC
QVQLVQSGAEVKKPGASVKVSCKSS
583




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARGA





RGGAGCSGWSCFDFWGQGTLVTVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKSS
584



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARGA





RGGAGCSGWSCFDFWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
RINPNSGGTNYAQKFQG
585






HCDR3
GARGGAGCSGWSCFDF
586






HFR1
QVQLVQSGAEVKKPGASVKVSCKSS
587




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRSDDT
588




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPRSVSGSPGQSVTISCTGT
589




SSDVGGYKYVSWYQQHPGKAPKLMI





YDVSKRPSGVPDRFSGSKSGNTASL





TISGLQAEDEGDYYCCSYAGTYSLV





FGGGTKVTVTVLGQPKAAPSVTLFP





PSSEELQANKATLVCLISDFYPGAV





TVAWKADSSPVKAGVETTTPSKQSN





NKYAASSYLSLTPEQWKSH







LC
QSALTQPRSVSGSPGQSVTISCTGT
590



variable
SSDVGGYKYVSWYQQHPGKAPKLMI





YDVSKRPSGVPDRFSGSKSGNTASL





TISGLQAEDEGDYYCCSYAGTYSLV





FGGGTKVTV







LCDR1
TGTSSDVGGYKYVS
591






LCDR2
DVSKRPS
592






LCDR3
CSYAGTYSLV
593






LFR1
QSALTQPRSVSGSPGQSVTISC
594






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTISGLQAE
595




DEGDYYC







LFR4
FGGGTKVTV
596





S144-339
HC
EVQLVESGGGLVKPGGSLRLSCAAS
597




GFTFSDYTMNWVRQAPGKGLEWVSS





ITRSSTYIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDP





YYDILTGYWNYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
EVQLVESGGGLVKPGGSLRLSCAAS
598



variable
GFTFSDYTMNWVRQAPGKGLEWVSS





ITRSSTYIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARDP





YYDILTGYWNYWGQGTLVTVSS







HCDR1
DYTMN
599






HCDR2
SITRSSTYIYYADSVKG
600






HCDR3
DPYYDILTGYWNY
601






HFR1
EVQLVESGGGLVKPGGSLRLSCAAS
602




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
603




SQSLSSSYLAWYQQKPGQSPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





INRLEPEDFAVYYCQQYRTSPRGTF





GGGTKVEIKRTVAAPSVFIFPPSDE





QLKSGTASVVCLLNNFYPREAKVQW





KVDNALQSGNSQESVTEQDSKDSTY





SLSSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
604



variable
SQSLSSSYLAWYQQKPGQSPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





INRLEPEDFAVYYCQQYRTSPRGTF





GGGTKVEIK







LCDR1
RASQSLSSSYLA
605






LCDR2
GASSRAT
135






LCDR3
QQYRTSPRGT
606






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQSPRLLIY
607






LFR3
GIPDRFSGSGSGTDFTLTINRLEPE
138




DFAVYYC







LFR4
FGGGTKVEIK
85





S144-359
HC
EVQLVESGGGLVQPGGSLRLSCAAS
608




GFTFSSYAMSWVRQAPGKGLEWVSS





IRGSGGSTYYADSVKGRFTISRDNS





KYTLYLQMNSLRAEDTAVYYCAKIT





GAVGGENWFDPWGQGTLVTVSSAST





KGPSVFPLAPCSRSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG




HC
EVQLVESGGGLVQPGGSLRLSCAAS
609



variable
GFTFSSYAMSWVRQAPGKGLEWVSS





IRGSGGSTYYADSVKGRFTISRDNS





KYTLYLQMNSLRAEDTAVYYCAKIT





GAVGGENWFDPWGQGTLVTVSS







HCDR1
SYAMS
610






HCDR2
SIRGSGGSTYYADSVKG
611






HCDR3
ITGAVGGENWFDP
612






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKYTLYLQMNSLRAEDT
614




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
615




SQSISSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFAIYYCQQTSRTPLTFGG





GTKVEVKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSSLSASVGDRVTITCRA
616



variable
SQSISSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFAIYYCQQTSRTPLTFGG





GTKVEVK







LCDR1
RASQSISSYLN
248






LCDR2
AASSLQS
249






LCDR3
QQTSRTPLT
617






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
618




DFAIYYC







LFR4
FGGGTKVEVK
619





S144-460
HC
EVRLVQSGGGLVKPGGSLRLSCAAS
620




GFTFSTAWVRWVRQAPGKGLECVGR





IKSKNDGDRAEYAAPARGRFIISRD





DAENILYLQMNNLKTEDTAFYYCTT





DQGNSSAFYSADYWGQGTLVTVSSA





SPTSPKVFPLSLDSTPQDGNVVVAC





LVQGFFPQEPLSVTWSESGQNVTAR





NF







HC
EVRLVQSGGGLVKPGGSLRLSCAAS
621



variable
GFTFSTAWVRWVRQAPGKGLECVGR





IKSKNDGDRAEYAAPARGRFIISRD





DAENILYLQMNNLKTEDTAFYYCTT





DQGNSSAFYSADYWGQGTLVTVSS







HCDR1
TAWVR
622






HCDR2
RIKSKNDGDRAEYAAPARG
623






HCDR3
DQGNSSAFYSADY
624






HFR1
EVRLVQSGGGLVKPGGSLRLSCAAS
625




GFTFS







HFR2
WVRQAPGKGLECVG
626






HFR3
RFIISRDDAENILYLQMNNLKTEDT
627




AFYYCTT







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSAMSASVGDRVTITCRA
628




SQDINTFLTWFQQKPGKVPQRLIFA





AYRLQSGVPSRFSGSGSGTEFTLTI





NSLQPEDVATYYCLHHKTYPYTFGQ





GTKLEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSAMSASVGDRVTITCRA
629



variable
SQDINTFLTWFQQKPGKVPQRLIFA





AYRLQSGVPSRFSGSGSGTEFTLTI





NSLQPEDVATYYCLHHKTYPYTFGQ





GTKLEIK







LCDR1
RASQDINTFLT
630






LCDR2
AAYRLQS
631






LCDR3
LHHKTYPYT
632






LFR1
DIQMTQSPSAMSASVGDRVTITC
633






LFR2
WFQQKPGKVPQRLIF
634






LFR3
GVPSRFSGSGSGTEFTLTINSLQPE
635




DVATYYC







LFR4
FGQGTKLEIK
380





S144-466
HC
EVQLVQSGAEVKKPGESLKISCKGS
636




GYRFTRYWIGWVRQMPGKGLEWMGI





IYLGDSETRYSPSFQGQVTISADNS





ISTAYLQWSSLKASDTAMYYCARSS





NWNYGDYWGQGTLVTVSSASTKGPS





VFPLAPCSRSTSGGTAALGCLVKDY





FPEPVTVSWNSGALTSGVHTFPAVL





QSSG







HC
EVQLVQSGAEVKKPGESLKISCKGS
637



variable
GYRFTRYWIGWVRQMPGKGLEWMGI





IYLGDSETRYSPSFQGQVTISADNS





ISTAYLQWSSLKASDTAMYYCARSS





NWNYGDYWGQGTLVTVSS







HCDR1
RYWIG
638






HCDR2
IIYLGDSETRYSPSFQG
639






HCDR3
SSNWNYGDY
640






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
641




GYRFT







HFR2
WVRQMPGKGLEWMG
174






HFR3
QVTISADNSISTAYLQWSSLKASDT
642




AMYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSASVGDRVTITCRA
643




SQSITSWLAWYQQKSGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSTLSASVGDRVTITCRA
644



variable
SQSITSWLAWYQQKSGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIK







LCDR1
RASQSITSWLA
645






LCDR2
DASSLES
387






LCDR3
QQYNSYPWT
646






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKSGKAPKLLIY
647






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S144-469
HC
QVQLQESGPGLVKPSETLSLTCTVS
648




GGSISSDYWSWIRQPPGKGLEWIGY





MYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARWDR





GSRPHYYYYGMDVWGQGTTVTVSSA





STKGPSVFPLAPSSKSTSGGTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSG







HC
QVQLQESGPGLVKPSETLSLTCTVS
649



variable
GGSISSDYWSWIRQPPGKGLEWIGY





MYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARWDR





GSRPHYYYYGMDVWGQGTTVTVSS







HCDR1
SDYWS
650






HCDR2
YMYYSGSTNYNPSLKS
88






HCDR3
WDRGSRPHYYYYGMDV
651






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
DIVMTQSPLSLPVTPGEPASISCRS
652




SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSASGTD





FTLKISRVEAEDVGVYYCMQALQAF





TFGPGTKVDIKRTVAAPSVFIFPPS





DEQLKSGTASVVCLLNNFYPREAKV





QWKVDNALQSGNSQESVTEQDSKDS





TYSLSSTLTLSKADYE







LC
DIVMTQSPLSLPVTPGEPASISCRS
653



variable
SQSLLHSNGYNYLDWYLQKPGQSPQ





LLIYLGSNRASGVPDRFSGSASGTD





FTLKISRVEAEDVGVYYCMQALQAF





TFGPGTKVDIK







LCDR1
RSSQSLLHSNGYNYLD
262






LCDR2
LGSNRAS
263






LCDR3
MQALQAFT
654






LFR1
DIVMTQSPLSLPVTPGEPASISC
265






LFR2
WYLQKPGQSPQLLIY
266






LFR3
GVPDRFSGSASGTDFTLKISRVEAE
655




DVGVYYC







LFR4
FGPGTKVDIK
443





S144-509
HC
EVQLVQSGAEVKKPGESLKISCKGS
656




AYTFTTYWIGWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVTISADKS





ISTAYLQWSSLKASDTAMYYCARLL





LVAGPFDYWGQGTLVTVSSASTKGP





SVFPLAPSSKSTSGGTAALGCLVKD





YFPEPVTVSWNSGALTSGVHTFPAV





LQSSGLYSLSSVVTVPSSSLGTQTY





ICNVNHKPSNTKVD







HC
EVQLVQSGAEVKKPGESLKISCKGS
657



variable
AYTFTTYWIGWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVTISADKS





ISTAYLQWSSLKASDTAMYYCARLL





LVAGPFDYWGQGTLVTVSS







HCDR1
TYWIG
658






HCDR2
IIYPGDSDTRYSPSFQG
543






HCDR3
LLLVAGPFDY
659






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
660




AYTFT







HFR2
WVRQMPGKGLEWMG
174






HFR3
QVTISADKSISTAYLQWSSLKASDT
661




AMYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSASVGDRVTITCRA
662




SQSISSWLAWYQQKPGKAPNLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DN







LC
DIQMTQSPSTLSASVGDRVTITCRA
663



variable
SQSISSWLAWYQQKPGKAPNLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIK







LCDR1
RASQSISSWLA
520






LCDR2
DASSLES
387






LCDR3
QQYNSYPWT
646






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPNLLIY
664






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S144-516
HC
QVQLLQSGAEVKKPGASVKVSCKAS
665




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLTSDDTAVYYCATKT





GIDRYYYYYMDVWGKGTTVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
QVQLLQSGAEVKKPGASVKVSCKAS
666



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLTSDDTAVYYCATKT





GIDRYYYYYMDVWGKGTTVTVSS







HCDR1
GYYMH
187






HCDR2
RINPNSGGTNYAQKFQG
585






HCDR3
KTGIDRYYYYYMDV
667






HFR1
QVQLLQSGAEVKKPGASVKVSCKAS
668




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLTSDDT
669




AVYYCAT







HFR4
WGKGTTVTVSS
670






LC
QSVLTQPPSVSEAPGQRVTISCTGS
671




SSNIGAGYDVHWYQQLPGTAPKLLI





YGNINRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDNSLNGS





VFGGGTKLTVLRQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QSVLTQPPSVSEAPGQRVTISCTGS
672



variable
SSNIGAGYDVHWYQQLPGTAPKLLI





YGNINRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDNSLNGS





VFGGGTKLTVL







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
GNINRPS
674






LCDR3
QSYDNSLNGSV
675






LFR1
QSVLTQPPSVSEAPGQRVTISC
676






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGGGTKLTVL
69





S144-568
HC
QVQLQESGPGLVKPSETLSLTCSVS
677




GGSISDYYWSWIRQPPGKGLEWIGY





IYNSGSTNYNPSLKSRVTISADPSK





NQFSLKLSSVTAADTAVYYCARPHG





GDYAFDIWGQGTMVTVSSASPTSPK





VFPLSLDSTPQDGNVVVACLVQGFF





PQEPLSVTWSESGQNVTARNF







HC
QVQLQESGPGLVKPSETLSLTCSVS
678



variable
GGSISDYYWSWIRQPPGKGLEWIGY





IYNSGSTNYNPSLKSRVTISADPSK





NQFSLKLSSVTAADTAVYYCARPHG





GDYAFDIWGQGTMVTVSS







HCDR1
DYYWS
679






HCDR2
YIYNSGSTNYNPSLKS
680






HCDR3
PHGGDYAFDI
681






HFR1
QVQLQESGPGLVKPSETLSLTCSVS
682




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISADPSKNQFSLKLSSVTAADT
683




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
EIVLTQSPGTLSLSPGERATLSCRA
684




SQSVSSNFLAWYQQKPGQPPRLLIY





GASVRATGIPDRFSGSGSGTDFTLT





ITRLEPEDFAVYYCQQYGSLPRTFG





QGTKVEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





LSSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
685



variable
SQSVSSNFLAWYQQKPGQPPRLLIY





GASVRATGIPDRFSGSGSGTDFTLT





ITRLEPEDFAVYYCQQYGSLPRTFG





QGTKVEIK







LCDR1
RASQSVSSNFLA
686






LCDR2
GASVRAT
687






LCDR3
QQYGSLPRT
688






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQPPRLLIY
689






LFR3
GIPDRFSGSGSGTDFTLTITRLEPE
690




DFAVYYC







LFR4
FGQGTKVEIK
53





S144-576
HC
QVQLVQSGAEVMKPGSSVKVSCKAS
691




GGTFSSYSITWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARGY





SGSPSNLDGMDVWGQGTTVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
QVQLVQSGAEVMKPGSSVKVSCKAS
692



variable
GGTFSSYSITWVRQAPGQGLEWMGR





IIPILGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARGY





SGSPSNLDGMDVWGQGTTVTVSS







HCDR1
SYSIT
693






HCDR2
RIIPILGIANYAQKFQG
157






HCDR3
GYSGSPSNLDGMDV
694






HFR1
QVQLVQSGAEVMKPGSSVKVSCKAS
695




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
IQMTQSPSTLSASVGDRVTITCRAS
696




QSISSWLAWYQQKPGKAPKLLIYDA





SSLQSGVPSRFSGSGSGTEFTLTIS





SLQPDDFATYYCQQYNSYSPITFGQ





GTRLEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
IQMTQSPSTLSASVGDRVTITCRAS
697



variable
QSISSWLAWYQQKPGKAPKLLIYDA





SSLQSGVPSRFSGSGSGTEFTLTIS





SLQPDDFATYYCQQYNSYSPITFGQ





GTRLEIK







LCDR1
RASQSISSWLA
520






LCDR2
DASSLQS
698






LCDR3
QQYNSYSPIT
699






LFR1
IQMTQSPSTLSASVGDRVTITC
700






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTRLEIK
701





S144-588
HC
QLQLQESGPGLVKPSETLSLTCTVS
702




GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRFTISVDT





SKNQFSLKLSSVTAADTAVYYCAAY





QRKLGYCRGNSCFSCFDPWGQGTLV





TVSSASTKGPSVFPLAPSSKSTSGG





TAALGCLVKDYFPEPVTVSWNSGAL





TSGVHTFPAVLQSSG







HC
QLQLQESGPGLVKPSETLSLTCTVS
703



variable
GGSISSSSYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRFTISVDT





SKNQFSLKLSSVTAADTAVYYCAAY





QRKLGYCRGNSCFSCFDPWGQGTLV





TVSS







HCDR1
SSSYYWG
242






HCDR2
SIYYSGSTYYNPSLKS
243






HCDR3
YQRKLGYCRGNSCFSCFDP
704






HFR1
QLQLQESGPGLVKPSETLSLTCTVS
245




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RFTISVDTSKNQFSLKLSSVTAADT
705




AVYYCAA







HFR4
WGQGTLVTVSS
60






LC
SYELTQPPSVSVSPGQTASITCSGD
706




KLGDKYACWYQQKPGQSPVLVIYQD





TKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTVLFGGG





TKLTVLGQPKAAPSVTLFPPSSEEL





QANKATLVCLISDFYPGAVTVAWKA





DSSPVKAGVETTTPSKQSNNKYAAS





SYLSLTPEQWKSH







LC
SYELTQPPSVSVSPGQTASITCSGD
707



variable
KLGDKYACWYQQKPGQSPVLVIYQD





TKRPSGIPERFSGSNSGNTATLTIS





GTQAMDEADYYCQAWDSSTVLFGGG





TKLTVL







LCDR1
SGDKLGDKYAC
502






LCDR2
QDTKRPS
366






LCDR3
QAWDSSTVL
708






LFR1
SYELTQPPSVSVSPGQTASITC
368






LFR2
WYQQKPGQSPVLVIY
369






LFR3
GIPERFSGSNSGNTATLTISGTQAM
370




DEADYYC







LFR4
FGGGTKLTVL
69





S144-628
HC
EVHLVQSGAEVKQPGESLKISCKGS
709




GYNFATYWIAWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVIISADKS





IGTAFLQWSSLKASDTAMYYCARRG





YSSSNYRVDEYYYYGMDVWGQGTTV





TVSSASPTSPKVFPLSLCSTQPDGN





VVIACLVQGFFPQEPLSVTWSESGQ





GVTARNFP







HC
EVHLVQSGAEVKQPGESLKISCKGS
710



variable
GYNFATYWIAWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGQVIISADKS





IGTAFLQWSSLKASDTAMYYCARRG





YSSSNYRVDEYYYYGMDVWGQGTTV





TVSS







HCDR1
TYWIA
527






HCDR2
IIYPGDSDTRYSPSFQG
543






HCDR3
RGYSSSNYRVDEYYYYGMDV
711






HFR1
EVHLVQSGAEVKQPGESLKISCKGS
712




GYNFA







HFR2
WVRQMPGKGLEWMG
174






HFR3
QVIISADKSIGTAFLQWSSLKASDT
713




AMYYCAR







HFR4
WGQGTTVTVSS
147






LC
QSVLTQPPSMSGAPGQRVTISCTGS
714




SSNIGAGYDVHWYQQLPGAAPKLLI





YGDTSRPSGVPDRFSGSKSDTSASL





AITGLQAEDEADYYCQSFDRSLSGL





VIFGGGTRLTVLGQPKAAPSVTLFP





PSSEELQANKATLVCLISDFYPGAV





TVAWKADSSPVKAGVETTTPSKQSN





NKYAASS*DRKS







LC
QSVLTQPPSMSGAPGQRVTISCTGS
715



variable
SSNIGAGYDVHWYQQLPGAAPKLLI





YGDTSRPSGVPDRFSGSKSDTSASL





AITGLQAEDEADYYCQSFDRSLSGL





VIFGGGTRLTVL







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
GDTSRPS
716






LCDR3
QSFDRSLSGLVI
717






LFR1
QSVLTQPPSMSGAPGQRVTISC
718






LFR2
WYQQLPGAAPKLLIY
719






LFR3
GVPDRFSGSKSDTSASLAITGLQAE
720




DEADYYC







LFR4
FGGGTRLTVL
721





S144-740
HC
QVQLVQSGAEVKKPGASVKVSCKAS
722




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGDTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARLG





KGMAAARTVFDSWGQGTLVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
723



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGDTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARLG





KGMAAARTVFDSWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
RINPNSGDTNYAQKFQG
724






HCDR3
LGKGMAAARTVFDS
725






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRSDDT
588




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EVVLTQSPGTLSLSPGERATLSCRA
726




SQSVSSSYLAWYQQKPGQAPRLVIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGSSPTFGR





GTRLEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
EVVLTQSPGTLSLSPGERATLSCRA
727



variable
SQSVSSSYLAWYQQKPGQAPRLVIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGSSPTFGR





GTRLEIK







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQFGSSPT
728






LFR1
EVVLTQSPGTLSLSPGERATLSC
729






LFR2
WYQQKPGQAPRLVIY
730






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGRGTRLEIK
731





S144-741
HC
QVHLVQSGAEVKKPGASVKVSCKAS
732




GYTFTGYYMNWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDAAVYYCARAE





RYSSSWYNLYYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVHLVQSGAEVKKPGASVKVSCKAS
733



variable
GYTFTGYYMNWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDAAVYYCARAE





RYSSSWYNLYYWGQGTLVTVSS







HCDR1
GYYMN
734






HCDR2
RINPNSGGTNYAQKFQG
585






HCDR3
AERYSSSWYNLYY
735






HFR1
QVHLVQSGAEVKKPGASVKVSCKAS
736




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRSDDA
737




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSASGTPGQRVTISCSGS
738




SSNIGSNTVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLNGVV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASSYLSLTPEQWKSH







LC
QSVLTQPPSASGTPGQRVTISCSGS
739



variable
SSNIGSNTVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLNGVV





FGGGTKLTVL







LCDR1
SGSSSNIGSNTVN
740






LCDR2
SNNQRPS
119






LCDR3
AAWDDSLNGVV
741






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLQSE
123




DEADYYC







LFR4
FGGGTKLTVL
69





S144-803
HC
EVQLVQSGAEVKKPGESLKISCKGS
742




RYSFTRYWIAWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGPVTISADKS





ISTAYLQWSSLKASDTAIYYCARLP





NSNYVDYWGQGTLVTVSSASTKGPS





VFPLAPSSKSTSGGTAALGCLVKDY





FPEPVTVSWNSGALTSGVHTFPAVL





QSSGLYSLSSVVTVPSSSLGTQTYI





CNVNHKPSNTKVD







HC
EVQLVQSGAEVKKPGESLKISCKGS
743



variable
RYSFTRYWIAWVRQMPGKGLEWMGI





IYPGDSDTRYSPSFQGPVTISADKS





ISTAYLQWSSLKASDTAIYYCARLP





NSNYVDYWGQGTLVTVSS







HCDR1
RYWIA
744






HCDR2
IIYPGDSDTRYSPSFQG
543






HCDR3
LPNSNYVDY
745






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
746




RYSFT







HFR2
WVRQMPGKGLEWMG
174






HFR3
PVTISADKSISTAYLQWSSLKASDT
747




AIYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSASVGDRVTITCRA
748




SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNIYPYTFGQ





GTKLDIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSTLSASVGDRVTITCRA
749



variable
SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNIYPYTFGQ





GTKLDIK







LCDR1
RASQSISSWLA
520






LCDR2
DASSLES
387






LCDR3
QQYNIYPYT
750






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKLDIK
751





S144-843
HC
QVQLVESGGGVVQPGGSVRLSCAAS
752




GFDFTNNGMYWVRQAPGKGLEWVAF





IRYDGNKQDYADSVKGRFTISRDNS





KNTLYLQMSSLRPEDTAVYYCAKGV





YTENYGWGQGTLVTVSSGTTVTVSS





ASTKGPSVFPLAPCSRSTSESTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSSGLYSLSSVVTVPSSN





FGTQTYTCNVDHKPSNTKVD







HC
QVQLVESGGGVVQPGGSVRLSCAAS
753



variable
GFDFTNNGMYWVRQAPGKGLEWVAF





IRYDGNKQDYADSVKGRFTISRDNS





KNTLYLQMSSLRPEDTAVYYCAKGV





YTENYGWGQGTLVTVSS







HCDR1
NNGMY
754






HCDR2
FIRYDGNKQDYADSVKG
755






HCDR3
GVYTENYG
756






HFR1
QVQLVESGGGVVQPGGSVRLSCAAS
757




GFDFT







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMSSLRPEDT
758




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
759




SQTVTSRYLAWYQQKPGQAPRLLIY





GASTRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGNSPPYTF





GQGTKLEIKRTVAAPSVFIFPPSDE





QLKSGTASVVCLLNNFYPREAKVQW





KVDNALQSGNSQESVTEQDSKDSTY





SLSSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
760



variable
SQTVTSRYLAWYQQKPGQAPRLLIY





GASTRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGNSPPYTF





GQGTKLEIK







LCDR1
RASQTVTSRYLA
761






LCDR2
GASTRAT
208






LCDR3
QQYGNSPPYT
762






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTKLEIK
380





S144-877
HC
QVQLVESGGGVVQPGRSLRLSCAAS
763




GFTFSTYGMHWVRQAPGKGLEWVAV





ISYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKQQ





GTYCSGGNCYSGYFDYWGQGTLVTV





SSASTKGPSVFPLAPSSKSTSGGTA





ALGCLVKDYFPEPVTVSWNSGALTS





GVHTFPAVLQSSGLYSLSSVVTVPS





SSLGTQTYIC







HC
QVQLVESGGGVVQPGRSLRLSCAAS
764



variable
GFTFSTYGMHWVRQAPGKGLEWVAV





ISYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKQQ





GTYCSGGNCYSGYFDYWGQGTLVTV





SS







HCDR1
TYGMH
765






HCDR2
VISYDGSNKYYADSVKG
497






HCDR3
QQGTYCSGGNCYSGYFDY
766






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
499




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCQA
767




SQDISNYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFSFSI





SSLQPEDIATYYCQQYDNVPLTFGG





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSSLSASVGDRVTITCQA
768



variable
SQDISNYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFSFSI





SSLQPEDIATYYCQQYDNVPLTFGG





GTKVEIK







LCDR1
QASQDISNYLN
769






LCDR2
DASNLET
770






LCDR3
QQYDNVPLT
771






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFSFSISSLQPE
772




DIATYYC







LFR4
FGGGTKVEIK
85





S144-952
HC
QVQLVQSGAEVKKPGASVKVSCTAS
773




GYTVTSYGISWVRQAPGQGLEWMGW





ISTYNGNTNYAQKLQGRVTMTTDTS





TSTAYMELRSLRSDDTAVYYCARE





YSYGYRLAYFDYWGQGTLVTVSSGS





ASAPTLFPLVSCENSPSDTSSVAVG





CLAQDFLPDSITFSWKYKNNSDISS





TRGFPSVLRGGKYAATSQVLLPSKD





VM







HC
QVQLVQSGAEVKKPGASVKVSCTAS
774



variable
GYTVTSYGISWVRQAPGQGLEWMGW





ISTYNGNTNYAQKLQGRVTMTTDTS





TSTAYMELRSLRSDDTAVYYCAREY





SYGYRLAYFDYWGQGTLVTVSS







HCDR1
SYGIS
775






HCDR2
WISTYNGNTNYAQKLQG
776






HCDR3
EYSYGYRLAYFDY
777






HFR1
QVQLVQSGAEVKKPGASVKVSCTAS
778




GYTVT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTTDTSTSTAYMELRSLRSDDT
779




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCKS
780




SQSVLNSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYST





PQTFGQGTKVEIKRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDNALQSGNSQESVTEQDSK





DSTYSLSSTLTLSKADYE







LC
DIVMTQSPDSLAVSLGERATINCKS
781



variable
SQSVLNSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYST





PQTFGQGTKVEIK







LCDR1
KSSQSVLNSSNNKNYLA
782






LCDR2
WASTRES
30






LCDR3
QQYYSTPQT
783






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTISSLQAE
293




DVAVYYC







LFR4
FGQGTKVEIK
53





S144-971
HC
EVQLVESGGGLVQPGGSLRISCSAS
784




GFTFSRYAMHWVRQAPGKGLEYVSA





IRSNGGSTYYADSVRGRFTISRDNS





RNTLYLQMSSLRAEDTAVYYCVIIN





NLAAAGTRFDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
EVQLVESGGGLVQPGGSLRISCSAS
785



variable
GFTFSRYAMHWVRQAPGKGLEYVSA





IRSNGGSTYYADSVRGRFTISRDNS





RNTLYLQMSSLRAEDTAVYYCVIIN





NLAAAGTRFDYWGQGTLVTVSS







HCDR1
RYAMH
786






HCDR2
AIRSNGGSTYYADSVRG
787






HCDR3
INNLAAAGTRFDY
788






HFR1
EVQLVESGGGLVQPGGSLRISCSAS
789




GFTFS







HFR2
WVRQAPGKGLEYVS
790






HFR3
RFTISRDNSRNTLYLQMSSLRAEDT
791




AVYYCVI







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCKS
792




SQSVLYSSNNKNFLTWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYTT





PWTFGQGTKVEIKRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDNALQSGNSQESVTEQDSK





DSTYSLSSTLTLSKADYE







LC
DIVMTQSPDSLAVSLGERATINCKS
793



variable
SQSVLYSSNNKNFLTWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYTT





PWTFGQGTKVEIK







LCDR1
KSSQSVLYSSNNKNFLT
794






LCDR2
WASTRES
30






LCDR3
QQYYTTPWT
795






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTISSLQAE
293




DVAVYYC







LFR4
FGQGTKVEIK
53





S144-
HC
QVQLQQWGAGLLKPSETLSLTCAVY
796


1036

GGSFSGYFWSWIRQPPGKGLEWIGE





INHSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARAPY





YDFLREGNWFDPWGQGTLVTVSSAS





TKGPSVFPLAPSSKSTSGGTAALGC





LVKDYFPEPVTVSWNSGALTSGVHT





FPAVLQSSGLYSLSSVVTVPSSSLG





TQTYICNVNHKPS







HC
QVQLQQWGAGLLKPSETLSLTCAVY
797



variable
GGSFSGYFWSWIRQPPGKGLEWIGE





INHSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARAPY





YDFLREGNWFDPWGQGTLVTVSS







HCDR1
GYFWS
798






HCDR2
EINHSGSTNYNPSLKS
799






HCDR3
APYYDFLREGNWFDP
800






HFR1
QVQLQQWGAGLLKPSETLSLTCAVY
801




GGSFS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCNS
802




SQSVLYSSINKNYLAWYQQKPAQPP





KVLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYRT





PWTFGQGTKVEIKRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDNALQSGNSQESVTEQDSK





DSTYSLSSTLTLSKADYE







LC
DIVMTQSPDSLAVSLGERATINCNS
803



variable
SQSVLYSSINKNYLAWYQQKPAQPP





KVLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYYRT





PWTFGQGTKVEIK







LCDR1
NSSQSVLYSSINKNYLA
804






LCDR2
WASTRES
30






LCDR3
QQYYRTPWT
805






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPAQPPKVLIY
806






LFR3
GVPDRFSGSGSGTDFTLTISSLQAE
293




DVAVYYC







LFR4
FGQGTKVEIK
53





S144-
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
807


1079

GDTFGSYSITWVRQAPGQGLEWMGR





IIPVLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCAGGG





CSGGNCYSWYNWFDPWGQGSLVTVS





SASTKGPSVFPLAPSSKSTSGGTAA





LGCLVKDYFPEPVTVSWNSGALTSG





VHTFPAVLQSSG







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
808



variable
GDTFGSYSITWVRQAPGQGLEWMGR





IIPVLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCAGGG





CSGGNCYSWYNWFDPWGQGSLVTVS





S







HCDR1
SYSIT
693






HCDR2
RIIPVLGIANYAQKFQG
809






HCDR3
GGCSGGNCYSWYNWFDP
810






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
811




GDTFG







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTSTAYMELSSLRSEDT
812




AVYYCAG







HFR4
WGQGSLVTVSS
813






LC
EIVLTQSPGTLSLSPGERATLSCRA
814




SQSVSSNYLAWYQQKPGQAPRLLIY





GASSRATGIPERFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGRSPYTFG





QGTKLEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





LSSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
815



variable
SQSVSSNYLAWYQQKPGQAPRLLIY





GASSRATGIPERFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGRSPYTFG





QGTKLEIK







LCDR1
RASQSVSSNYLA
816






LCDR2
GASSRAT
135






LCDR3
QQYGRSPYT
817






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPERFSGSGSGTDFTLTISRLEPE
818




DFAVYYC







LFR4
FGQGTKLEIK
380





825S144-
HC
QVQLQESGPGLVKPSETLSLTCTVS
819


1299

GGSISSYYWSWIRQPPGKGLEWIGY





INYRGITNYNPSLKSRVTISVDMSK





NQFSLKLSSVTAADTAVYSCARLAV





ASRGTVDYWGQGTLVTVSSASTKGP





SVFPLAPSSKSTSGGTAALGCLVKD





YFPEPVTVSWNSGALTSGVHTFPAV





LQSSGLYSLSSVVTVPSSNFGTQTY





TCNVDHKPSNTKVD







HC
QVQLQESGPGLVKPSETLSLTCTVS
820



variable
GGSISSYYWSWIRQPPGKGLEWIGY





INYRGITNYNPSLKSRVTISVDMSK





NQFSLKLSSVTAADTAVYSCARLAV





ASRGTVDYWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
YINYRGITNYNPSLKS
821






HCDR3
LAVASRGTVDY
822






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDMSKNQFSLKLSSVTAADT
823




AVYSCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSASGTPGQRVTISCSGS
824




SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDSLSVNV





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTKPSKQSNN





KYAASSYLSLTPEQWKSH







LC
QSVLTQPPSASGTPGQRVTISCSGS
825



variable
SSNIGSNYVYWYQQLPGTAPKLLIY





RNNQRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDDSLSVNV





VFGGGTKLTVL







LCDR1
SGSSSNIGSNYVY
403






LCDR2
RNNQRPS
404






LCDR3
AAWDDSLSVNVV
826






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLRSE
406




DEADYYC







LFR4
FGGGTKLTVL
69





S144-
HC
QVQLVQSGTEVKKPGASVKVSCKAS
827


1339

GYTFTDYYMHWVRQAPGQGLEWMGR





INPTSGGTNYPQKFQGSVTMTRDTS





LSTVYMELSGLRSDDTAVYYCARE





RVTLIQGKNHYYMDVWGTGTTVTVS





SASTKGPSVFPLAPSSKSTSGGTAA





LGCLVKDYFPEPVTVSWNSGALTSG





VHTFPAVLQSSG







HC
QVQLVQSGTEVKKPGASVKVSCKAS
828



variable
GYTFTDYYMHWVRQAPGQGLEWMGR





INPTSGGTNYPQKFQGSVTMTRDTS





LSTVYMELSGLRSDDTAVYYCARER





VTLIQGKNHYYMDVWGTGTTVTVSS







HCDR1
DYYMH
829






HCDR2
RINPTSGGTNYPQKFQG
830






HCDR3
ERVTLIQGKNHYYMDV
831






HFR1
QVQLVQSGTEVKKPGASVKVSCKAS
832




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
SVTMTRDTSLSTVYMELSGLRSDDT
833




AVYYCAR







HFR4
WGTGTTVTVSS
834






LC
QSALTQPASVSGSPGQSITISCTGT
835




NSDVGGYNYVSWYQQHPGKAPRLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLV





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASSYLSLTPEQWKSH







LC
QSALTQPASVSGSPGQSITISCTGT
836



variable
NSDVGGYNYVSWYQQHPGKAPRLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLV





VFGGGTKLTVL







LCDR1
TGTNSDVGGYNYVS
837






LCDR2
DVSNRPS
64






LCDR3
SSYTSSSTLVV
838






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPRLMIY
839






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S144-
HC
QVQLVQSGAEVKKPGASVKVSCKAS
840


1406

GYTFTTYAMHWVRQAPGQRLEWMGW





INAGNGNTKYSQNFQGRVTITRDTS





ASTAYMELSSLRSEDTAVYYCASLV





GGDSSSWYDYMDVWGKGTTVTVSSA





STKGPSVFPLAPCSRSTSESTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSGLYSLSSVVTVPSSNF







HC
QVQLVQSGAEVKKPGASVKVSCKAS
841



variable
GYTFTTYAMHWVRQAPGQRLEWMGW





INAGNGNTKYSQNFQGRVTITRDTS





ASTAYMELSSLRSEDTAVYYCASLV





GGDSSSWYDYMDVWGKGTTVTVSS







HCDR1
TYAMH
842






HCDR2
WINAGNGNTKYSQNFQG
843






HCDR3
LVGGDSSSWYDYMDV
844






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQRLEWMG
287






HFR3
RVTITRDTSASTAYMELSSLRSEDT
845




AVYYCAS







HFR4
WGKGTTVTVSS
670






LC
DIQMTQSPSTLSASVGDRVTITCRA
846




SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSTLSASVGDRVTITCRA
847



variable
SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYPWTFGQ





GTKVEIK







LCDR1
RASQSISSWLA
520






LCDR2
DASSLES
387






LCDR3
QQYNSYPWT
646






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S144-
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
848


1407

GGTFSSYTISWVRQAPGQGLEWMGR





IIPVRDIANYAQKFQGRVTITADKS





TRTAYMEVSSLRSEDTAVYYCAATE





LRSDGLDIWGQGTMVTVSSASTKGP





SVFPLAPSSKSTSGGTAALGCLVKD





YFPEPVTVSWNSGALTSGVHTFPAV





LQSSG







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
849



variable
GGTFSSYTISWVRQAPGQGLEWMGR





IIPVRDIANYAQKFQGRVTITADKS





TRTAYMEVSSLRSEDTAVYYCAATE





LRSDGLDIWGQGTMVTVSS







HCDR1
SYTIS
850






HCDR2
RIIPVRDIANYAQKFQG
851






HCDR3
TELRSDGLDI
852






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTRTAYMEVSSLRSEDT
853




AVYYCAA







HFR4
WGQGTMVTVSS
44






LC
DIQMTQSPSTLSASVGDRVTITCRA
854




SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTV





SSLQPDDFATYYCQQYNNYSPITFG





QGTKLEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





LSSTLTLSKADYE







LC
DIQMTQSPSTLSASVGDRVTITCRA
855



variable
SQSISSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTV





SSLQPDDFATYYCQQYNNYSPITFG





QGTKLEIK







LCDR1
RASQSISSWLA
520






LCDR2
DASSLES
387






LCDR3
QQYNNYSPIT
856






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTVSSLQPD
857




DFATYYC







LFR4
FGQGTKLEIK
380





S144-
HC
QVQLVQSGAEVKKPGASVKVSCKAS
858


1569

GYTFSNYGISWVRQAPGQGLEWMGW





ISAYNGNTKYPQKLQGRVTMSTDTS





TSTAYMELRSLRSDDTAVYYCARET





RYGMDVWGQGTTVTVSSASTKGPSV





FPLAPSSKSTSGGTAALGCLVKDYF





PEPVTVSWNSGALTSGVHTFPAVLQ





SSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
859



variable
GYTFSNYGISWVRQAPGQGLEWMGW





ISAYNGNTKYPQKLQGRVTMSTDTS





TSTAYMELRSLRSDDTAVYYCARET





RYGMDVWGQGTTVTVSS







HCDR1
NYGIS
860






HCDR2
WISAYNGNTKYPQKLQG
861






HCDR3
ETRYGMDV
862






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
863




GYTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMSTDTSTSTAYMELRSLRSDDT
864




AVYYCAR




HFR4
WGQGTTVTVSS
147






LC
QPVLTQPPSASASLGASVTLTCTLS
865




SGYSNYKVDWYQQRPGKGPQFVMRV





GTGGIVGSKGDGIPDRFSVLGSGLN





RYLTIKNIQEEDESDYHCGADHGSG





SNFVRVFGGGTKLTVLGQPKAAPSV





TLFPPSSEELQANKATLVCLISDFY





PGAVTVAWKADSSPVKAGVETTTPS





KQSNNKYAASSYLSLTPEQWKSH







LC
QPVLTQPPSASASLGASVTLTCTLS
866



variable
SGYSNYKVDWYQQRPGKGPQFVMRV





GTGGIVGSKGDGIPDRFSVLGSGLN





RYLTIKNIQEEDESDYHCGADHGSG





SNFVRVFGGGTKLTVL







LCDR1
TLSSGYSNYKVD
867






LCDR2
VGTGGIVGSKGD
868






LCDR3
GADHGSGSNFVRV
869






LFR1
QPVLTQPPSASASLGASVTLTC
870






LFR2
WYQQRPGKGPQFVMR
871






LFR3
GIPDRFSVLGSGLNRYLTIKNIQEE
872




DESDYHC







LFR4
FGGGTKLTVL
69





S144-
HC
EVQLVQSGAEVKKPGESLKISCKGS
873


1641

GYTFTSYWIGWVRQMPGKGLEWMGI





IYLGDSDTRYSPSFQGQVTISADKS





ISTAYLQWNSLKASDTAMYYCARQV





TGTTSWFDPWGQGTLVTVSSASTKG





PSVFPLAPSSKSTSGGTAALGCLVK





DYFPEPVTVSWNSGALTSGVHTFPA





VLQSSG







HC
EVQLVQSGAEVKKPGESLKISCKGS
874



variable
GYTFTSYWIGWVRQMPGKGLEWMGI





IYLGDSDTRYSPSFQGQVTISADKS





ISTAYLQWNSLKASDTAMYYCARQV





TGTTSWFDPWGQGTLVTVSS







HCDR1
SYWIG
542






HCDR2
IIYLGDSDTRYSPSFQG
875






HCDR3
QVTGTTSWFDP
876






HFR1
EVQLVQSGAEVKKPGESLKISCKGS
877




GYTFT







HFR2
WVRQMPGKGLEWMG
174






HFR3
QVTISADKSISTAYLQWNSLKASDT
878




AMYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSASVGERVTITCRA
879




SQSISRWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYHCHQYSTYSLTFGG





GTKVDIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSTLSASVGERVTITCRA
880



variable
SQSISRWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYHCHQYSTYSLTFGG





GTKVDIK







LCDR1
RASQSISRWLA
881






LCDR2
DASSLES
387






LCDR3
HQYSTYSLT
882






LFR1
DIQMTQSPSTLSASVGERVTITC
883






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
884




DFATYHC







LFR4
FGGGTKVDIK
885





S144-
HC
EVQLVESGGDVVQPGGSLRLSCAAS
886


1827

GITFSNYWMTWVRQAPGKGLEWVAT





IKKDGGEQYYVDSVKGRFTISRDNA





RNSLYLQINSLRAEDTAVYYCARGG





SSSSYYWIYWGQGTLVTVSSGSASA





PTLFPLVSCENSPSDTSSV







HC
EVQLVESGGDVVQPGGSLRLSCAAS
887



variable
GITFSNYWMTWVRQAPGKGLEWVAT





IKKDGGEQYYVDSVKGRFTISRDNA





RNSLYLQINSLRAEDTAVYYCARGG





SSSSYYWIYWGQGTLVTVSS







HCDR1
NYWMT
888






HCDR2
TIKKDGGEQYYVDSVKG
889






HCDR3
GGSSSSYYWIY
890






HFR1
EVQLVESGGDVVQPGGSLRLSCAAS
891




GITFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNARNSLYLQINSLRAEDT
892




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
893




SQSISNSYLVWYQQKPGQAPRLLIY





GASTRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPWTFG





QGTTVEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





LSSTLTLSKADYE







LC
EIVLTQSPGTLSLSPGERATLSCRA
894



variable
SQSISNSYLVWYQQKPGQAPRLLIY





GASTRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPWTFG





QGTTVEIK







LCDR1
RASQSISNSYLV
895






LCDR2
GASTRAT
208






LCDR3
QQYGSSPWT
303






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTTVEIK
896





S144-
HC
EVQLVESGGGLVKPGGSLRLSCAAS
897


1848

GFTFSSYSMNWVRQAPGKGLEWVSS





ISSSSSYIYYADSVKGRFTISRDNA





KNSLYLQLNSLRAEDTAVYYCARDR





DQLIFSAAFDIWGQGTMVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
EVQLVESGGGLVKPGGSLRLSCAAS
898



variable
GFTFSSYSMNWVRQAPGKGLEWVSS





ISSSSSYIYYADSVKGRFTISRDNA





KNSLYLQLNSLRAEDTAVYYCARDR





DQLIFSAAFDIWGQGTMVTVSS







HCDR1
SYSMN
126






HCDR2
SISSSSSYIYYADSVKG
899






HCDR3
DRDQLIFSAAFDI
900






HFR1
EVQLVESGGGLVKPGGSLRLSCAAS
602




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQLNSLRAEDT
901




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
QSVLTQPPSASGTPGQRVTISCSGS
902




SSNIEHNYVFWYQQLPGTAPKLLIY





SNNHRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDASLSGPV





VFAGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QSVLTQPPSASGTPGQRVTISCSGS
903



variable
SSNIEHNYVFWYQQLPGTAPKLLIY





SNNHRPSGVPDRFSGSKSGTSASLA





ISGLRSEDEADYYCAAWDASLSGPV





VFAGGTKLTVL







LCDR1
SGSSSNIEHNYVF
904






LCDR2
SNNHRPS
905






LCDR3
AAWDASLSGPVV
906






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLRSE
406




DEADYYC







LFR4
FAGGTKLTVL
907





S144-
HC
EVQLVESGGGLVQPGGSLRLSCAAS
908


1850

GFTFSSYAMSWVRQAPGKGLEWVSA





ISGSGGSTYYADSVKGRFTISRANS





KNTLYLQMNSLRAEDTAVYYCAKGP





RFSRDYFDYWGQGTLVTVSSASTKG





PSVFPLAPSSKSTSGGTAALGCLVK





DYFPEPVTVSWNSGALTSGVHTFPA





VLQSSG







HC
EVQLVESGGGLVQPGGSLRLSCAAS
909



variable
GFTFSSYAMSWVRQAPGKGLEWVSA





ISGSGGSTYYADSVKGRFTISRANS





KNTLYLQMNSLRAEDTAVYYCAKGP





RFSRDYFDYWGQGTLVTVSS







HCDR1
SYAMS
610






HCDR2
AISGSGGSTYYADSVKG
910






HCDR3
GPRFSRDYFDY
911






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRANSKNTLYLQMNSLRAEDT
912




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSTLSASVGDRVTITCRA
913




SQSITSWLAWYQQKPGKAPKLLIYD





ASNLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNNYLGTFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSTLSASVGDRVTITCRA
914



variable
SQSITSWLAWYQQKPGKAPKLLIYD





ASNLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNNYLGTFGQ





GTKVEIK







LCDR1
RASQSITSWLA
645






LCDR2
DASNLES
915






LCDR3
QQYNNYLGT
916






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S144-
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
917


2234

GGTFSRYTISWVRQAPGQGLEWMGR





IIPILGTANYAQNFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARHG





YSYGPFDYWGQGTLVTVSSASTKGP





SVFPLAPSSKSTSGGTAALGCLVKD





YFPEPVTVSWNSGALTSGVHTFPAV





LQSSG







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
918



variable
GGTFSRYTISWVRQAPGQGLEWMGR





IIPILGTANYAQNFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARHG





YSYGPFDYWGQGTLVTVSS







HCDR1
RYTIS
919






HCDR2
RIIPILGTANYAQNFQG
920






HCDR3
HGYSYGPFDY
921






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLTVSLGERATINCKS
922




SQSVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTVSSLQAEDVAVYYCQQYYST





PGTFGQGTKVEIKRTVAAPSVFIFP





PSDEQLKSGTASVVCLLNNFYPREA





KVQWKVDNALQSGNSQESVTEQDSK





DSTYSLSSTLTLSKADYE







LC
DIVMTQSPDSLTVSLGERATINCKS
923



variable
SQSVLYSSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTVSSLQAEDVAVYYCQQYYST





PGTFGQGTKVEIK







LCDR1
KSSQSVLYSSNNKNYLA
291






LCDR2
WASTRES
30






LCDR3
QQYYSTPGT
924






LFR1
DIVMTQSPDSLTVSLGERATINC
925






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTVSSLQAE
926




DVAVYYC







LFR4
FGQGTKVEIK
53





S564-105
HC
QVRLQESGPGLVKPSQTLSLTCTVS
927




GGSISSGSYYWSWIRQPAGKGLEWI





GRFHTSGSTNYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARD





LKGKTWIQTPFDYWGQGILVTVSSA





STKGPSVFPLAPSSKSTSGGTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSG







HC
QVRLQESGPGLVKPSQTLSLTCTVS
928



variable
GGSISSGSYYWSWIRQPAGKGLEWI





GRFHTSGSTNYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARD





LKGKTWIQTPFDYWGQGILVTVSS







HCDR1
SGSYYWS
929






HCDR2
RFHTSGSTNYNPSLKS
930






HCDR3
DLKGKTWIQTPFDY
931






HFR1
QVRLQESGPGLVKPSQTLSLTCTVS
932




GGSIS







HFR2
WIRQPAGKGLEWIG
25






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGILVTVSS
220






LC
QSALTQPASVSGSPGQSITISCTGT
933




SSDVGAYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSTFFG





TGTTVTVLGQPKANPTVTLFPPSSE





ELQANKATLVCLISDFYPGAVTVAW





KADGSPVKAGVETTTPSKQSNNKYA





ASSY







LC
QSALTQPASVSGSPGQSITISCTGT
934



variable
SSDVGAYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSTFFG





TGTTVTVL







LCDR1
TGTSSDVGAYNYVS
935






LCDR2
EVSNRPS
151






LCDR3
SSYTSSTF
936






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGTGTTVTVL
937





S564-14
HC
EVQLVESGGGLVQPGGSLRLSCAAS
938




GLTFSSYWMSWARQAPGKGLEWVAN





IKKDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRVEDTAVYYCASEP





PHYGGNSGAEYFQHWGQGTLVTVSS





APTKAPDVFPIISGCRHPKDNSPVV





LACLITGYH







HC
EVQLVESGGGLVQPGGSLRLSCAAS
939



variable
GLTFSSYWMSWARQAPGKGLEWVAN





IKKDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRVEDTAVYYCASEP





PHYGGNSGAEYFQHWGQGTLVTVSS







HCDR1
SYWMS
270






HCDR2
NIKKDGSEKYYVDSVKG
940






HCDR3
EPPHYGGNSGAEYFQH
941






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
942




GLTFS







HFR2
WARQAPGKGLEWVA
943






HFR3
RFTISRDNAKNSLYLQMNSLRVEDT
944




AVYYCAS







HFR4
WGQGTLVTVSS
60






LC
SYVLTQPPSVSVAPGKTARITCGGN
945




NIGSKSVHWYQQRPGQAPVLVIYYD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSDHHYVF





GTGTKVTVLGQPKANPTVTLFPPSS





EELQANKATLVCLISDFYPGAVTVA





WKADSSPVKAGVETTKPSKQSNNKY





AASS







LC
SYVLTQPPSVSVAPGKTARITCGGN
946



variable
NIGSKSVHWYQQRPGQAPVLVIYYD





SDRPSGIPERFSGSNSGNTATLTIS





RVEAGDEADYYCQVWDSSSDHHYVF





GTGTKVTVL







LCDR1
GGNNIGSKSVH
12






LCDR2
YDSDRPS
947






LCDR3
QVWDSSSDHHYV
948






LFR1
SYVLTQPPSVSVAPGKTARITC
949






LFR2
WYQQRPGQAPVLVIY
950






LFR3
GIPERFSGSNSGNTATLTISRVEAG
17




DEADYYC







LFR4
FGTGTKVTVL
18





S564-68
HC
QVQLVQSGAEVKKPGASVKVSCKAS
951




GYIFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ITTAYMELSRLRSDDTAFYYCARVK





RFSIFGVELDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
952



variable
GYIFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ITTAYMELSRLRSDDTAFYYCARVK





RFSIFGVELDYWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
VKRFSIFGVELDY
954






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
955




GYIFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSITTAYMELSRLRSDDT
956




AFYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPPSASGSPGQSVTISCTGT
957




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYFCSSYADSNNLV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFCPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASSY







LC
QSALTQPPSASGSPGQSVTISCTGT
958



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYFCSSYADSNNLV





FGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSKRPS
94






LCDR3
SSYADSNNLV
959






LFR1
QSALTQPPSASGSPGQSVTISC
96






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTVSGLQAE
960




DEADYFC







LFR4
FGGGTKLTVL
69





S564-98
HC
QVQLQESGPGLVKPSETLSLTCTVS
961




GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARHQS





RWNIVATMDFDYWGQGTLVTVSSAS





TKGPSVFPL







HC
QVQLQESGPGLVKPSETLSLTCTVS
962



variable
GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTISVDTSK





NQFSLKLSSVTAADTAVYYCARHQS





RWNIVATMDFDYWGQGTLVTVSS







HCDR1
SYYWS
56






HCDR2
YIYYSGSTNYNPSLKS
4






HCDR3
HQSRWNIVATMDFDY
963






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
964




SQSIRSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





GSLQPEDFATYYCQQSYSTSVAFGQ





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNALQSGNSQESVTEQDSKDSTYSL





SSTLTLSKADYE







LC
DIQMTQSPSSLSASVGDRVTITCRA
965



variable
SQSIRSYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





GSLQPEDFATYYCQQSYSTSVAFGQ





GTKVEIK







LCDR1
RASQSIRSYLN
432






LCDR2
AASSLQS
249






LCDR3
QQSYSTSVA
966






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTIGSLQPE
967




DFATYYC







LFR4
FGQGTKVEIK
53





S564-105
HC
QVRLQESGPGLVKPSQTLSLTCTVS
927




GGSISSGSYYWSWIRQPAGKGLEWI





GRFHTSGSTNYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARD





LKGKTWIQTPFDYWGQGILVTVSSA





STKGPSVFPLAPSSKSTSGGTAALG





CLVKDYFPEPVTVSWNSGALTSGVH





TFPAVLQSSG







HC
QVRLQESGPGLVKPSQTLSLTCTVS
928



variable
GGSISSGSYYWSWIRQPAGKGLEWI





GRFHTSGSTNYNPSLKSRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARD





LKGKTWIQTPFDYWGQGILVTVSS







HCDR1
SGSYYWS
929






HCDR2
RFHTSGSTNYNPSLKS
930






HCDR3
DLKGKTWIQTPFDY
931






HFR1
QVRLQESGPGLVKPSQTLSLTCTVS
932




GGSIS







HFR2
WIRQPAGKGLEWIG
25






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGILVTVSS
220






LC
QSALTQPASVSGSPGQSITISCTGT
933




SSDVGAYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSTFFG





TGTTVTVLGQPKANPTVTLFPPSSE





ELQANKATLVCLISDFYPGAVTVAW





KADGSPVKAGVETTTPSKQSNNKYA





ASSY







LC
QSALTQPASVSGSPGQSITISCTGT
934



variable
SSDVGAYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSTFFG





TGTTVTVL







LCDR1
TGTSSDVGAYNYVS
935






LCDR2
EVSNRPS
151






LCDR3
SSYTSSTF
936






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGTGTTVTVL
937





S564-134
HC
QVQLVQSGAEVKKPGASVKVSCKAS
968




GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





INTAYMELSRLRSDDTAVYYCTRVG





RFSIFGVELDYWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
969



variable
GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





INTAYMELSRLRSDDTAVYYCTRVG





RFSIFGVELDYWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
VGRFSIFGVELDY
970






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSINTAYMELSRLRSDDT
971




AVYYCTR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPPSASGSPGQSVTISCTGT
972




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVNKRPSGVPDRFSGSKSGNTASL





TVSGLQADDEADYYCSSYAGSNNLV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASS







LC
QSALTQPPSASGSPGQSVTISCTGT
973



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVNKRPSGVPDRFSGSKSGNTASL





TVSGLQADDEADYYCSSYAGSNNLV





FGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVNKRPS
974






LCDR3
SSYAGSNNLV
975






LFR1
QSALTQPPSASGSPGQSVTISC
96






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTVSGLQAD
976




DEADYYC







LFR4
FGGGTKLTVL
69





S564-138
HC
QVLLVQSGAEVKKPGASVKVSCKAS
977




GYTFTGYYLHWVRQAPGQGLEWMGW





INPISGGTNYAQNFQDRVTMTRDTS





IITAYMELSRLRSDDTAVYYCARLA





YYYDSSAYRGAFDIWGQGTMVTVSS





ASTKGPSVFPLAPSSKSTSGGTAAL





GCLVKDYFPEPVTVSWNSGALTSGV





HTFPAVLQSS







HC
QVLLVQSGAEVKKPGASVKVSCKAS
978



variable
GYTFTGYYLHWVRQAPGQGLEWMGW





INPISGGTNYAQNFQDRVTMTRDTS





IITAYMELSRLRSDDTAVYYCARLA





YYYDSSAYRGAFDIWGQGTMVTVSS







HCDR1
GYYLH
979






HCDR2
WINPISGGTNYAQNFQD
980






HCDR3
LAYYYDSSAYRGAFDI
981






HFR1
QVLLVQSGAEVKKPGASVKVSCKAS
982




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSIITAYMELSRLRSDDT
983




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
QSALTQPASVSGSPGQSITISCTGT
984




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSDRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTYV





FGTGTKVTVLGQPKANPTVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADGSPVKAGVETTKPSKQSNNK





YAASS







LC
QSALTQPASVSGSPGQSITISCTGT
985



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSDRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTYV





FGTGTKVTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSNRPS
151






LCDR3
SSYTSSSTYV
986






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSDRFSGSKSGNTASLTISGLQAE
987




DEADYYC







LFR4
FGTGTKVTVL
18





S564-152
HC
QVQLVESGGGVVQPGRSLRLSCAAS
988




GFTFSYYGMHWVRQAPGKGLEWVAV





IWYDGSNKHYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKNA





APYCSGGSCYGTYFDYWGQGTLVTV





SSASTKGPSVFPLAPSSKSTSGGTA





ALGCLVKDYFPEPVTVSWNSGALTS





GVHTFPAVLQSSG







HC
QVQLVESGGGVVQPGRSLRLSCAAS
989



variable
GFTFSYYGMHWVRQAPGKGLEWVAV





IWYDGSNKHYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKNA





APYCSGGSCYGTYFDYWGQGTLVTV





SS







HCDR1
YYGMH
990






HCDR2
VIWYDGSNKHYADSVKG
991






HCDR3
NAAPYCSGGSCYGTYFDY
992






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
499




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCQA
993




SQDINNYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFTFTI





SSLQPEDIATYYCQQYDNVPPHTFG





QGTKLEIKRTVAAPSVFIFPPSDEQ





LKSGTASVVCLLNNFYPREAKVQWK





VDNALQSGNSQESVTEQDSKDSTYS





LSSTLTLSKADYE







LC
DIQMTQSPSSLSASVGDRVTITCQA
994



variable
SQDINNYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFTFTI





SSLQPEDIATYYCQQYDNVPPHTFG





QGTKLEIK







LCDR1
QASQDINNYLN
995






LCDR2
DASNLET
770






LCDR3
QQYDNVPPHT
996






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTFTISSLQPE
997




DIATYYC







LFR4
FGQGTKLEIK
380





S564-218
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
998




GGTFSSYAISWVRQAPGQGLEWMGG





IIPIFGTAKYAQKFQGRVTITADES





TSTAYMELSSLRSEDTAVYYCARGK





DGYNPWGAFDIWGQGTMVTVSSGSA





SAPTLFPLVSCENSPSDTSSV







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
999



variable
GGTFSSYAISWVRQAPGQGLEWMGG





IIPIFGTAKYAQKFQGRVTITADES





TSTAYMELSSLRSEDTAVYYCARGK





DGYNPWGAFDIWGQGTMVTVSS







HCDR1
SYAIS
308






HCDR2
GIIPIFGTAKYAQKFQG
1000






HCDR3
GKDGYNPWGAFDI
1001






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTITADESTSTAYMELSSLRSEDT
1002




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
QSALTQPPSASGSPGQSVTISCTGT
1003




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYYCSSYAGSNNFG





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASSYLSLTPEQWKSH







LC
QSALTQPPSASGSPGQSVTISCTGT
1004



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYYCSSYAGSNNFG





VFGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSKRPS
94






LCDR3
SSYAGSNNFGV
1005






LFR1
QSALTQPPSASGSPGQSVTISC
96






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTVSGLQAE
1006




DEADYYC







LFR4
FGGGTKLTVL
69





S564-249
HC
EVQLVESGGGLVQPGGSLRLSCVAS
1007




GFTFSDYAMHWVRQAPGKGLEYIAA





ISSNGGRTYYADSVKDKFTISRDNS





KNILYLHMGSLRAEDTAVYFCARDP





QSWVTSTTAHFQHWGQGTLVTVSSA





SPTSPKVFPLSLCSTQPDGNVVIAC





LVQGFFPQEPLSVTWSESGQGVTAR





NF







HC
EVQLVESGGGLVQPGGSLRLSCVAS
1008



variable
GFTFSDYAMHWVRQAPGKGLEYIAA





ISSNGGRTYYADSVKDKFTISRDNS





KNILYLHMGSLRAEDTAVYFCARDP





QSWVTSTTAHFQHWGQGTLVTVSS







HCDR1
DYAMH
1009






HCDR2
AISSNGGRTYYADSVKD
1010






HCDR3
DPQSWVTSTTAHFQH
1011






HFR1
EVQLVESGGGLVQPGGSLRLSCVAS
1012




GFTFS







HFR2
WVRQAPGKGLEYIA
1013






HFR3
KFTISRDNSKNILYLHMGSLRAEDT
1014




AVYFCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1015




SSDIGGYNYVSWYQQHPGKAPKLII





SDVSNRPSGVSSRFSGSKSGNTASL





TISGLQTEDEAHYYCSSFRSGITLG





VFGGGTKLTVLGQPKAAPSVTLFPP





SSEELQANKATLVCLISDFYPGAVT





VAWKADSSPVKAGVETTTPSKQSNN





KYAASS







LC
QSALTQPASVSGSPGQSITISCTGT
1016



variable
SSDIGGYNYVSWYQQHPGKAPKLII





SDVSNRPSGVSSRFSGSKSGNTASL





TISGLQTEDEAHYYCSSFRSGITLG





VFGGGTKLTVL







LCDR1
TGTSSDIGGYNYVS
1017






LCDR2
DVSNRPS
64






LCDR3
SSFRSGITLGV
1018






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLIIS
1019






LFR3
GVSSRFSGSKSGNTASLTISGLQTE
1020




DEAHYYC







LFR4
FGGGTKLTVL
69





S564-265
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1021




GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGAINYAQKFQGRVTMTRDTS





ISTAYMELSSLRSDDTAVYYCARVG





RFSIFGVELDNWGQGTLVTVSSAST





KGPSVFPLAPSSKSTSGGTAALGCL





VKDYFPEPVTVSWNSGALTSGVHTF





PAVLQSSG







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1022



variable
GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGAINYAQKFQGRVTMTRDTS





ISTAYMELSSLRSDDTAVYYCARVG





RFSIFGVELDNWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
WINPNSGAINYAQKFQG
1023






HCDR3
VGRFSIFGVELDN
1024






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSSLRSDDT
1025




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPPSASGSPGQSVTISCTGT
1026




SSDVGGYNFVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYYCSSYGGSNNLI





FGGGTRLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASSYLSLTPEQWKSH







LC
QSALTQPPSASGSPGQSVTISCTGT
1027



variable
SSDVGGYNFVSWYQQHPGKAPKLMI





YEVSKRPSGVPDRFSGSKSGNTASL





TVSGLQAEDEADYYCSSYGGSNNLI





FGGGTRLTVL







LCDR1
TGTSSDVGGYNFVS
1028






LCDR2
EVSKRPS
94






LCDR3
SSYGGSNNLI
1029






LFR1
QSALTQPPSASGSPGQSVTISC
96






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTVSGLQAE
1006




DEADYYC







LFR4
FGGGTRLTVL
721





S564-275
HC
QVQLQESGPGLVKPSETLSLTCTVS
1030




GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTKYNPSLKSRVTISVDTSK





KQFSLKLSSVTAADTAVYYCARHIK





IGVVGGLTFDFWGQGTLVTVSSGSA





SAPTLFPLVSCENSPSDTSSV







HC
QVQLQESGPGLVKPSETLSLTCTVS
1031



variable
GGSISSYYWSWIRQPPGKGLEWIGY





IYYSGSTKYNPSLKSRVTISVDTSK





KQFSLKLSSVTAADTAVYYCARHIK





IGVVGGLTFDFWGQGTLVTVSS




HCDR1
SYYWS
56






HCDR2
YIYYSGSTKYNPSLKS
333






HCDR3
HIKIGVVGGLTFDF
1032






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
24




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKKQFSLKLSSVTAADT
1033




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASIGDRVTITCRA
1034




SQSISTYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGADFTLTI





SSLQPEDFATYYCQQSYSTPLTFGG





GTKVEIKRTVAAPSVFIFPPSDEQL





KSGTASVVCLLNNFYPREAKVQWKV





DNA







LC
DIQMTQSPSSLSASIGDRVTITCRA
1035



variable
SQSISTYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGADFTLTI





SSLQPEDFATYYCQQSYSTPLTFGG





GTKVEIK







LCDR1
RASQSISTYLN
1036






LCDR2
AASSLQS
249






LCDR3
QQSYSTPLT
1037






LFR1
DIQMTQSPSSLSASIGDRVTITC
1038






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGADFTLTISSLQPE
1039




DFATYYC







LFR4
FGGGTKVEIK
85





S564-287
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1040




GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRCDDTAVYYCARAS





TPYSSGSWADYWGQGTLVTVSSGSA





SAPTLFPLVSCENSPSDTSSV







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1041



variable
GYTFTGYYMHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRCDDTAVYYCARAS





TPYSSGSWADYWGQGTLVTVSS







HCDR1
GYYMH
187






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
ASTPYSSGSWADY
1042






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRCDDT
1043




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1044




SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYASSSTWV





FGGGTKLTVLGQPKAAPSVTLFPPS





SEELQANKATLVCLISDFYPGAVTV





AWKADSSPVKAGVETTTPSKQSNNK





YAASSYLSLT







LC
QSALTQPASVSGSPGQSITISCTGT
1045



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YDVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYASSSTWV





FGGGTKLTVL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
DVSNRPS
64






LCDR3
SSYASSSTWV
1046






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC




LFR4
FGGGTKLTVL
69





S166-32
HC
QVQLVESGGGLVKPGGSLRLSCAAS
1047




GFTFSDYYMSWIRQAPGKGLEWVSY





ISISDTTIYYADAVQGRFTMSRDNA





KNSLYLQMNSLKAEDTAVYYCARAS





PYCGGDCSFGNAFDIWGLGTMVTVS





S







HC
QVQLVESGGGLVKPGGSLRLSCAAS
1048



variable
GFTFSDYYMSWIRQAPGKGLEWVSY





ISISDTTIYYADAVQGRFTMSRDNA





KNSLYLQMNSLKAEDTAVYYCAR







HCDR1
DYYMS
1049






HCDR2
YISISDTTIYYADAVQG
1050






HCDR3
ASPYCGGDCSFGNAFDI
1051






HFR1
QVQLVESGGGLVKPGGSLRLSCAAS
1052




GFTFS







HFR2
WIRQAPGKGLEWVS
1053






HFR3
RFTMSRDNAKNSLYLQMNSLKAEDT
1054




AVYYCAR







HFR4
WGLGTMVTVSS
1055






LC
DIQMTQSPSTLSASVGDRVTITCRA
1056




SQSIFSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSYWTFGQG





TKVEIK







LC
DIQMTQSPSTLSASVGDRVTITCRA
1057



variable
SQSIFSWLAWYQQKPGKAPKLLIYD





ASSLESGVPSRFSGSGSGTEFTLTI





SSLQPDDFATYYCQQYNSY







LCDR1
RASQSIFSWLA
1058






LCDR2
DASSLES
387






LCDR3
QQYNSYWT
1059






LFR1
DIQMTQSPSTLSASVGDRVTITC
523






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTEFTLTISSLQPD
524




DFATYYC







LFR4
FGQGTKVEIK
53





S305-223
HC
QVQLVESGGGVVQPGRSLRLSCAAS
1060




GFTFRNFGMHWVRQAPGKGLEWVAF





IWTAESDKFYADSVKGRFTVSRDNS





KNTLYLEMNSLRAEDTAVYYCTKAM





DVWGRGTTVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCAAS
1061



variable
GFTFRNFGMHWVRQAPGKGLEWVAF





IWTAESDKFYADSVKGRFTVSRDNS





KNTLYLEMNSLRAEDTAVYYCTK







HCDR1
NFGMH
1062






HCDR2
FIWTAESDKFYADSVKG
1063






HCDR3
AMDV
1064






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
1065




GFTFR







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTVSRDNSKNTLYLEMNSLRAEDT
1066




AVYYCTK







HFR4
WGRGTTVTVSS
1067






LC
EIVLTQSPATLSLSPGERATLSCRA
1068




SQSVSTSLAWYQQKCGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRGNWPFTFGP





GTRVDIK







LC
EIVLTQSPATLSLSPGERATLSCRA
1069



variable
SQSVSTSLAWYQQKCGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRGNWP







LCDR1
RASQSVSTSLA
1070






LCDR2
DASNRAT
441






LCDR3
QQRGNWPFT
1071






LFR1
EIVLTQSPATLSLSPGERATLSC
181






LFR2
WYQQKCGQAPRLLIY
1072






LFR3
GIPARFSGSGSGTDFTLTISSLEPE
183




DFAVYYC







LFR4
FGPGTRVDIK
1073





S305-399
HC
QVQLVQSGAEVKKPGASVKVSCKVS
1074




GYTLTELSMHWVRQAPGKGLEWMGG





FDPEDGETIYAQKFQGRVTMTEDTS





TDTAYMELSSLRSEDTAVYYCATGG





LGCSNGVCNNWFDPWGLGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKVS
1075



variable
GYTLTELSMHWVRQAPGKGLEWMGG





FDPEDGETIYAQKFQGRVTMTEDTS





TDTAYMELSSLRSEDTAVYYCAT







HCDR1
ELSMH
457






HCDR2
GFDPEDGETIYAQKFQG
458






HCDR3
GGLGCSNGVCNNWFDP
1076






HFR1
QVQLVQSGAEVKKPGASVKVSCKVS
1077




GYTLT







HFR2
WVRQAPGKGLEWMG
42






HFR3
RVTMTEDTSTDTAYMELSSLRSEDT
1078




AVYYCAT







HFR4
WGLGTLVTVSS
1079






LC
EIVMTQSPATLSVSPGERATLSCRA
1080




SQSITSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SNLQSEDFAVYYCQQYNNWPLTFGQ





GTKVEIK







LC
EIVMTQSPATLSVSPGERATLSCRA
1081



variable
SQSITSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SNLQSEDFAVYYCQQYNNWP







LCDR1
RASQSITSNLA
1082






LCDR2
GASTRAT
208






LCDR3
QQYNNWPLT
1083






LFR1
EIVMTQSPATLSVSPGERATLSC
210






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTEFTLTISNLQSE
1084




DFAVYYC







LFR4
FGQGTKVEIK
53





S305-1456
HC
QVQLVQSGAEVKKPGASVKVSCKVS
1085




GYTLTELSMHWVRQAPGKGLEWMGG





FDPEDAETIYAQKFQGRVTMTEDTS





TDTAYMELSSLRSEDTAVYYCATGG





FPVNSLYDILTGYLDYWGQGTLVTV





SS







HC
QVQLVQSGAEVKKPGASVKVSCKVS
1086



variable
GYTLTELSMHWVRQAPGKGLEWMGG





FDPEDAETIYAQKFQGRVTMTEDTS





TDTAYMELSSLRSEDTAVYYCAT







HCDR1
ELSMH
457






HCDR2
GFDPEDAETIYAQKFQG
1087






HCDR3
GGFPVNSLYDILTGYLDY
1088






HFR1
QVQLVQSGAEVKKPGASVKVSCKVS
1077




GYTLT







HFR2
WVRQAPGKGLEWMG
42






HFR3
RVTMTEDTSTDTAYMELSSLRSEDT
1078




AVYYCAT







HFR4
WGQGTLVTVSS
60






LC
EIVMTQSPATLSVSPGERATLSCRA
1089




SQNVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYNNWPHTFGP





GTKVDIK







LC
EIVMTQSPATLSVSPGERATLSCRA
1090



variable
SQNVSSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SSLQSEDFAVYYCQQYNNWP







LCDR1
RASQNVSSNLA
1091






LCDR2
GASTRAT
208






LCDR3
QQYNNWPHT
1092






LFR1
EIVMTQSPATLSVSPGERATLSC
210






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTEFTLTISSLQSE
211




DFAVYYC







LFR4
FGPGTKVDIK
443





R125-306
HC
QVQMVESGGGVVQPGGSLRLSCAVS
1093




GFTFNNFGMHWVRQAPGKGLEWVAF





ISYEGSKKSYADSVKGRFTISRDSS





KNTLYLQMNSLRPEDTSVYYCAKEL





AIFMIYAGRYGLDVWGQGTTVTVSS







HC
QVQMVESGGGVVQPGGSLRLSCAVS
1094



variable
GFTFNNFGMHWVRQAPGKGLEWVAF





ISYEGSKKSYADSVKGRFTISRDSS





KNTLYLQMNSLRPEDTSVYYCAK







HCDR1
NFGMH
1062






HCDR2
FISYEGSKKSYADSVKG
1095






HCDR3
ELAIFMIYAGRYGLDV
1096






HFR1
QVQMVESGGGVVQPGGSLRLSCAVS
1097




GFTFN







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDSSKNTLYLQMNSLRPEDT
1098




SVYYCAK







HFR4
WGQGTTVTVSS
147






LC
SALTQPASVSGSPGQSITISCTGIY
1099




SDVDDYTSVSWYQQHPGKAPTLIIY





DVTKRPSGVSNRFSASNSDNTASLT





ISGLQAEDEAEYYCCSRGSATNSYV





FGTGTKVTVL







LC
SALTQPASVSGSPGQSITISCTGIY
1100



variable
SDVDDYTSVSWYQQHPGKAPTLIIY





DVTKRPSGVSNRFSASNSDNTASLT





ISGLQAEDEAEYYCCSRGS







LCDR1
TGIYSDVDDYTSVS
1101






LCDR2
DVTKRPS
1102






LCDR3
CSRGSATNSYV
1103






LFR1
SALTQPASVSGSPGQSITISC
1104






LFR2
WYQQHPGKAPTLIIY
1105






LFR3
GVSNRFSASNSDNTASLTISGLQAE
1106




DEAEYYC







LFR4
FGTGTKVTVL
18





R125-444
HC
QVQLQESGPGLVKPSETLSLTCNVS
1107




GGSVKFFYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTMSVDSPN





NQFSLKLRSVTAADTAVYYCARVGR





DCSSGICRTYDYYAMDVWGQGTTVT





VSS







HC
QVQLQESGPGLVKPSETLSLTCNVS
1108



variable
GGSVKFFYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTMSVDSPN





NQFSLKLRSVTAADTAVYYCAR







HCDR1
FFYWS
1109






HCDR2
YIYYSGSTNYNPSLKS
4






HCDR3
VGRDCSSGICRTYDYYAMDV
1110






HFR1
QVQLQESGPGLVKPSETLSLTCNVS
1111




GGSVK







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTMSVDSPNNQFSLKLRSVTAADT
1112




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
QSVLTQPPSLSGAPGQRVTISCTGS
1113




RSNIGAGYAVHWYQQLPGTAPKLLI





SENTNGPSGVPDRFSGSKSDSSASL





AITDLQAADEADYYCQSYDGSLSGW





VFGGGTKLTVL







LC
QSVLTQPPSLSGAPGQRVTISCTGS
1114



variable
RSNIGAGYAVHWYQQLPGTAPKLLI





SENTNGPSGVPDRFSGSKSDSSASL





AITDLQAADEADYYCQSYDGSLSG




LCDR1
TGSRSNIGAGYAVH
1115






LCDR2
ENTNGPS
1116






LCDR3
QSYDGSLSGWV
1117






LFR1
QSVLTQPPSLSGAPGQRVTISC
1118






LFR2
WYQQLPGTAPKLLIS
1119






LFR3
GVPDRFSGSKSDSSASLAITDLQAA
1120




DEADYYC







LFR4
FGGGTKLTVL
69





R3-428
HC
QVTLKESGPVLVKPTETLTLTCTVS
1121




GFSPSNARMGVSWIRQPPGKALEWL





AHVYSNDEKSYSTSLKRRLTISKDT





SKRQVVLIMTNLDPADTGTYYCARA





QDPRIRFGELLPVYFDNWGQGTLVT





VSS







HC
QVTLKESGPVLVKPTETLTLTCTVS
1122



variable
GFSPSNARMGVSWIRQPPGKALEWL





AHVYSNDEKSYSTSLKRRLTISKDT





SKRQVVLIMTNLDPADTGTYYCAR







HCDR1
NARMGVS
1123






HCDR2
HVYSNDEKSYSTSLKR
1124






HCDR3
AQDPRIRFGELLPVYFDN
1125






HFR1
QVTLKESGPVLVKPTETLTLTCTVS
1126




GFSPS







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTISKDTSKRQVVLIMTNLDPADT
1127




GTYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSAFVGDRVTISCRA
1128




SQSIVSYLNWYQQKPGKAPKLLLYS





ASTLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQGYTTPWTFGQ





GTKVEIK







LC
DIQMTQSPSSLSAFVGDRVTISCRA
1129



variable
SQSIVSYLNWYQQKPGKAPKLLLYS





ASTLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQGYTTP







LCDR1
RASQSIVSYLN
1130






LCDR2
SASTLQS
1131






LCDR3
QQGYTTPWT
1132






LFR1
DIQMTQSPSSLSAFVGDRVTISC
1133






LFR2
WYQQKPGKAPKLLLY
1134






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKVEIK
53





R478910-
HC
EVQLLESGGGLVLPGGSLRLSCAAS
1135


171

GFSFSSYAMSWVRQAPGKGLEWVSG





ISGRGTSTYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAKDR





VSYGSPYYFDYWGQGTLVTVSS







HC
EVQLLESGGGLVLPGGSLRLSCAAS
1136



variable
GFSFSSYAMSWVRQAPGKGLEWVSG





ISGRGTSTYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAK







HCDR1
SYAMS
610






HCDR2
GISGRGTSTYYADSVKG
1137






HCDR3
DRVSYGSPYYFDY
1138






HFR1
EVQLLESGGGLVLPGGSLRLSCAAS
1139




GFSFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
499




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIVLTQSPATLSLSPGERATLSCGA
1140




SQSVSSNYLAWYQQEPGLAPRLLIY





DASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSSTFGQ





GTRLEIK







LC
DIVLTQSPATLSLSPGERATLSCGA
1141



variable
SQSVSSNYLAWYQQEPGLAPRLLIY





DASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSS







LCDR1
GASQSVSSNYLA
1142






LCDR2
DASSRAT
1143






LCDR3
QQYGSSST
1144






LFR1
DIVLTQSPATLSLSPGERATLSC
1145






LFR2
WYQQEPGLAPRLLIY
1146






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTRLEIK
701





R478910-23
HC
QVQLVESGGGVVQPGRSLRLSCAAS
1147




GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARAP





DYWGQGTLVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCAAS
1148



variable
GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAR







HCDR1
SYGMH
141






HCDR2
VIWYDGSNKYYADSVKG
142






HCDR3
APDY
1149






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
AIQMTQSPSSLSASVGDRVTITCRA
1150




SQGIRNDLGWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCLQDYNYPYTFGQ





GTKLEIK







LC
AIQMTQSPSSLSASVGDRVTITCRA
1151



variable
SQGIRNDLGWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCLQDYNYP







LCDR1
RASQGIRNDLG
1152






LCDR2
AASSLQS
249






LCDR3
LQDYNYPYT
1153






LFR1
AIQMTQSPSSLSASVGDRVTITC
1154






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKLEIK
380





R478910-25
HC
EVQLLESGGGLVQPGGSLRLSCAVS
1155




GFTVSNYGLSWVRQGPGKGLEWVAA





ISGSGGRTYYADSVKGRFTISRDNS





KNTLFLQLNSLRAEDTAVYYCAKGR





DELVVGATQDYWGQGTLVTVSS







HC
EVQLLESGGGLVQPGGSLRLSCAVS
1156



variable
GFTVSNYGLSWVRQGPGKGLEWVAA





ISGSGGRTYYADSVKGRFTISRDNS





KNTLFLQLNSLRAEDTAVYYCAK







HCDR1
NYGLS
1157






HCDR2
AISGSGGRTYYADSVKG
1158






HCDR3
GRDELVVGATQDY
1159






HFR1
EVQLLESGGGLVQPGGSLRLSCAVS
1160




GFTVS







HFR2
WVRQGPGKGLEWVA
1161






HFR3
RFTISRDNSKNTLFLQLNSLRAEDT
1162




AVYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
1163




NQNIRSYLNWYQQTPGKAPKLLIYA





TSSLQSGVPSRFSGSGSGTQFTLTI





SSLQPEDFATYYCQQSYSIPFDFGP





GTKVDIK







LC
DIQMTQSPSSLSASVGDRVTITCRA
1164



variable
NQNIRSYLNWYQQTPGKAPKLLIYA





TSSLQSGVPSRFSGSGSGTQFTLTI





SSLQPEDFATYYCQQSYSIP







LCDR1
RANQNIRSYLN
1165






LCDR2
ATSSLQS
1166






LCDR3
QQSYSIPFD
1167






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQTPGKAPKLLIY
453






LFR3
GVPSRFSGSGSGTQFTLTISSLQPE
1168




DFATYYC







LFR4
FGPGTKVDIK
443





R478910-3
HC
EVQLLESGGDLVQPGGSLRLSCVAS
1169




GFTFRSYAMTWVRQAPGKGLEWVSS





ISGSGGGTYYADSVKGRFTISRDNS





KNTLFLQMNSLRAEDTAVYYCARGR





EDWLLSLTYGYWGQGALVTVSS







HC
EVQLLESGGDLVQPGGSLRLSCVAS
1170



variable
GFTFRSYAMTWVRQAPGKGLEWVSS





ISGSGGGTYYADSVKGRFTISRDNS





KNTLFLQMNSLRAEDTAVYYCAR







HCDR1
SYAMT
1171






HCDR2
SISGSGGGTYYADSVKG
1172






HCDR3
GREDWLLSLTYGY
1173






HFR1
EVQLLESGGDLVQPGGSLRLSCVAS
1174




GFTFR







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNTLFLQMNSLRAEDT
1175




AVYYCAR







HFR4
WGQGALVTVSS
1176






LC
DIQMTQSPSSLSASVGDRVPITCRA
1177




SQSISSYLNWYQQRPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYTIPPTFGG





GTKVEIK







LC
DIQMTQSPSSLSASVGDRVPITCRA
1178



variable
SQSISSYLNWYQQRPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYTIPP







LCDR1
RASQSISSYLN
248






LCDR2
AASSLQS
249






LCDR3
QQSYTIPPT
1179






LFR1
DIQMTQSPSSLSASVGDRVPITC
1180






LFR2
WYQQRPGKAPKLLIY
1181






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGGGTKVEIK
85





R478910-
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1182


421

GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARGH





SLGEWGQGSPVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1183



variable
GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCAR







HCDR1
SYWMN
1184






HCDR2
NINEDGSEKYYVDSVKG
1185






HCDR3
GHSLGE
1186






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
1187




GFTFG







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR




HFR4
WGQGSPVTVSS
1188






LC
SSELTQDPAVSVALGQTVRITCQGD
1189




SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHLVFG





GGTKLTVL







LC
SSELTQDPAVSVALGQTVRITCQGD
1190



variable
SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHL







LCDR1
QGDSLRSYSAS
1191






LCDR2
IKNKRPS
1192






LCDR3
NSRDSSGDHLV
1193






LFR1
SSELTQDPAVSVALGQTVRITC
1194






LFR2
WYQQKPGQAPVLVIY
1195






LFR3
GIPDRFSGSSSGNTASLTITGAQAE
1196




DEADYYC







LFR4
FGGGTKLTVL
69





R478910-8
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1197




GFTFSSYSMNWVRQAPGKGLEWVSY





ISSSSSTIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARAN





WNDMYFDLWGRGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1198



variable
GFTFSSYSMNWVRQAPGKGLEWVSY





ISSSSSTIYYADSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCA







HCDR1
SYSMN
126






HCDR2
YISSSSSTIYYADSVKG
127






HCDR3
ANWNDMYFDL
1199






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGRGTLVTVSS
9






LC
EIVLTQSPGTLSLSPGERATLSCRA
1200




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPFGQG





TKLEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1201



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSP







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQYGSSP
1202






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTKLEIK
380





S195-637
HC
QVQLVESGGGVVQPGRSLRLSCAAS
120




GFTFSSNAMHWVRQAPGKGLEWVAV





ISYDGDNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRTEDTAVYYCARSL





GGNYFYGMDVWGQGTTVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCAAS
1204



variable
GFTFSSNAMHWVRQAPGKGLEWVAV





ISYDGDNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRTEDTAVYYCA







HCDR1
SNAMH
1205






HCDR2
VISYDGDNKYYADSVKG
1206






HCDR3
SLGGNYFYGMDV
1207






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRTEDT
1208




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
EIVLTQSPGTLSLSPGERATLSCRA
1209




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRAAGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGGSWTFGP





GTKVEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1210



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRAAGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGGS







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAA
1211






LCDR3
QQFGGSWT
1212






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGPGTKVEIK
1213





S380-1191
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1214




GFTFSGYIMNWVRQAPGKGLEWVSS





ISGGSISISYAGSVKGRFTISRDNA





KNSLYLQMNSLRAGDSAVYYCALTT





FGVVTSYPSFDYWGQGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1215



variable
GFTFSGYIMNWVRQAPGKGLEWVSS





ISGGSISISYAGSVKGRFTISRDNA





KNSLYLQMNSLRAGDSAVYYCA







HCDR1
GYIMN
1216






HCDR2
SISGGSISISYAGSVKG
1217






HCDR3
TTFGVVTSYPSFDY
1218






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAGDS
1219




AVYYCAL







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSVSGAPGQRVTISCTGS
1220




SSNIGAGYDVHWYQQLPGTAPKLLI





YGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGY





VFGGGTELTVL







LC
QSVLTQPPSVSGAPGQRVTISCTGS
1221



variable
SSNIGAGYDVHWYQQLPGTAPKLLI





YGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSG







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
GNSNRPS
350






LCDR3
QSYDSSLSGYV
1222






LFR1
QSVLTQPPSVSGAPGQRVTISC
537






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGGGTELTVL
1223





S451-101
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
1224




GGTFSNYAISWVRQAPGPGLEWMGG





IIPFLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARAP





GYSSVGSTNYFDPWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
1225



variable
GGTFSNYAISWVRQAPGPGLEWMGG





IIPFLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCA







HCDR1
NYAIS
1226






HCDR2
GIIPFLGIANYAQKFQG
1227






HCDR3
APGYSSVGSTNYFDP
1228






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGPGLEWMG
1229






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSVSGAPGQRVTISCTGS
1230




SSNIGAGYDVHWYQQLPGAAPKLLI





YANSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGY





VFGTGTKVTVL







LC
QSVLTQPPSVSGAPGQRVTISCTGS
1231



variable
SSNIGAGYDVHWYQQLPGAAPKLLI





YANSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSG







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
ANSNRPS
1232






LCDR3
QSYDSSLSGYV
1222






LFR1
QSVLTQPPSVSGAPGQRVTISC
537






LFR2
WYQQLPGAAPKLLIY
719






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGTGTKVTVL
18





S451-11
HC
QVQLQESGPGLVEPSQTLSLTCTVS
1233




GGSISSGGYYWSWIRQHPGKGLEWI





GYISYSGGSTYYNPSLKSVVTISLD





TSKNQFSLKLSSVTAADTAVYYCAR





VSYGSGSFRFDYWGQGTLVTVSS







HC
QVQLQESGPGLVEPSQTLSLTCTVS
1234



variable
GGSISSGGYYWSWIRQHPGKGLEWI





GYISYSGGSTYYNPSLKSVVTISLD





TSKNQFSLKLSSVTAADTAVYYCAR







HCDR1
SGGYYWS
1235






HCDR2
YISYSGGSTYYNPSLKS
1236






HCDR3
VSYGSGSFRFDY
1237






HFR1
QVQLQESGPGLVEPSQTLSLTCTVS
1238




GGSIS







HFR2
WIRQHPGKGLEWIG
1239






HFR3
VVTISLDTSKNQFSLKLSSVTAADT
1240




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPRSVSGSPGQSVTISCTGT
1241




SSDVGGYNYFSWYQHHAGKAPKLMI





YDVSKRPSGVPDRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGTYTWV





FGGGTKLTVL







LC
QSALTQPRSVSGSPGQSVTISCTGT
1242



variable
SSDVGGYNYFSWYQHHAGKAPKLMI





YDVSKRPSGVPDRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGTYT







LCDR1
TGTSSDVGGYNYFS
1243






LCDR2
DVSKRPS
592






LCDR3
CSYAGTYTWV
1244






LFR1
QSALTQPRSVSGSPGQSVTISC
594






LFR2
WYQHHAGKAPKLMIY
1245






LFR3
GVPDRFSGSKSGNTASLTISGLQAE
1246




DEADYYC







LFR4
FGGGTKLTVL
69





S451-1101
HC
QVQLQESGPGLVKPSETLSLTCTVS
1247




GGSINSYSWSWIRQPAGKGLEWIGR





ISTSGSTNNNPSLKSRVTMSVDTSK





DQFSLKLTSVTAADTAVYYCARING





AAAGTPFDYWGQGTLVTVSS







HC
QVQLQESGPGLVKPSETLSLTCTVS
1248



variable
GGSINSYSWSWIRQPAGKGLEWIGR





ISTSGSTNNNPSLKSRVTMSVDTSK





DQFSLKLTSVTAADTAVYYCAR







HCDR1
SYSWS
1249






HCDR2
RISTSGSTNNNPSLKS
1250






HCDR3
INGAAAGTPFDY
1251






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
324




GGSIN







HFR2
WIRQPAGKGLEWIG
25






HFR3
RVTMSVDTSKDQFSLKLTSVTAADT
1252




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
1253




SQSISNYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYRTFGQGTK





VEIK







LC
DIQMTQSPSSLSASVGDRVTITCRA
1254



variable
SQSISNYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQSYRT







LCDR1
RASQSISNYLN
570






LCDR2
AASSLQS
249






LCDR3
QQSYRT
1255






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKVEIK
53





S451-1439
HC
EVQLVESGGGLVQPGRSLRLSCAAS
1256




GFTFDDFAMHWVRQAPGKGLEWVSG





ISWNGGIIGYADSVKARFTISRDNA





KNSLYLQMNSLRAEDTALYYCAKTR





GDYDYVWGSRSSNYYFDYWGQGTLV





TVSS







HC
EVQLVESGGGLVQPGRSLRLSCAAS
1257



variable
GFTFDDFAMHWVRQAPGKGLEWVSG





ISWNGGIIGYADSVKARFTISRDNA





KNSLYLQMNSLRAEDTALYYCA







HCDR1
DFAMH
1258






HCDR2
GISWNGGIIGYADSVKA
1259






HCDR3
TRGDYDYVWGSRSSNYYFDY
1260






HFR1
EVQLVESGGGLVQPGRSLRLSCAAS
1261




GFTFD







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
1262




ALYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCQA
1263




SQDISNYLNWYQKKPGKAPKLLIYD





ATNLETGVPSRFSGSGSGTEFTFTI





SSLQPEDIATYYCQQYDNVPPITFG





PGTKVDMK







LC
DIQMTQSPSSLSASVGDRVTITCQA
1264



variable
SQDISNYLNWYQKKPGKAPKLLIYD





ATNLETGVPSRFSGSGSGTEFTFTI





SSLQPEDIATYYCQQYDNVPP







LCDR1
QASQDISNYLN
769






LCDR2
DATNLET
1265






LCDR3
QQYDNVPPIT
1266






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQKKPGKAPKLLIY
1267






LFR3
GVPSRFSGSGSGTEFTFTISSLQPE
1268




DIATYYC







LFR4
FGPGTKVDMK
1269





S451-1451
HC
QVQLVESGGGVVQPGRSLRLSCAAS
1203




GFTFSSNAMHWVRQAPGKGLEWVAV





ISYDGDNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRTEDTAVYYCARSL





GGNYFYGMDVWGQGTTVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCAAS
1204



variable
GFTFSSNAMHWVRQAPGKGLEWVAV





ISYDGDNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRTEDTAVYYCA




HCDR1
SNAMH
1205






HCDR2
VISYDGDNKYYADSVKG
1206






HCDR3
SLGGNYFYGMDV
1207






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRTEDT
1208




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
EIVLTQSPGTLSLSPGERATLSCRA
1209




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRAAGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGGSWTFGP





GTKVEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1210



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRAAGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQFGGS







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAA
1211






LCDR3
QQFGGSWT
1212






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGPGTKVEIK
1213





S451-1477
HC
EPQLVESGGGLVQPGGSLRLSCAGS
1270




GFGFISYPMNWVRQAPGKGPEWISN





IRTTAEGGTFYADSVKGRFTMSRDD





GKTSIYLQMNSLRDEDTATYYCARD





SSYGFDLWGQGTVVTVSS







HC
EPQLVESGGGLVQPGGSLRLSCAGS
1271



variable
GFGFISYPMNWVRQAPGKGPEWISN





IRTTAEGGTFYADSVKGRFTMSRDD





GKTSIYLQMNSLRDEDTATYYCAR







HCDR1
SYPMN
1272






HCDR2
NIRTTAEGGTFYADSVKG
1273






HCDR3
DSSYGFDL
1274






HFR1
EPQLVESGGGLVQPGGSLRLSCAGS
1275




GFGFI







HFR2
WVRQAPGKGPEWIS
1276






HFR3
RFTMSRDDGKTSIYLQMNSLRDEDT
1277




ATYYCAR







HFR4
WGQGTVVTVSS
421






LC
QSALTQPRSVSGSPGQSVTISCTGT
1278




SSDVGGYNYVSWYQQRPGKAPELMI





YHVSERPSGVPDRFSGSKSGNTASL





TISRLQAEDEADYYCCSYAGSHFWV





FGGGTKLTVL







LC
QSALTQPRSVSGSPGQSVTISCTGT
1279



variable
SSDVGGYNYVSWYQQRPGKAPELMI





YHVSERPSGVPDRFSGSKSGNTASL





TISRLQAEDEADYYCCSYAGSH







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
HVSERPS
1280






LCDR3
CSYAGSHFWV
1281






LFR1
QSALTQPRSVSGSPGQSVTISC
594






LFR2
WYQQRPGKAPELMIY
1282






LFR3
GVPDRFSGSKSGNTASLTISRLQAE
1283




DEADYYC







LFR4
FGGGTKLTVL
69





S451-1503
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1182




GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARGH





SLGEWGQGSPVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1183



variable
GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCAR







HCDR1
SYWMN
1184






HCDR2
NINEDGSEKYYVDSVKG
1185






HCDR3
GHSLGE
1186






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
1187




GFTFG







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGQGSPVTVSS
1188






LC
SSELTQDPAVSVALGQTVRITCQGD
1189




SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHLVFG





GGTKLTVL







LC
SSELTQDPAVSVALGQTVRITCQGD
1190



variable
SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHL







LCDR1
QGDSLRSYSAS
1191






LCDR2
IKNKRPS
1192






LCDR3
NSRDSSGDHLV
1193






LFR1
SSELTQDPAVSVALGQTVRITC
1194






LFR2
WYQQKPGQAPVLVIY
1195






LFR3
GIPDRFSGSSSGNTASLTITGAQAE
1196




DEADYYC







LFR4
FGGGTKLTVL
69





S451-1522
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1214




GFTFSGYIMNWVRQAPGKGLEWVSS





ISGGSISISYAGSVKGRFTISRDNA





KNSLYLQMNSLRAGDSAVYYCALTT





FGVVTSYPSFDYWGQGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1215



variable
GFTFSGYIMNWVRQAPGKGLEWVSS





ISGGSISISYAGSVKGRFTISRDNA





KNSLYLQMNSLRAGDSAVYYCA







HCDR1
GYIMN
1216






HCDR2
SISGGSISISYAGSVKG
1217






HCDR3
TTFGVVTSYPSFDY
1218






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAGDS
1219




AVYYCAL







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSVSGAPGQRVTISCTGS
1220




SSNIGAGYDVHWYQQLPGTAPKLLI





YGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGY





VFGGGTELTVL







LC
QSVLTQPPSVSGAPGQRVTISCTGS
1221



variable
SSNIGAGYDVHWYQQLPGTAPKLLI





YGNSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSG







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
GNSNRPS
350






LCDR3
QSYDSSLSGYV
1222






LFR1
QSVLTQPPSVSGAPGQRVTISC
537






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGGGTELTVL
1223





S451-1921
HC
QVQLQESGPGLVKPSQTLSLTCTVS
1284




GGSISSGDYYWSWIRQPPGKGLEWL





GYIYYSGSTFYNPSLKSRVTISVDT





SKNQFSLRLTSVTAADTAVYFCARE





ENKFNYGHHPLNGVFAYWGQGTLVT





VSS







HC
QVQLQESGPGLVKPSQTLSLTCTVS
1285



variable
GGSISSGDYYWSWIRQPPGKGLEWL





GYIYYSGSTFYNPSLKSRVTISVDT





SKNQFSLRLTSVTAADTAVYFCAR







HCDR1
SGDYYWS
72






HCDR2
YIYYSGSTFYNPSLKS
1286






HCDR3
EENKFNYGHHPLNGVFAY
1287






HFR1
QVQLQESGPGLVKPSQTLSLTCTVS
1288




GGSIS







HFR2
WIRQPPGKGLEWLG
1289






HFR3
RVTISVDTSKNQFSLRLTSVTAADT
1290




AVYFCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCKS
1291




SQSVLYSPNNKNYLAWYQQKPGQPP





NLLIYWASTRESGVPDRFSGSGSGT





DFTLTINSLQAEDVAVYYCQQSYNT





PRTFGQGTKVEIK







LC
DIVMTQSPDSLAVSLGERATINCKS
1292



variable
SQSVLYSPNNKNYLAWYQQKPGQPP





NLLIYWASTRESGVPDRFSGSGSGT





DFTLTINSLQAEDVAVYYCQQSYNT





P







LCDR1
KSSQSVLYSPNNKNYLA
1293






LCDR2
WASTRES
30






LCDR3
QQSYNTPRT
1294






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPNLLIY
1295






LFR3
GVPDRFSGSGSGTDFTLTINSLQAE
1296




DVAVYYC







LFR4
FGQGTKVEIK
53





S451-337
HC
QVTLKESGPVLVKPTETLTLTCTVS
1297




GFSLINARLGVSWIRQPPGKALEWL





AHIFSDDEKSYSTSLKSRLTISKDT





SKSQVVLTMTNMDPVDTATYYCARI





SWPPYGSGTYYIKAFDIWGQGTLVT





VSS







HC
QVTLKESGPVLVKPTETLTLTCTVS
1298



variable
GFSLINARLGVSWIRQPPGKALEWL





AHIFSDDEKSYSTSLKSRLTISKDT





SKSQVVLTMTNMDPVDTATYYCARI







HCDR1
NARLGVS
1299






HCDR2
HIFSDDEKSYSTSLKS
1300






HCDR3
ISWPPYGSGTYYIKAFDI
1301






HFR1
QVTLKESGPVLVKPTETLTLTCTVS
1302




GFSLI







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTISKDTSKSQVVLTMTNMDPVDT
1303




ATYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPVSVSGSPGQSITISCTGT
1304




SSDVGGYNYVSWYQQHPGKAPKLMI





SEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYASSSTLW





VFGGGTKLTVL







LC
QSALTQPVSVSGSPGQSITISCTGT
1305



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





SEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYASSSTL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSNRPS
151






LCDR3
SSYASSSTLWV
1306






LFR1
QSALTQPVSVSGSPGQSITISC
1307






LFR2
WYQQHPGKAPKLMIS
1308






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S451-650
HC
QVQLQESGPGLVKPSETLSLTCTVS
1309




GASISNFYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTMSLDTSK





NQFSLNLSSVTAADTAVYYCARIPN





FWFGELLFDFWGHGTLVTVSS







HC
QVQLQESGPGLVKPSETLSLTCTVS
1310



variable
GASISNFYWSWIRQPPGKGLEWIGY





IYYSGSTNYNPSLKSRVTMSLDTSK





NQFSLNLSSVTAADTAVYYCAR







HCDR1
NFYWS
1311






HCDR2
YIYYSGSTNYNPSLKS
4






HCDR3
IPNFWFGELLFDF
1312






HFR1
QVQLQESGPGLVKPSETLSLTCTVS
1313




GASIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTMSLDTSKNQFSLNLSSVTAADT
1314




AVYYCAR







HFR4
WGHGTLVTVSS
1315






LC
EIVLTQSPGTLSLSPGERATLSCRA
1316




SQSVSSNYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPPITF





GQGTRLEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1317



variable
SQSVSSNYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPP







LCDR1
RASQSVSSNYLA
816






LCDR2
GASSRAT
135






LCDR3
QQYGSSPPIT
1318






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTRLEIK
701





S626-362
HC
QVQLVQSGAEVKKPGSSVKVSCKAS
1224




GGTFSNYAISWVRQAPGPGLEWMGG





IIPFLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCARAP





GYSSVGSTNYFDPWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGSSVKVSCKAS
1225



variable
GGTFSNYAISWVRQAPGPGLEWMGG





IIPFLGIANYAQKFQGRVTITADKS





TSTAYMELSSLRSEDTAVYYCA







HCDR1
NYAIS
1226






HCDR2
GIIPFLGIANYAQKFQG
1227






HCDR3
APGYSSVGSTNYFDP
1228






HFR1
QVQLVQSGAEVKKPGSSVKVSCKAS
310




GGTFS







HFR2
WVRQAPGPGLEWMG
1229






HFR3
RVTITADKSTSTAYMELSSLRSEDT
161




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSVSGAPGQRVTISCTGS
1230




SSNIGAGYDVHWYQQLPGAAPKLLI





YANSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSGY





VFGTGTKVTVL







LC
QSVLTQPPSVSGAPGQRVTISCTGS
1231



variable
SSNIGAGYDVHWYQQLPGAAPKLLI





YANSNRPSGVPDRFSGSKSGTSASL





AITGLQAEDEADYYCQSYDSSLSG







LCDR1
TGSSSNIGAGYDVH
673






LCDR2
ANSNRPS
1232






LCDR3
QSYDSSLSGYV
1222






LFR1
QSVLTQPPSVSGAPGQRVTISC
537






LFR2
WYQQLPGAAPKLLIY
719






LFR3
GVPDRFSGSKSGTSASLAITGLQAE
539




DEADYYC







LFR4
FGTGTKVTVL
18





S626-651
HC
EVQLVESGGGLVQPGRSLRLSCAAS
1256




GFTFDDFAMHWVRQAPGKGLEWVSG





ISWNGGIIGYADSVKARFTISRDNA





KNSLYLQMNSLRAEDTALYYCAKTR





GDYDYVWGSRSSNYYFDYWGQGTLV





TVSS







HC
EVQLVESGGGLVQPGRSLRLSCAAS
1257



variable
GFTFDDFAMHWVRQAPGKGLEWVSG





ISWNGGIIGYADSVKARFTISRDNA





KNSLYLQMNSLRAEDTALYYCA







HCDR1
DFAMH
1258






HCDR2
GISWNGGIIGYADSVKA
1259






HCDR3
TRGDYDYVWGSRSSNYYFDY
1260






HFR1
EVQLVESGGGLVQPGRSLRLSCAAS
1261




GFTFD







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
1262




ALYYCAK







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCQA
1263




SQDISNYLNWYQKKPGKAPKLLIYD





ATNLETGVPSRFSGSGSGTEFTFTI





SSLQPEDIATYYCQQYDNVPPITFG





PGTKVDMK







LC
DIQMTQSPSSLSASVGDRVTITCQA
1264



variable
SQDISNYLNWYQKKPGKAPKLLIYD





ATNLETGVPSRFSGSGSGTEFTFTI





SSLQPEDIATYYCQQYDNVPP







LCDR1
QASQDISNYLN
769






LCDR2
DATNLET
1265






LCDR3
QQYDNVPPIT
1266






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQKKPGKAPKLLIY
1267






LFR3
GVPSRFSGSGSGTEFTFTISSLQPE
1268




DIATYYC







LFR4
FGPGTKVDMK
1269





S626-692
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1319




GYAFTSYDINWVRQATGQGLEWMGW





MNPNSGDTFYAQKFQGRVTMTRSTS





ISTAYMELSSLRSEDTAVYYCARGR





VGADYVSGNRGYYYYYYMDVWGKGT





TVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1320



variable
GYAFTSYDINWVRQATGQGLEWMGW





MNPNSGDTFYAQKFQGRVTMTRSTS





ISTAYMELSSLRSEDTAVYYCARG







HCDR1
SYDIN
1321






HCDR2
WMNPNSGDTFYAQKFQG
1322






HCDR3
GRVGADYVSGNRGYYYYYYMDV
1323






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
1324




GYAFT







HFR2
WVRQATGQGLEWMG
1325






HFR3
RVTMTRSTSISTAYMELSSLRSEDT
1326




AVYYCAR







HFR4
WGKGTTVTVSS
670






LC
SSELTQDPAVSVALGQTVRITCQGE
1327




NLRSYYATWYQQKPGQAPILVIYGK





NNRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGNHLRVF





GGGTKLTVL







LC
SSELTQDPAVSVALGQTVRITCQGE
1328



variable
NLRSYYATWYQQKPGQAPILVIYGK





NNRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGNHL







LCDR1
QGENLRSYYAT
1329






LCDR2
GKNNRPS
1330






LCDR3
NSRDSSGNHLRV
1331






LFR1
SSELTQDPAVSVALGQTVRITC
1194






LFR2
WYQQKPGQAPILVIY
1332






LFR3
GIPDRFSGSSSGNTASLTITGAQAE
1196




DEADYYC







LFR4
FGGGTKLTVL
69





S626-7
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1319




GYAFTSYDINWVRQATGQGLEWMGW





MNPNSGDTFYAQKFQGRVTMTRSTS





ISTAYMELSSLRSEDTAVYYCARGR





VGADYVSGNRGYYYYYYMDVWGKGT





TVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1320



variable
GYAFTSYDINWVRQATGQGLEWMGW





MNPNSGDTFYAQKFQGRVTMTRSTS





ISTAYMELSSLRSEDTAVYYCARG







HCDR1
SYDIN
1321






HCDR2
WMNPNSGDTFYAQKFQG
1322






HCDR3
GRVGADYVSGNRGYYYYYYMDV
1323






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
1324




GYAFT







HFR2
WVRQATGQGLEWMG
1325






HFR3
RVTMTRSTSISTAYMELSSLRSEDT
1326




AVYYCAR







HFR4
WGKGTTVTVSS
670






LC
SSELTQDPAVSVALGQTVRITCQGE
1327




NLRSYYATWYQQKPGQAPILVIYGK





NNRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGNHLRVF





GGGTKLTVL







LC
SSELTQDPAVSVALGQTVRITCQGE
1328



variable
NLRSYYATWYQQKPGQAPILVIYGK





NNRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGNHL







LCDR1
QGENLRSYYAT
1329






LCDR2
GKNNRPS
1330






LCDR3
NSRDSSGNHLRV
1331






LFR1
SSELTQDPAVSVALGQTVRITC
1194






LFR2
WYQQKPGQAPILVIY
1332






LFR3
GIPDRFSGSSSGNTASLTITGAQAE
1196




DEADYYC







LFR4
FGGGTKLTVL
69





S626-747
HC
EPQLVESGGGLVQPGGSLRLSCAGS
1270




GFGFISYPMNWVRQAPGKGPEWISN





IRTTAEGGTFYADSVKGRFTMSRDD





GKTSIYLQMNSLRDEDTATYYCARD





SSYGFDLWGQGTVVTVSS







HC
EPQLVESGGGLVQPGGSLRLSCAGS
1271



variable
GFGFISYPMNWVRQAPGKGPEWISN





IRTTAEGGTFYADSVKGRFTMSRDD





GKTSIYLQMNSLRDEDTATYYCAR







HCDR1
SYPMN
1272






HCDR2
NIRTTAEGGTFYADSVKG
1273






HCDR3
DSSYGFDL
1274






HFR1
EPQLVESGGGLVQPGGSLRLSCAGS
1275




GFGFI







HFR2
WVRQAPGKGPEWIS
1276






HFR3
RFTMSRDDGKTSIYLQMNSLRDEDT
1277




ATYYCAR







HFR4
WGQGTVVTVSS
421






LC
QSALTQPRSVSGSPGQSVTISCTGT
1278




SSDVGGYNYVSWYQQRPGKAPELMI





YHVSERPSGVPDRFSGSKSGNTASL





TISRLQAEDEADYYCCSYAGSHFWV





FGGGTKLTVL







LC
QSALTQPRSVSGSPGQSVTISCTGT
1279



variable
SSDVGGYNYVSWYQQRPGKAPELMI





YHVSERPSGVPDRFSGSKSGNTASL





TISRLQAEDEADYYCCSYAGSH







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
HVSERPS
1280






LCDR3
CSYAGSHFWV
1281






LFR1
QSALTQPRSVSGSPGQSVTISC
594






LFR2
WYQQRPGKAPELMIY
1282






LFR3
GVPDRFSGSKSGNTASLTISRLQAE
1283




DEADYYC







LFR4
FGGGTKLTVL
69





S626-75
HC
QVQLQESGPGLVKPSQTLSLTCTVS
1284




GGSISSGDYYWSWIRQPPGKGLEWL





GYIYYSGSTFYNPSLKSRVTISVDT





SKNQFSLRLTSVTAADTAVYFCARE





ENKFNYGHHPLNGVFAYWGQGTLVT





VSS







HC
QVQLQESGPGLVKPSQTLSLTCTVS
1285



variable
GGSISSGDYYWSWIRQPPGKGLEWL





GYIYYSGSTFYNPSLKSRVTISVDT





SKNQFSLRLTSVTAADTAVYFCAR







HCDR1
SGDYYWS
72






HCDR2
YIYYSGSTFYNPSLKS
1286






HCDR3
EENKFNYGHHPLNGVFAY
1287






HFR1
QVQLQESGPGLVKPSQTLSLTCTVS
1288




GGSIS







HFR2
WIRQPPGKGLEWLG
1289






HFR3
RVTISVDTSKNQFSLRLTSVTAADT
1290




AVYFCAR







HFR4
WGQGTLVTVSS
60






LC
DIVMTQSPDSLAVSLGERATINCKS
1291




SQSVLYSPNNKNYLAWYQQKPGQPP





NLLIYWASTRESGVPDRFSGSGSGT





DFTLTINSLQAEDVAVYYCQQSYNT





PRTFGQGTKVEIK







LC
DIVMTQSPDSLAVSLGERATINCKS
1292



variable
SQSVLYSPNNKNYLAWYQQKPGQPP





NLLIYWASTRESGVPDRFSGSGSGT





DFTLTINSLQAEDVAVYYCQQSYNT





P







LCDR1
KSSQSVLYSPNNKNYLA
1293






LCDR2
WASTRES
30






LCDR3
QQSYNTPRT
1294






LFR1
DIVMTQSPDSLAVSLGERATINC
32






LFR2
WYQQKPGQPPNLLIY
1295






LFR3
GVPDRFSGSGSGTDFTLTINSLQAE
1296




DVAVYYC







LFR4
FGQGTKVEIK
53





S626-8
HC
QVQLVESGGGVVQPGRSLRLSCVSS
1333




EVTFNRYTMHWVRQAPGKGLEWVAS





ISFEGSVKTYVDSVKGRFTISRDDS





KKTLFLQLNSLRDEDTAMYYCARGQ





WPSGGDYWGRGTLVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCVSS
1334



variable
EVTFNRYTMHWVRQAPGKGLEWVAS





ISFEGSVKTYVDSVKGRFTISRDDS





KKTLFLQLNSLRDEDTAMYYCAR







HCDR1
RYTMH
1335






HCDR2
SISFEGSVKTYVDSVKG
1336






HCDR3
GQWPSGGDY
1337






HFR1
QVQLVESGGGVVQPGRSLRLSCVSS
1338




EVTFN







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDDSKKTLFLQLNSLRDEDT
1339




AMYYCAR







HFR4
WGRGTLVTVSS
9






LC
DVVLTQSPLSLSVTLGQPASISCRS
1340




SQSLVYSDGSTYLNWFHQRPGQSPR





RLIYKVSNRDSGVPDRFSGSGSGTD





FTLKITRVAAEDVGVYYCMQGTYWP





PTFGQGTKVEIK







LC
DVVLTQSPLSLSVTLGQPASISCRS
134



variable
SQSLVYSDGSTYLNWFHQRPGQSPR





RLIYKVSNRDSGVPDRFSGSGSGTD





FTLKITRVAAEDVGVYYCMQGTYWP





P







LCDR1
RSSQSLVYSDGSTYLN
1342






LCDR2
KVSNRDS
1343






LCDR3
MQGTYWPPT
1344






LFR1
DVVLTQSPLSLSVTLGQPASISC
1345






LFR2
WFHQRPGQSPRRLIY
1346






LFR3
GVPDRFSGSGSGTDFTLKITRVAAE
1347




DVGVYYC







LFR4
FGQGTKVEIK
53





S68-253
HC
EVQLVQSGAEIKKPGESLKISCQGS
1348




GYIFTNNWIGWVRQQPGKGLEWMGI





IYPGDSDARYSPSFQGHVSFSADKS





INTAFLQWHSLKASDTAMYYCARIR





RRGQGATAAFDIWGPGTKVTVSS







HC
EVQLVQSGAEIKKPGESLKISCQGS
1349



variable
GYIFTNNWIGWVRQQPGKGLEWMGI





IYPGDSDARYSPSFQGHVSFSADKS





INTAFLQWHSLKASDTAMYYCAR







HCDR1
NNWIG
1350






HCDR2
IIYPGDSDARYSPSFQG
1351






HCDR3
IRRRGQGATAAFDI
1352






HFR1
EVQLVQSGAEIKKPGESLKISCQGS
1353




GYIFT







HFR2
WVRQQPGKGLEWMG
1354






HFR3
HVSFSADKSINTAFLQWHSLKASDT
1355




AMYYCAR







HFR4
WGPGTKVTVSS
1356






LC
DIVMTQSPDSLTVSLGERATINCKS
1357




SQNILTTSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYFNS





PPYTFGQGTKLEIK







LC
DIVMTQSPDSLTVSLGERATINCKS
1358



variable
SQNILTTSNNKNYLAWYQQKPGQPP





KLLIYWASTRESGVPDRFSGSGSGT





DFTLTISSLQAEDVAVYYCQQYFNS





PP







LCDR1
KSSQNILTTSNNKNYLA
1359






LCDR2
WASTRES
30






LCDR3
QQYFNSPPYT
1360






LFR1
DIVMTQSPDSLTVSLGERATINC
925






LFR2
WYQQKPGQPPKLLIY
33






LFR3
GVPDRFSGSGSGTDFTLTISSLQAE
293




DVAVYYC







LFR4
FGQGTKLEIK
380





S728-1502
HC
QVQLVQSGAEVKKPGASVKVSCKAS
136




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARAH





QPLLYGLGYYFDYWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1362



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCAR







HCDR1
GYYMH
187






HCDR2
RINPNSGGTNYAQKFQG
585






HCDR3
AHQPLLYGLGYYFDY
1363






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRSDDT
588




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1364




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLV





FGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1365



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSNRPS
151






LCDR3
SSYTSSSTLV
1366






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S728-1789
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1367




GFTFSSYWMHWVRQAPGKGLVWVSR





INSDGSSTSYADSVKGRFTISRDNA





KNTLYLQMNSLRAEDTAVYYCARDR





YSSLDYWGQGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1368



variable
GFTFSSYWMHWVRQAPGKGLVWVSR





INSDGSSTSYADSVKGRFTISRDNA





KNTLYLQMNSLRAEDTAVYYCAR







HCDR1
SYWMH
1369






HCDR2
RINSDGSSTSYADSVKG
1370






HCDR3
DRYSSLDY
1371






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLVWVS
1372






HFR3
RFTISRDNAKNTLYLQMNSLRAEDT
1373




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
1374




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPALTF





GGGTKVEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1201



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSP







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQYGSSPALT
1375






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGGGTKVEIK
85





S728-1806
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1361




GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCARAH





QPLLYGLGYYFDYWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1362



variable
GYTFTGYYMHWVRQAPGQGLEWMGR





INPNSGGTNYAQKFQGRVTMTRDTS





ISTAYMELSRLRSDDTAVYYCAR







HCDR1
GYYMH
187






HCDR2
RINPNSGGTNYAQKFQG
585






HCDR3
AHQPLLYGLGYYFDY
1363






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSISTAYMELSRLRSDDT
588




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1364




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTLV





FGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1365



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCSSYTSSSTL







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSNRPS
151






LCDR3
SSYTSSSTLV
1366






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S728-1981
HC
QVQLVQSGAEVKKPGASVKVSCKTS
1376




GYTFTNYFMHWVRQAPGQGLEWMGI





INPSGGSASYAQKFQGRITMTSDTS





TSTVYMELSSLRSEDTAVYYCARED





IIVVVPARPLDYWGHGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKTS
1377



variable
GYTFTNYFMHWVRQAPGQGLEWMGI





INPSGGSASYAQKFQGRITMTSDTS





TSTVYMELSSLRSEDTAVYYCAR







HCDR1
NYFMH
1378






HCDR2
IINPSGGSASYAQKFQG
1379






HCDR3
EDIIVVVPARPLDY
1380






HFR1
QVQLVQSGAEVKKPGASVKVSCKTS
1381




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RITMTSDTSTSTVYMELSSLRSEDT
1382




AVYYCAR







HFR4
WGHGTLVTVSS
1315






LC
EIVLTQSPATLSLSPGERATLSCRA
1383




SQSFSNYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPPLLTF





GGGTKVEIK







LC
EIVLTQSPATLSLSPGERATLSCRA
1384



variable
SQSFSNYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPP







LCDR1
RASQSFSNYLA
1385






LCDR2
DASNRAT
441






LCDR3
QQRSNWPPLLT
1386






LFR1
EIVLTQSPATLSLSPGERATLSC
181






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTDFTLTISSLEPE
183




DFAVYYC







LFR4
FGGGTKVEIK
85





S728-2036
HC
QVHLVQSGAEIRKPGASVMVSCKAS
1387




GYTFTDYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





IRTAYMELSRLRSDDAAVYYCAREG





ISMLRGVRSWFDPWGQGTLVTVSS







HC
QVHLVQSGAEIRKPGASVMVSCKAS
1388



variable
GYTFTDYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





IRTAYMELSRLRSDDAAVYYCAR







HCDR1
DYYIH
1389






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
EGISMLRGVRSWFDP
1390






HFR1
QVHLVQSGAEIRKPGASVMVSCKAS
1391




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSIRTAYMELSRLRSDDA
1392




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1393




SSDVGSYNLVSWYQQHPGKVPKLII





YEVTKRPSGVSNRFSGSKSGNTASL





TISGLQTEDEADYYCCSYAGFSAWV





FGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1394



variable
SSDVGSYNLVSWYQQHPGKVPKLII





YEVTKRPSGVSNRFSGSKSGNTASL





TISGLQTEDEADYYCCSYAGFSA







LCDR1
TGTSSDVGSYNLVS
1395






LCDR2
EVTKRPS
1396






LCDR3
CSYAGFSAWV
1397






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKVPKLIIY
1398






LFR3
GVSNRFSGSKSGNTASLTISGLQTE
1399




DEADYYC







LFR4
FGGGTKLTVL
69





S728-2111
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1367




GFTFSSYWMHWVRQAPGKGLVWVSR





INSDGSSTSYADSVKGRFTISRDNA





KNTLYLQMNSLRAEDTAVYYCARDR





YSSLDYWGQGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1368



variable
GFTFSSYWMHWVRQAPGKGLVWVSR





INSDGSSTSYADSVKGRFTISRDNA





KNTLYLQMNSLRAEDTAVYYCAR







HCDR1
SYWMH
1369






HCDR2
RINSDGSSTSYADSVKG
1370






HCDR3
DRYSSLDY
1371






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
613




GFTFS







HFR2
WVRQAPGKGLVWVS
1372






HFR3
RFTISRDNAKNTLYLQMNSLRAEDT
1373




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
EIVLTQSPGTLSLSPGERATLSCRA
1374




SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPALTF





GGGTKVEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1201



variable
SQSVSSSYLAWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSP







LCDR1
RASQSVSSSYLA
338






LCDR2
GASSRAT
135






LCDR3
QQYGSSPALT
1375






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGGGTKVEIK
85





S728-2148
HC
QVQLVESGGGVVQPGRSLRLSCAAS
1147




GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCARAP





DYWGQGTLVTVSS







HC
QVQLVESGGGVVQPGRSLRLSCAAS
1148



variable
GFTFSSYGMHWVRQAPGKGLEWVAV





IWYDGSNKYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAR







HCDR1
SYGMH
141






HCDR2
VIWYDGSNKYYADSVKG
142






HCDR3
APDY
1149






HFR1
QVQLVESGGGVVQPGRSLRLSCAAS
144




GFTFS







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
AIQMTQSPSSLSASVGDRVTITCRA
1150




SQGIRNDLGWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCLQDYNYPYTFGQ





GTKLEIK







LC
AIQMTQSPSSLSASVGDRVTITCRA
1151



variable
SQGIRNDLGWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCLQDYNYP







LCDR1
RASQGIRNDLG
1152






LCDR2
AASSLQS
249






LCDR3
LQDYNYPYT
1153






LFR1
AIQMTQSPSSLSASVGDRVTITC
1154






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGQGTKLEIK
380





S728-656
HC
EVQLLESGGGLVQPGGSLRLSCAAS
1400




GFTFSSYVLSWVRQAPGKGLEWVSA





ISGSGGITYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCAIRI





TISGVFTPAWDSWGQGTLVTVSS







HC
EVQLLESGGGLVQPGGSLRLSCAAS
1401



variable
GFTFSSYVLSWVRQAPGKGLEWVSA





ISGSGGITYYADSVKGRFTISRDNS





KNTLYLQMNSLRAEDTAVYYCA







HCDR1
SYVLS
1402






HCDR2
AISGSGGITYYADSVKG
1403






HCDR3
RITISGVFTPAWDS
1404






HFR1
EVQLLESGGGLVQPGGSLRLSCAAS
566




GFTFS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
1405




AVYYCAI







HFR4
WGQGTLVTVSS
60






LC
DIQMTQSPSSLSASVGDRVTITCRA
1406




SQSISTYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYFCQQSYSSPFTFGP





GTKVDIK







LC
DIQMTQSPSSLSASVGDRVTITCRA
1407



variable
SQSISTYLNWYQQKPGKAPKLLIYA





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYFCQQSYSSP







LCDR1
RASQSISTYLN
1036






LCDR2
AASSLQS
249






LCDR3
QQSYSSPFT
1408






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
1409




DFATYFC







LFR4
FGPGTKVDIK
443





S728-723
HC
QVQLVQSGAEVKKPGASVKVSCKTS
1376




GYTFTNYFMHWVRQAPGQGLEWMGI





INPSGGSASYAQKFQGRITMTSDTS





TSTVYMELSSLRSEDTAVYYCARED





IIVVVPARPLDYWGHGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKTS
1377



variable
GYTFTNYFMHWVRQAPGQGLEWMGI





INPSGGSASYAQKFQGRITMTSDTS





TSTVYMELSSLRSEDTAVYYCAR







HCDR1
NYFMH
1378






HCDR2
IINPSGGSASYAQKFQG
1379






HCDR3
EDIIVVVPARPLDY
1380






HFR1
QVQLVQSGAEVKKPGASVKVSCKTS
1381




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RITMTSDTSTSTVYMELSSLRSEDT
1382




AVYYCAR







HFR4
WGHGTLVTVSS
1315






LC
EIVLTQSPATLSLSPGERATLSCRA
1383




SQSFSNYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPPLLTF





GGGTKVEIK







LC
EIVLTQSPATLSLSPGERATLSCRA
1384



variable
SQSFSNYLAWYQQKPGQAPRLLIYD





ASNRATGIPARFSGSGSGTDFTLTI





SSLEPEDFAVYYCQQRSNWPP







LCDR1
RASQSFSNYLA
1385






LCDR2
DASNRAT
441






LCDR3
QQRSNWPPLLT
1386






LFR1
EIVLTQSPATLSLSPGERATLSC
181






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTDFTLTISSLEPE
183




DFAVYYC







LFR4
FGGGTKVEIK
85





S728-826
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1182




GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCARGH





SLGEWGQGSPVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1183



variable
GFTFGSYWMNWVRQAPGKGLEWVAN





INEDGSEKYYVDSVKGRFTISRDNA





KNSLYLQMNSLRAEDTAVYYCAR







HCDR1
SYWMN
1184






HCDR2
NINEDGSEKYYVDSVKG
1185






HCDR3
GHSLGE
1186






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
1187




GFTFG







HFR2
WVRQAPGKGLEWVA
145






HFR3
RFTISRDNAKNSLYLQMNSLRAEDT
273




AVYYCAR







HFR4
WGQGSPVTVSS
1188






LC
SSELTQDPAVSVALGQTVRITCQGD
1189




SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHLVFG





GGTKLTVL







LC
SSELTQDPAVSVALGQTVRITCQGD
1190



variable
SLRSYSASWYQQKPGQAPVLVIYIK





NKRPSGIPDRFSGSSSGNTASLTIT





GAQAEDEADYYCNSRDSSGDHL







LCDR1
QGDSLRSYSAS
1191






LCDR2
IKNKRPS
1192






LCDR3
NSRDSSGDHLV
1193






LFR1
SSELTQDPAVSVALGQTVRITC
1194






LFR2
WYQQKPGQAPVLVIY
1195






LFR3
GIPDRFSGSSSGNTASLTITGAQAE
1196




DEADYYC







LFR4
FGGGTKLTVL
69





S728-959
HC
QVHLVQSGAEIRKPGASVMVSCKAS
1387




GYTFTDYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





IRTAYMELSRLRSDDAAVYYCAREG





ISMLRGVRSWFDPWGQGTLVTVSS







HC
QVHLVQSGAEIRKPGASVMVSCKAS
1388



variable
GYTFTDYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





IRTAYMELSRLRSDDAAVYYCAR







HCDR1
DYYIH
1389






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
EGISMLRGVRSWFDP
1390






HFR1
QVHLVQSGAEIRKPGASVMVSCKAS
1391




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSIRTAYMELSRLRSDDA
1392




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1393




SSDVGSYNLVSWYQQHPGKVPKLII





YEVTKRPSGVSNRFSGSKSGNTASL





TISGLQTEDEADYYCCSYAGFSAWV





FGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1394



variable
SSDVGSYNLVSWYQQHPGKVPKLII





YEVTKRPSGVSNRFSGSKSGNTASL





TISGLQTEDEADYYCCSYAGFSA







LCDR1
TGTSSDVGSYNLVS
1395






LCDR2
EVTKRPS
1396






LCDR3
CSYAGFSAWV
1397






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKVPKLIIY
1398






LFR3
GVSNRFSGSKSGNTASLTISGLQTE
1399




DEADYYC







LFR4
FGGGTKLTVL
69





S210-530
HC
QVQLVQSGAEVKKPGASVKVSCKAS
1410




GYTFTGYFIHWVRQAPGQGLEYMGW





INPNSAGTNYAQKFQGRVTMTGDTS





ISTVYMELSRLRSDDTAMYYCARVF





FDWLLPFDYWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCKAS
1411



variable
GYTFTGYFIHWVRQAPGQGLEYMGW





INPNSAGTNYAQKFQGRVTMTGDTS





ISTVYMELSRLRSDDTAMYYCAR







HCDR1
GYFIH
1412






HCDR2
WINPNSAGTNYAQKFQG
1413






HCDR3
VFFDWLLPFDY
1414






HFR1
QVQLVQSGAEVKKPGASVKVSCKAS
190




GYTFT







HFR2
WVRQAPGQGLEYMG
1415






HFR3
RVTMTGDTSISTVYMELSRLRSDDT
1416




AMYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1417




SSDVGSYNLVSWYQQHPGKAPKLMI





YEVSKRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGSNYVF





GTGTKVTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1418



variable
SSDVGSYNLVSWYQQHPGKAPKLMI





YEVSKRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGS







LCDR1
TGTSSDVGSYNLVS
1395






LCDR2
EVSKRPS
94






LCDR3
CSYAGSNYV
1419






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGTGTKVTVL
18





S210-1129
HC
EVQLLESGGGLVQPGGSLRLSCVAS
1420




RFTFSDYAMSWVRQPPGKGLEWVSS





ISGSGGITYYADSVKGRFTISRDNS





KNTLYLQIKSLRAEDTAIYYCAKER





SNWNYVENFDYWGQGTLVTVSS







HC
EVQLLESGGGLVQPGGSLRLSCVAS
1421



variable
RFTFSDYAMSWVRQPPGKGLEWVSS





ISGSGGITYYADSVKGRFTISRDNS





KNTLYLQIKSLRAEDTAIYYCAK







HCDR1
DYAMS
199






HCDR2
SISGSGGITYYADSVKG
1422






HCDR3
ERSNWNYVENFDY
1423






HFR1
EVQLLESGGGLVQPGGSLRLSCVAS
1424




RFTFS







HFR2
WVRQPPGKGLEWVS
104






HFR3
RFTISRDNSKNTLYLQIKSLRAEDT
1425




AIYYCAK







HFR4
WGQGTLVTVSS
60






LC
QTVVTQEPSLTVSPGGTVTLTCASS
1426




TGTVTSAFFPNWFQQKPGQAPRALI





YSTTNKYSWTPARFSGSLLGGKAAL





TLSGVQPEDEADYYCLLFYGGARPH





VVFGGGTKLTVL







LC
QTVVTQEPSLTVSPGGTVTLTCASS
1427



variable
TGTVTSAFFPNWFQQKPGQAPRALI





YSTTNKYSWTPARFSGSLLGGKAAL





TLSGVQPEDEADYYCLLFYGGA







LCDR1
ASSTGTVTSAFFPN
1428






LCDR2
STTNKYS
1429






LCDR3
LLFYGGARPHVV
1430






LFR1
QTVVTQEPSLTVSPGGTVTLTC
1431






LFR2
WFQQKPGQAPRALIY
1432






LFR3
WTPARFSGSLLGGKAALTLSGVQPE
1433




DEADYYC







LFR4
FGGGTKLTVL
69





S451-5
HC
QVQLQQWGAGLLKPSETLSLTCAVY
1434




GASVSGYFWSWIRQPPGKGLEWIGE





INRFGSTNYNPSLKSRVTLSVDTSR





NQFSLKLGSVTAADTAMYYCARGSQ





ANPLVRFFDSPVTAFDIWGQGTMVT





VSS







HC
QVQLQQWGAGLLKPSETLSLTCAVY
1435



variable
GASVSGYFWSWIRQPPGKGLEWIGE





INRFGSTNYNPSLKSRVTLSVDTSR





NQFSLKLGSVTAADTAMYYCARG







HCDR1
GYFWS
798






HCDR2
EINRFGSTNYNPSLKS
1436






HCDR3
GSQANPLVRFFDSPVTAFDI
1437






HFR1
QVQLQQWGAGLLKPSETLSLTCAVY
1438




GASVS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTLSVDTSRNQFSLKLGSVTAADT
1439




AMYYCAR







HFR4
WGQGTMVTVSS
44






LC
EIVMTQSPATLSVSPGERATLSCRA
1440




SQSIKSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SRLQSEDFALYYCQQYDNWPPYTFG





QGTKLEIK







LC
EIVMTQSPATLSVSPGERATLSCRA
1441



variable
SQSIKSNLAWYQQKPGQAPRLLIYG





ASTRATGIPARFSGSGSGTEFTLTI





SRLQSEDFALYYCQQYDNWPP







LCDR1
RASQSIKSNLA
1442






LCDR2
GASTRAT
208






LCDR3
QQYDNWPPYT
1443






LFR1
EIVMTQSPATLSVSPGERATLSC
210






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPARFSGSGSGTEFTLTISRLQSE
1444




DFALYYC







LFR4
FGQGTKLEIK
380





S451-506
HC
QITLKESGPTLVKPTQTLTLTCTFS
1445




GFSFTSSGVGVGWIRQPPGKAMEWL





ALIYWDDDKRYSPSLKSRLTITKDT





SKNQVVLKMTNMDPVDTATYYCARH





TVATIVDYWGQGTLVTVSS







HC
QITLKESGPTLVKPTQTLTLTCTFS
1446



variable
GFSFTSSGVGVGWIRQPPGKAMEWL





ALIYWDDDKRYSPSLKSRLTITKDT





SKNQVVLKMTNMDPVDTATYYCA







HCDR1
SSGVGVG
1447






HCDR2
LIYWDDDKRYSPSLKS
473






HCDR3
HTVATIVDY
1448






HFR1
QITLKESGPTLVKPTQTLTLTCTFS
1449




GFSFT







HFR2
WIRQPPGKAMEWLA
1450






HFR3
RLTITKDTSKNQVVLKMTNMDPVDT
1451




ATYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1452




SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVPDRFSGSKSGNTASL





TISGLQAEDEADYYCGSYTTSSTPV





VFGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1453



variable
SSDVGGYNYVSWYQQHPGKAPKLMI





YEVSNRPSGVPDRFSGSKSGNTASL





TISGLQAEDEADYYCGSYTTSST







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
EVSNRPS
151






LCDR3
GSYTTSSTPVV
1454






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQHPGKAPKLMIY
67






LFR3
GVPDRFSGSKSGNTASLTISGLQAE
1246




DEADYYC







LFR4
FGGGTKLTVL
69





S451-1140
HC
EVQLVETGGGLIQPGGSLRLSCAAS
1455




GITVSSNYMNWVRLAPGKGLEWVSL





IYSGGSTFYADSVKGRFTISRDNSK





NTLYLQMNSLRAEDTAVYYCAREGL





VGATTAFDYWGQGTLVTVSS







HC
EVQLVETGGGLIQPGGSLRLSCAAS
1456



variable
GITVSSNYMNWVRLAPGKGLEWVSL





IYSGGSTFYADSVKGRFTISRDNSK





NTLYLQMNSLRAEDTAVYYCAR







HCDR1
SNYMN
1457






HCDR2
LIYSGGSTFYADSVKG
1458






HCDR3
EGLVGATTAFDY
1459






HFR1
EVQLVETGGGLIQPGGSLRLSCAAS
1460




GITVS







HFR2
WVRLAPGKGLEWVS
1461






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
DIQLTQSPSFLSASVGDRVTITCRA
1462




SQGISSYLAWYQLQPGKAPKLLIYA





ASTLQSGVPSRFSGSGSGTEFTLTI





SSLQPEDFATYYCQQLNGHPQGTFG





QGTKVEIK







LC
DIQLTQSPSFLSASVGDRVTITCRA
1463



variable
SQGISSYLAWYQLQPGKAPKLLIYA





ASTLQSGVPSRFSGSGSGTEFTLTI





SSLQPEDFATYYCQQLNGHP







LCDR1
RASQGISSYLA
1464






LCDR2
AASTLQS
1465






LCDR3
QQLNGHPQGT
1466






LFR1
DIQLTQSPSFLSASVGDRVTITC
1467






LFR2
WYQLQPGKAPKLLIY
1468






LFR3
GVPSRFSGSGSGTEFTLTISSLQPE
1469




DFATYYC







LFR4
FGQGTKVEIK
53





S451-1190
HQ
QVTLRESGPALVKPTQTLTLTCTFS
1470




GFSLTTSGMCVSWIRQPPGKALEWL





ARIDWDDDKYYSTSLKARLTISKDT





SKNQVVLTMTNMDPVDTATYYCART





SVGGTKYYFDYWGQGTLVTVSS







HC
QVTLRESGPALVKPTQTLTLTCTFS
1471



variable
GFSLTTSGMCVSWIRQPPGKALEWL





ARIDWDDDKYYSTSLKARLTISKDT





SKNQVVLTMTNMDPVDTATYYCAR







HCDR1
TSGMCVS
1472






HCDR2
RIDWDDDKYYSTSLKA
1473






HCDR3
TSVGGTKYYFDY
1474






HFR1
QVTLRESGPALVKPTQTLTLTCTFS
1475




GFSLT







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTISKDTSKNQVVLTMTNMDPVDT
517




ATYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSVLTQPPSASGTPGQRVTISCSGS
1476




SSNIGRNTVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLNGGV





FGGGTKLTVL







LC
QSVLTQPPSASGTPGQRVTISCSGS
1477



variable
SSNIGRNTVNWYQQLPGTAPKLLIY





SNNQRPSGVPDRFSGSKSGTSASLA





ISGLQSEDEADYYCAAWDDSLNG







LCDR1
SGSSSNIGRNTVN
1478






LCDR2
SNNQRPS
119






LCDR3
AAWDDSLNGGV
1479






LFR1
QSVLTQPPSASGTPGQRVTISC
121






LFR2
WYQQLPGTAPKLLIY
122






LFR3
GVPDRFSGSKSGTSASLAISGLQSE
123




DEADYYC







LFR4
FGGGTKLTVL
69





S626-84
HC
QLQLQESGPGLVKPSEALSLTCTVS
1480




GGSISTSNYYWGWIRQPPGKGLEWI





GSIYYRGGTHYNPSLKTRVTISVDT





SKNQFSLKLSSVTAADTAVYYCARH





TYFYDIVGAAVWEPFDIWGQGTMVT





VSS







HC
QLQLQESGPGLVKPSEALSLTCTVS
1481



variable
GGSISTSNYYWGWIRQPPGKGLEWI





GSIYYRGGTHYNPSLKTRVTISVDT





SKNQFSLKLSSVTAADTAVYYCAR







HCDR1
TSNYYWG
1482






HCDR2
SIYYRGGTHYNPSLKT
1483






HCDR3
HTYFYDIVGAAVWEPFDI
1484






HFR1
QLQLQESGPGLVKPSEALSLTCTVS
1485




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTISVDTSKNQFSLKLSSVTAADT
115




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
EIVLTQSPGTLSLSPGERATLSCRA
1486




SQSVSSSYLAWYQQKPGQAPRLLIS





DASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPPWTF





GQGTKVEIK







LC
EIVLTQSPGTLSLSPGERATLSCRA
1487



variable
SQSVSSSYLAWYQQKPGQAPRLLIS





DASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYGSSPP







LCDR1
RASQSVSSSYLA
338






LCDR2
DASSRAT
1143






LCDR3
QQYGSSPPWT
1488






LFR1
EIVLTQSPGTLSLSPGERATLSC
50






LFR2
WYQQKPGQAPRLLIS
1489






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGQGTKVEIK
53





S626-161
HC
QLQLQESGPGLVKPSETLSLTCTVS
1490




GGSISSNNYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTMSVDT





SKNQFSLKLSSVTAADTAVYHCARQ





GPNYYDRSGYYYVGPFDIWGQGTMV





TVSS







HC
QLQLQESGPGLVKPSETLSLTCTVS
1491



variable
GGSISSNNYYWGWIRQPPGKGLEWI





GSIYYSGSTYYNPSLKSRVTMSVDT





SKNQFSLKLSSVTAADTAVYHCAR







HCDR1
SNNYYWG
1492






HCDR2
SIYYSGSTYYNPSLKS
243






HCDR3
QGPNYYDRSGYYYVGPFDI
1493






HFR1
QLQLQESGPGLVKPSETLSLTCTVS
245




GGSIS







HFR2
WIRQPPGKGLEWIG
7






HFR3
RVTMSVDTSKNQFSLKLSSVTAADT
1494




AVYHCAR







HFR4
WGQGTMVTVSS
44






LC
QSVLTQPPSVSAAPGQKVTISCSGS
1495




SSNIGNNSVSWYQHLPGTAPKLLIY





ENNERPSGIPDRFSGSKSGTSATLG





ITGLQTGDEADYYCETWDRSLSASF





GTGTKVTVL







LC
QSVLTQPPSVSAAPGQKVTISCSGS
1496



variable
SSNIGNNSVSWYQHLPGTAPKLLIY





ENNERPSGIPDRFSGSKSGTSATLG





ITGLQTGDEADYYCETWDRSLSA







LCDR1
SGSSSNIGNNSVS
1497






LCDR2
ENNERPS
1498






LCDR3
ETWDRSLSAS
1499






LFR1
QSVLTQPPSVSAAPGQKVTISC
1500






LFR2
WYQHLPGTAPKLLIY
1501






LFR3
GIPDRFSGSKSGTSATLGITGLQTG
1502




DEADYYC







LFR4
FGTGTKVTVL
18





S626-664
HC
QVQLVQSGAEVKKPGASVKVSCRVS
1503




GYTFTGYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ITTAYMELSRLRSDDTAVYYCARVP





MILVVDHWGSYFDYWGQGTLVTVSS







HC
QVQLVQSGAEVKKPGASVKVSCRVS
1504



variable
GYTFTGYYIHWVRQAPGQGLEWMGW





INPNSGGTNYAQKFQGRVTMTRDTS





ITTAYMELSRLRSDDTAVYYCAR







HCDR1
GYYIH
1505






HCDR2
WINPNSGGTNYAQKFQG
953






HCDR3
VPMILVVDHWGSYFDY
1506






HFR1
QVQLVQSGAEVKKPGASVKVSCRVS
1507




GYTFT







HFR2
WVRQAPGQGLEWMG
160






HFR3
RVTMTRDTSITTAYMELSRLRSDDT
1508




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
QSALTQPASVSGSPGQSITISCTGT
1509




SSDVGGYNYVSWYQQYPGKAPKLMI





YDVSKRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGSSALV





FGGGTKLTVL







LC
QSALTQPASVSGSPGQSITISCTGT
1510



variable
SSDVGGYNYVSWYQQYPGKAPKLMI





YDVSKRPSGVSNRFSGSKSGNTASL





TISGLQAEDEADYYCCSYAGSSA







LCDR1
TGTSSDVGGYNYVS
63






LCDR2
DVSKRPS
592






LCDR3
CSYAGSSALV
1511






LFR1
QSALTQPASVSGSPGQSITISC
66






LFR2
WYQQYPGKAPKLMIY
1512






LFR3
GVSNRFSGSKSGNTASLTISGLQAE
68




DEADYYC







LFR4
FGGGTKLTVL
69





S728-209
HC
QITLKESGPTLVKPTQTLTLTCTLS
1513




GFSLSTSGVSVGWIRQPPGKALEWL





AVIFWDDDKRYNPSLKSRLTIAKDT





SKSQVVLTMTNLDPVDTGTYYCVSG





SSYYYYYYMDVWGKGTTVTVSS







HC
QITLKESGPTLVKPTQTLTLTCTLS
1514



variable
GFSLSTSGVSVGWIRQPPGKALEWL





AVIFWDDDKRYNPSLKSRLTIAKDT





SKSQVVLTMTNLDPVDTGTYYCV







HCDR1
TSGVSVG
1515






HCDR2
VIFWDDDKRYNPSLKS
1516






HCDR3
GSSYYYYYYMDV
1517






HFR1
QITLKESGPTLVKPTQTLTLTCTLS
1518




GFSLS







HFR2
WIRQPPGKALEWLA
476






HFR3
RLTIAKDTSKSQVVLTMTNLDPVDT
1519




GTYYCVS







HFR4
WGKGTTVTVSS
670






LC
DIQMTQSPSSVSASIGDRVTITCRA
1520




SQDISTWLAWYQQKPGRAPNLLIYG





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQATSFPLTFGG





GTKVEIK







LC
DIQMTQSPSSVSASIGDRVTITCRA
1521



variable
SQDISTWLAWYQQKPGRAPNLLIYG





ASSLQSGVPSRFSGSGSGTDFTLTI





SSLQPEDFATYYCQQATSFP







LCDR1
RASQDISTWLA
1522






LCDR2
GASSLQS
1523






LCDR3
QQATSFPLT
1524






LFR1
DIQMTQSPSSVSASIGDRVTITC
1525






LFR2
WYQQKPGRAPNLLIY
1526






LFR3
GVPSRFSGSGSGTDFTLTISSLQPE
253




DFATYYC







LFR4
FGGGTKVEIK
85





S728-369
HC
QVQLQESGPGLVKPSQTLSLTCSVS
1527




GGSISSGGYYWSWIRQHPGKGLEWI





GYMYYSGSTYYNPSLKSRVTIFVDT





SKNHFSLKLTSVTAADTAVYYCARD





SYENYYGSGSLEPNYHHYNMDVWGQ





GTTVTVSS







HC
QVQLQESGPGLVKPSQTLSLTCSVS
1528



variable
GGSISSGGYYWSWIRQHPGKGLEWI





GYMYYSGSTYYNPSLKSRVTIFVDT





SKNHFSLKLTSVTAADTAVYYCAR







HCDR1
SGGYYWS
1235






HCDR2
YMYYSGSTYYNPSLKS
1529






HCDR3
DSYENYYGSGSLEPNYHHYNMDV
1530






HFR1
QVQLQESGPGLVKPSQTLSLTCSVS
1531




GGSIS







HFR2
WIRQHPGKGLEWIG
1239






HFR3
RVTIFVDTSKNHFSLKLTSVTAADT
1532




AVYYCAR







HFR4
WGQGTTVTVSS
147






LC
DVQMTQSPSTLSASIGDRVTITCRA
1533




SQSISGWLAWYQQRPGKAPKLLIYR





ASSLDFGVPSRFSGNGSGTEFTLTI





SSLQPDDFATYYCQQYHTYRTFGQG





TKVEVK







LC
DVQMTQSPSTLSASIGDRVTITCRA
1534



variable
SQSISGWLAWYQQRPGKAPKLLIYR





ASSLDFGVPSRFSGNGSGTEFTLTI





SSLQPDDFATYYCQQYHTY







LCDR1
RASQSISGWLA
1535






LCDR2
RASSLDF
1536






LCDR3
QQYHTYRT
1537






LFR1
DVQMTQSPSTLSASIGDRVTITC
1538






LFR2
WYQQRPGKAPKLLIY
1181






LFR3
GVPSRFSGNGSGTEFTLTISSLQPD
1539




DFATYYC







LFR4
FGQGTKVEVK
1540





S728-430
HC
EVQLVESGGGLIQPGGSLRLSCAAS
1541




GFTVSSNYMSWVRQAPGKGLEWVSV





IYSGGSTYYADSVKGRFTISRDNSK





NTLYLQMNSLRAEDTAVYYCARTPR





GSRRGAFDIWGQGTMVTVSS







HC
EVQLVESGGGLIQPGGSLRLSCAAS
1542



variable
GFTVSSNYMSWVRQAPGKGLEWVSV





IYSGGSTYYADSVKGRFTISRDNSK





NTLYLQMNSLRAEDTAVYYCAR







HCDR1
SNYMS
358






HCDR2
VIYSGGSTYYADSVKG
392






HCDR3
TPRGSRRGAFDI
1543






HFR1
EVQLVESGGGLIQPGGSLRLSCAAS
1544




GFTVS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDNSKNTLYLQMNSLRAEDT
146




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
DIQMTQSPSSLSASVGDRVTITCQA
1545




SQDISDYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFTFTI





SSLQPEDIATYYCQQYDNLPPLTFG





GGTKVEIK







LC
DIQMTQSPSSLSASVGDRVTITCQA
1546



variable
SQDISDYLNWYQQKPGKAPKLLIYD





ASNLETGVPSRFSGSGSGTDFTFTI





SSLQPEDIATYYCQQYDNLPP







LCDR1
QASQDISDYLN
1547






LCDR2
DASNLET
770






LCDR3
QQYDNLPPLT
1548






LFR1
DIQMTQSPSSLSASVGDRVTITC
251






LFR2
WYQQKPGKAPKLLIY
252






LFR3
GVPSRFSGSGSGTDFTFTISSLQPE
997




DIATYYC







LFR4
FGGGTKVEIK
85





S728-537
HC
QVQLVQSGAEVKKPGASVKVSCKTS
1549




GYTFTGFYLHWLRQAPGQGLEWMGR





INPNTGDTDYAQKFQGRVTMTRDTS





ISTAYMELSRLRADDTAVYYCARTP





GQTRQLFVGTNVLDVWGQGTMVTVS





S







HC
QVQLVQSGAEVKKPGASVKVSCKTS
1550



variable
GYTFTGFYLHWLRQAPGQGLEWMGR





INPNTGDTDYAQKFQGRVTMTRDTS





ISTAYMELSRLRADDTAVYYCAR







HCDR1
GFYLH
1551






HCDR2
RINPNTGDTDYAQKFQG
1552






HCDR3
TPGQTRQLFVGTNVLDV
1553






HFR1
QVQLVQSGAEVKKPGASVKVSCKTS
1381




GYTFT







HFR2
WLRQAPGQGLEWMG
1554






HFR3
RVTMTRDTSISTAYMELSRLRADDT
1555




AVYYCAR







HFR4
WGQGTMVTVSS
44






LC
DIQMTQSPSSVSASVGDRVTITCRA
1556




SQGISSWLAWYQQKPGKAPKVLIFA





ASSLQSGVPSRFSGSGSGTDFTLTI





TSLQPEDFATYFCQQTNSFPPTFGG





GTKVEIK







LC
DIQMTQSPSSVSASVGDRVTITCRA
1557



variable
SQGISSWLAWYQQKPGKAPKVLIFA





ASSLQSGVPSRFSGSGSGTDFTLTI





TSLQPEDFATYFCQQTNSFPP







LCDR1
RASQGISSWLA
1558






LCDR2
AASSLQS
249






LCDR3
QQTNSFPPT
1559






LFR1
DIQMTQSPSSVSASVGDRVTITC
1560






LFR2
WYQQKPGKAPKVLIF
1561






LFR3
GVPSRFSGSGSGTDFTLTITSLQPE
1562




DFATYFC







LFR4
FGGGTKVEIK
85





S728-1157
HC
EVQLVESGGGLVQPGGSLRLSCAAS
1563




GLLVSRNYMNWVRQAPGKGLEWVSI





IYSGGSTFYADSVEGRFTISRDESK





NTLYLQMNSLRTDDTAVYYCARDLS





DYGGIDCWGQGTLVTVSS







HC
EVQLVESGGGLVQPGGSLRLSCAAS
1564



variable
GLLVSRNYMNWVRQAPGKGLEWVSI





IYSGGSTFYADSVEGRFTISRDESK





NTLYLQMNSLRTDDTAVYYCAR







HCDR1
RNYMN
1565






HCDR2
IIYSGGSTFYADSVEG
1566






HCDR3
DLSDYGGIDC
1567






HFR1
EVQLVESGGGLVQPGGSLRLSCAAS
1568




GLLVS







HFR2
WVRQAPGKGLEWVS
130






HFR3
RFTISRDESKNTLYLQMNSLRTDDT
1569




AVYYCAR







HFR4
WGQGTLVTVSS
60






LC
YELTQPLSVSMALGQTARISCGGDN
1570




VGSQNVHWYQQRPGQAPVLVIYRDS





NRPSGIPERFSGSKSGNTATLTISR





AQAGDEADYYCQVWDSSTVAFGGGT





KLTVL







LC
YELTQPLSVSMALGQTARISCGGDN
1571



variable
VGSQNVHWYQQRPGQAPVLVIYRDS





NRPSGIPERFSGSKSGNTATLTISR





AQAGDEADYYCQVWDSST







LCDR1
GGDNVGSQNVH
1572






LCDR2
RDSNRPS
1573






LCDR3
QVWDSSTVA
1574






LFR1
YELTQPLSVSMALGQTARISC
1575






LFR2
WYQQRPGQAPVLVIY
950






LFR3
GIPERFSGSKSGNTATLTISRAQAG
1576




DEADYYC







LFR4
FGGGTKLTVL
69





S728-1261
HC
QVQLQESGPGLVKPSGTLSLTCAVS
1577




GGSISNNNWWIWVRQPPGKGLEWIG





EIHHSGSTDYNPSLKSRVTISIDKS





KNQFSLRLSSVTAADTAVYYCARKP





EPYYYYYYMDVWGKGTTVTVSS







HC
QVQLQESGPGLVKPSGTLSLTCAVS
1578



variable
GGSISNNNWWIWVRQPPGKGLEWIG





EIHHSGSTDYNPSLKSRVTISIDKS





KNQFSLRLSSVTAADTAVYYCAR




HCDR1
NNNWWI
1579






HCDR2
EIHHSGSTDYNPSLKS
1580






HCDR3
KPEPYYYYYYMDV
1581






HFR1
QVQLQESGPGLVKPSGTLSLTCAVS
217




GGSIS







HFR2
WVRQPPGKGLEWIG
218






HFR3
RVTISIDKSKNQFSLRLSSVTAADT
1582




AVYYCAR







HFR4
WGKGTTVTVSS
670






LC
ETVLTQSPGTLSLSPGERATLSCRA
1583




SQSVSSSYITWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYRSPWGLTF





GPGTKVDIK







LC
ETVLTQSPGTLSLSPGERATLSCRA
1584



variable
SQSVSSSYITWYQQKPGQAPRLLIY





GASSRATGIPDRFSGSGSGTDFTLT





ISRLEPEDFAVYYCQQYRS







LCDR1
RASQSVSSSYIT
1585






LCDR2
GASSRAT
135






LCDR3
QQYRSPWGLT
1586






LFR1
ETVLTQSPGTLSLSPGERATLSC
1587






LFR2
WYQQKPGQAPRLLIY
182






LFR3
GIPDRFSGSGSGTDFTLTISRLEPE
196




DFAVYYC







LFR4
FGPGTKVDIK
443





S728-1690
HC
QVQLVQSGAEVVKPGSSVKVSCKAS
1588




GGTFTRYAISWVRQAPGQGPEWMGR





IIPMFGIANYAQRFQGRVTMTADKS





TSTAYMELSSLRSEDTAVYYCATCQ





YYYDSSGYGSLDYWGQGTQVTVSS







HC
QVQLVQSGAEVVKPGSSVKVSCKAS
1589



variable
GGTFTRYAISWVRQAPGQGPEWMGR





IIPMFGIANYAQRFQGRVTMTADKS





TSTAYMELSSLRSEDTAVYYCA







HCDR1
RYAIS
1590






HCDR2
RIIPMFGIANYAQRFQG
1591






HCDR3
CQYYYDSSGYGSLDY
1592






HFR1
QVQLVQSGAEVVKPGSSVKVSCKAS
1593




GGTFT







HFR2
WVRQAPGQGPEWMG
1594






HFR3
RVTMTADKSTSTAYMELSSLRSEDT
1595




AVYYCAT







HFR4
WGQGTQVTVSS
1596






LC
EIVLTQSPGTLSLSPGERVTLSCRA
1597




SQSISSNFLAWYQQKPGQAPRLLIS





GASSRATGIPDRFSGGGSGTDFTLT





ISRLEPEDFAVYYCQQYHSSPRTFG





QGTKVEIK







LC
EIVLTQSPGTLSLSPGERVTLSCRA
1598



variable
SQSISSNFLAWYQQKPGQAPRLLIS





GASSRATGIPDRFSGGGSGTDFTLT





ISRLEPEDFAVYYCQQYHSSP







LCDR1
RASQSISSNFLA
1599






LCDR2
GASSRAT
135






LCDR3
QQYHSSPRT
1600






LFR1
EIVLTQSPGTLSLSPGERVTLSC
1601






LFR2
WYQQKPGQAPRLLIS
1489






LFR3
GIPDRFSGGGSGTDFTLTISRLEPE
1602




DFAVYYC







LFR4
FGQGTKVEIK
53
















TABLE 2







Nucleic Acid Sequences













SEQ





ID


Clone
Description
Sequence
NO





S20-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAGGCCTTCGGA
1603


15

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTCA





CTACTGGAGCTGGATCCGGCAGCCCCCCGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTATAGTGGGAGCACCAATTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAACTTATCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGAGCCGGGGGCGTTTTTGGAGTGGTTCTGGACTTTGACCACTG





GGGCCGGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCC





CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA





CAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG





ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT





CCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAG
1604




ACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAGTGT





GCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCTGTGCTGGTCGTCT





ATGATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCC





GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGA





GCATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTCAGCC





CAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCT





CCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCC





GGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGG





CGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTA





CGCGGCCAGCAGCTA






S20-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1605


22

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTT





CTACTGGGGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGA





TTGGGCGTTTCCATACTAGTGGGAGCACCAACTACAACCCCTCCTTCA





AGAGTCGAGTCACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT





GCGAGCGGCCGGGGCAGCAGCTGGTACGTAGGCTGGTTCTTCGATCT





CTGGGGCCGTGGCACCCTGGTCACTGTCTCCTCAGCCTCCACCAAGGG





CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGG





CACAGCAGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG





TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC





TTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1606




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGACTGTTTTATACAG





CTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAAGTTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGGAGATGTGGCAGTTTATTACTGTCAGC





AATATTATAATACTCCGGACACTTTCGGCGGAGGGACCAAGGTGGAG





ATCAATCGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT





GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT





AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S20-
HC-DNA
CAGGTCCAACTCATACAGTCAGGGGCTGAGGTGAAGAAGCCTGGGGC
1607


31

CTCAGTGAAGGTCTCCTGCACGGCCTCCGGATACTCCCTCAATGAGTT





GCCCATACAGTGGGTGCGGCAGGCTCCTGGTAAAGGGCTTGAGTGGA





TGGGAGAATTTGATCCCGAAGATGGTGAAACAATCTACGCAGAGAAA





TTCCAGGGCAGAGTCACCCTGACCGAGGAAACATCTACAAACACAGC





CTACATGGAGTTGAGCAGCCTGAAATCTGAGGACACGGCCGCGTATT





TTTGTTCAACCGGCTCGACTATTGGCGTCGTCATTTATGCTTTTGCTAT





CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCTTCCACCAAGG





GCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGA





GCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG





GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC





CTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCCCCAGGCACCCTGTCTTTGTCTCCAGGG
1608




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGGATATTACCAACAA





CTTCTTAGCCTGGTACCAGCAGAAAGCCGGCCAGGCTCCCAAACTCTT





CATCTATGGTGCATCCAGGAGGGCCCCTGGCATCCCACACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTG





GAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTACGGTCCCTCT





CCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S20-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1609


40

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGA





TTGGGCGTATCTATACCAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT





GCGAGAGGGGGCAGTGGCTGGCGCTTTGACTACTGGGGCCAGGGAAC





CCTGGTCACCGTCTCCTCAGGGAGTGCATCCGCCCCAACCCTTTTCCC





CCTCGTCTCCTGTGAGAATTCCCCGTCGGATACGAGCAGCGTG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1610




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTCTCGGAGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTA






S20-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1611


58

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGG





TGATTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG





AGTGGATTGGGTACATCTATTTCAGTGGGAGCACCTACTACAACCCGT





CCCTCAAGAGTCGAGTTACCATATCACTAGACAGGTCCAAGAACCAG





TTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCAGACACGGCCGTGTAT





TACTGTGCCAGAGAGGAAAGTATGATTACGCTTGGGGGAGTTATCGT





CGACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCA





AGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTG





GGGGCACAGCAGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA





CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA





CACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GATATTGTGATGACCCAGACTCCACTCTCCTCACCTGTCACCCTTGGA
1612




CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTACACAGT





GATGGAGACACCTACTTGAGTTGGCTTCAGCAGAGGCCAGGCCAGCC





TCCAAGACTCCTAATTTACAAGATTTCTAACCGGTTCTCTGGGGTCCC





AGACAGATTCAGTGGCAGTGGGGCAGGGACAGATTTCACACTGAAAA





TCAGCAGGGTGGAAGCTGAGGATGTCGGGGTTTATTACTGCATGCAA





GCTACACAATTTCCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGAT





CAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA





TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAA





CTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC





TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAG





GACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGA





CTACGAGAA






S20-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1613


74

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTCA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGCAGA





TTGGGTATATGTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCATCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGTTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGGGTCGTGACCAGCTGTTATACGGGGCCGATGGTTTTGATATCTGG





GGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCC





ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC





AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGA





CGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTC





CCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAG
1614




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTA





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA





GCAGCAATCATGTGATATTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTA






S20-
HC-DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAG
1615


86

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGGTGACTA





TGCCATGTACTGGGTCCGGCAACCTCCAGGGAAGGGCCTGGAGTGGG





TCTCAGGTATTAGTTGGAATAGAGGTACTATAGGCTATGCGGACTCTG





TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTG





TATCTGCAAATGAACAGTCTGACACCTGAGGACACGGCCTTGTATTAC





TGTGCAAAAGATATGCTACCAGCTAGTAGGTTCTTCTACTACATGGAC





GTCTGGGGCAAAGGGACCACGGTCATCGTCTCCTCAGCCTCCACCAA





GGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG





GGGCACAGCAGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC





CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC





ACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1616




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTCTCGGCGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA





GGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGA





CTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAA





CAACAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1617


68

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCACTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGAATATATCCATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGATTGCTCAAGTATAGCAGGGGGGGGTGCTACTTTGACCACTG





GGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCC





CATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCA





CAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG





ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT





CCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1618




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAGGTA





ATCCTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC





CTCATCTATAGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





CCTGAAGGGTCCGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG





GTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTG





AGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGAC





TTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCC





CGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCTGAGCAGTG





GAAGTCCCACA






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGG
1619


105

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCCTCAGCAGCTA





TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TTTCATACATTAGTAGTAGTAGTAGCACCATATACTACGCAGACTCTG





TGAAGGGCCGATTCACCATCTCCAAAGACAACGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATTA





CTGTGCGGTCGGACGGGGATACTTTGTCTACTGGGGCCAGGGAACCC





TGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCC





TGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC





TGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA





CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACA





GTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1620




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCGG





TTACTTAGCCTGGTACCAGCAAAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTTTGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAACAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA






S24-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1621


178

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATGGTATGATGGAAGTAATAAATATTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAATCGAGGGATACAGCTATGGCGACGTGAGGGTCTAC





TACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGT





CTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTC





CTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA





AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC





CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1622




TCGATCACCATCTCCTGCACTGGAACCACCAGTGACGTTGGTGGTTAT





GACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATACTTTCTGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATCCAAGCA





GCAGCACTCTAGTCTTCGGAACTGGGACCAAGGTCACCGTCTTAGGTC





AGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGG





AGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCT





ACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTC





AAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACA





AGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTCCACCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1623


188

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTG





TGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGGATGGGAGTTTGGTTCGGGGAGTTATTATCGAACT





GATTACTACTACTACGCTATGGACGTCTGGGGCCAAGGGACCACGGT





CACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGC





GCCCTGCTCCAGGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCC





TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCA





GGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC





TCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1624




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCACTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAGGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCCTTTATGTCTTCGGAACTGGGACCAAGGTCGCCGTCCTAGGTC





AGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGG





AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCT





ACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTC





AAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACA





AGTACGCGGCCAGCAGCTA






S24-
HC-DNA
GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1625


202

AGTCTCTGAGGATCTCCTGTAAGGGTTCTGGATACAGCTTTAGCAGCT





ACTGGATCAGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGAGGATTGATCCTAGTGACTCTAACACCAACTACAGCCCGTC





CTTCCAAGGCCACGTCACCATCTCAGCTGACAAGTCCATCAGCACTGC





CTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGACTCTCCGTCCGGGTATGGTTCGGGGAGTTACCCCATT





ACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA





GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG





AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTA





CTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA





GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1626




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTA





CCTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCA





TCTATGATGCATCCAACAGGGCCTCTGGCATCCCAGCCAGGTTCAGTG





GCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG





CCTGAAGATTTTGCAGTTTATTACTGTCAGCAACGTCGCAACTGGCCT





CTCACTTTCGGCGGAGGGACCAAGGTGGAGACCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1627


278

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGACACAAACTATGCACAGAAG





TTTCAGGGCTGGGTCACCATGACCAGGGACACGTCCCTCAGCACAGC





CTACATGGAGCTGAGCAGGCTGAAATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGTAGGGGTTGGTGAATATAGTGGGAGGCACTACTAC





TACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTC





CTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTC





CAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG





ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG





ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1628




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCAGGGCG
1629


339

GTCCCTGAGACTCTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTAT





GCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGT





AGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACACAACACGCCG





CCTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGC





ATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGT





GTATCACTGTGCTAGAGATGGATATGATTGTAGTGGTGGTAGATGCTA





CTCCCATATATTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC





CTCAGGTGAGTCCTCACCACCCCCTCTCTGAGTCCACTTAGGGAGACT





CAGCTTGCCAGGGTCTCAGGGTCAGAGTCTTGTAG







LC-DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
1630




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAA





CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG





TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATGATAACTGGTGG





ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGC





ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG





AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGC





CAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGG
1631


472

GACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGCAGTAT





TAACTGGTGGAGTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGT





GGATCGGGGAAATCTATCATAGTGGGAACACCAACTATAACCCGTCC





CTCAAGAGTCGAGTCACCATATCAGGAGACAAGTCCAAGAACCAGTT





CTCCCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTA





CTGTGCGAGAGGTTACTATGATAGTAGTCCTTATTACGAGCCACAGG





GAATTGACTACTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCAGCCT





CCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA





CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC





CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG





CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGCTTGTGCTGACTCAATCGCCCTCTGCCTCTGCCTCCCTGGGAGCC
1632




TCGGTCAAGCTCACCTGCACTCTGAGCAGTGGGCACAGCAGCTACAC





CATCGCATGGCATCAGCAGCAGCCAGAGAAGGGCCCTCGGTACTTGA





TGAAAGTTAACAGTGATGGCAGCCACACCAAGGGGGACGGGATCCCT





GATCGCTTCTCAGGCTCCAGCTCTGGGGCTGAGCGCTACCTCACCATC





TCCAGCCTCCAGTCTGAGGATGAGGCTGACTATTACTGTCAGACCTGG





GGCACTGGCATTCGAGTATTCGGCGGAGGGACCAAGCTGACCGTCCT





AGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTC





TGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTG





ACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGC





CCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAA





CAACAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1633


490

CTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTA





CTTTATTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAATAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGT





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGACACACAACCCCGACAAGATACTTTGACTACTGGGGC





CAGGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATCCGCCCCAAC





CCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGATACGAGCAG





CGTG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1634




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCAGCAG





CTACTTAGCCTGGTACCAGCAGAGACGTGGCCAGGCTCCCAGGCTCC





TCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTC





AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACT





GGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTC





ACCTCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTG





TGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA





AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA





GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1635


494

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAG





TAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG





AGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCG





TCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTA





TTACTGTGCGAGAAAGCCACGTAGTGACTACGGGTACTTCGATCTCTG





GGGCCGTGGCACCCTGGTCACTGTCTCCTCAGCCTCCACCAAGGGCCC





ATCGGTC







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1636




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTC





AACTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTG





GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA





TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGA





GAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTAAAGCCAGGGCG
1637


566

GTCCCTGAGACTCTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTAT





GCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGT





AGGTTTCACTAGAAGGAAAGCTTATGGTGGGACAACAGAGTACGCCG





CGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGC





ATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGT





GTATTACTGTACTAGAATTAAGGTGGGCCGTTTCGATCTTACCGACAG





TGGGAGCTACCGATACTTTGACTACTGGGGCCAGGGAACCCTGGTCA





CCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCAC





CCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG





GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGG





CGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTC





AGGA







LC-DNA
GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
1638




GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGT





AATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC





TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC





TGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA





TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA





CCTCTACAAACTCCTTGGACGTTCGGCCAAGGGACCAAGGTGGAAAT





CAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGA





TGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAA





CTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1639


636

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTAAGTAGCTA





TTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATT





ACTGTGCGAGAGATCTAACTGCCACCTGGTTCGACCCCTGGGGCCAG





GGAACCCTGGTCACCGTCTCCTCAGCACCCACCAAGGCTCCGGATGT





GTTCCCCATCATATCAGGGTGCAGACACCCAAAGGATAACAGCCCTG





TGGTCCTGGCATGCTTGATAACTGGGTACCACC







LC-DNA
CAGACTGTGGTGACCCAGGAGCCATCGTTCTCAGTGTCCCCTGGAGG
1640




GACAGTCACACTCACTTGTGGCTTGAGCTCTGGCTCAGTCTCTACTAG





TTACTACCCCAGCTGGTACCAGCAGACCCCAGGCCAGGCTCCACGCA





CGCTCATCTACAGCACAAACAAACGCTCTTCTGGGGTCCCTGATCGCT





TCTCTGGCTCCATCCTTGGGAACAAAGCTGCCCTCACCATCACGGGGG





CCCAGGCAGATGATGAATCTGATTATTACTGTGTGCTCTATATGGGTA





GTGGCATGTCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1641


740

CTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATACACCTTCACTAGCTA





TGCTTTGCATTGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGA





TGGGATGGATCAACGCTGGCAATGGTAACACAAAATATTCACAGAGG





TTCCAGGGCAGAGTCACCATTATTAGGGACACATCCGCGAGCACAAC





CTACATGGAGCTGAGCAGCCTGAGATCTGAAGACACGGCTGTGTATT





ACTGTGCGAGAGGCTATGCCCGAGCCGGGGTTATTACTATCAAAGAA





TCACTCCACCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCC





TCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC





ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT





CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCG





GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1642




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAG





CTCCAACAATAAGAACTACTTAGCCTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATATTATAGTACTCCTCCCCTCACTTTCGGCGGAGGGACCAAGGTGG





AGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCAT





CTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGA





ATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC





GC






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1643


791

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTC





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTACAGTGGGAACACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCCTATCAATAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGTGCAGTGTTACGATTTTTGGAGTGGTTACCCCTGCTTTTGATATCT





GGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGC





CCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGC





ACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGT





GACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCT





TCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAGATTGTGTTGACGCACTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1644




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTCCGCAGCTA





CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTG





GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAG





CCTGACGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCACCT





TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAG






S24-
HC-DNA
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1645


902

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTA





TGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGATGGGATTTTGGAGTGGTTATTCAATACGGTATGGAC





GTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACCAA





GGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG





GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC





CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC





ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC





GTGGTGACCGTGCCCTCCAGCAGCTTGGG







LC-DNA
CAGGCTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGG
1646




GACAGTCACTCTCACCTGTGGCTCCAGCACTGGAGCTGTCACCAGTGG





TCATTATCCCTACTGGTTCCAGCAGAAGCCTGGCCAAGCCCCCAGGAC





ACTGATTTATGATACAAGCAACAAACACTCCTGGACACCTGCCCGGTT





CTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACCCTTTCGGGTGC





GCAGCCTGAGGATGAGGCTGAGTATTACTGCTTGCTCTCCTATAGTGG





TTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCA





AGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTC





AAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCG





GGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGC





GGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC





GCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1647


921

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAATAGTTT





CTACTGGAACTGGATCCGGCAGCCCCCCGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTACAGTGGGAACACCAAGTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAACAGCCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGGCGCTCAAAAAGCAGGAGCTGGTATCGTTGCAGGCTTTTGATAT





CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGG





GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGG





GCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG





GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC





CTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTCTGGGA
1648




GACGGGGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA





TTTAAGTTGGTATCAGCAGAAACCCGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAATACCCCCG





TGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGCAGATCGGAAGAGC






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1649


1063

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGATATATCTATTACAGTGGGAGCACCAAGTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGACCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGAATCTATGATAGTAGTGGTTATTACCATCCCGTCTTTGACTAC





TGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGG





CCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGG





CACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG





TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC





TTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1650




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGACATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1651


1224

CTCAGTGAGGGTTTCCTGCAAGGCATCTGGATACACCTTCACCAGCTA





CTATATCTACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAGTAATCAACCCTAGTGGTGGTAGCACAAGCTACGCACAGAAG





TTCCAGGGCAGAGTCACCTTGACCAGGGACACGTCCACGAGCACAGT





CTACATGGACCTGAGCAGTCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGATCCTATAATGTGGGAGGTAGTAACTCGGGGGAGG





GGCAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTC





CTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTC





CAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG





ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG





ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1652




GAGGGTCACCATCCCCTGCACTGGGAGCAGCTTCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA





CTCCTCATCTTTGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAGGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGT





AGCCTGAGTGGTGTGGTATTCGGCGGAGGGACTACGCTGACCGTCCT





AGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTC





TGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTG





ACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGC





CCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAA





CAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCTGAGCAGT





GGAAGTCCCAC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1653


1271

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAGCAA





CTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGTTATTTATAGCGATGGTAACACATACTATGCAGACTCCGTGA





AGGGCAGATTCACCATCTCCAGAGACAATTCCAAGAACATGTTATAT





CTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG





TGCGAGAGACCCCGGCCAGGGGTATTGTAGTGGTGGTAGCTGCGCTC





CGTCCTATTCTCTTGACTACTGGGGCCAGGGAACCCTGGTCACTGTCT





CCTCAGGGAGTGCATCCGCCCCAACCCTTTTCCCCCTCGTCTCCTGTG





AGAATTCCCCGTCGGATACGAGCAGCGTG







LC-DNA
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAG
1654




ACAGCCAGCATCACCTGCTCTGGGGATAAATTGGGGGATAGATATGT





TTGTTGGTATCAGCAGAAGCCAGGTCAGTCCCCTGTGCTGGTCATCTA





TCAAGATACCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTC





CAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTA





TGGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCACTTGG





GTGTTCGGCGGAGGGACCAAGCTGACCGTCCTGGGTCAGCCCAAGGC





TGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGC





CAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAG





CCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGA





GTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGC





CAGCAGCTA






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGG
1655


1339

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAA





CTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGATATTTATAGCGGTGGTAGCACATACTACGCAGACTCCGTGA





AGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACGCTGTAT





CTTCAAATGAACAGCCTGAGAGCTGAGGACACGGCCGTGTATTACTG





TGCGAGAGATCGACGGGGATACAGCTATGGTTTGCACCACGGTATGG





ACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACC





AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCT





GGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA





ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC





ACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1656




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGACCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCTAACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1657


1345

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAG





TAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG





AGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCG





TCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTA





TTACTGTGCGAGACGAATCAGACGCCCCACCTCGGAAGTGGTTATTA





CTTATGTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCT





CAGCACCCACCAAGGCTCCGGATGTGTTCCCCATCATATCAGGGTGC





AGACACCCAAAGGATAACAGCCCTGTGGTCCTGGCATGCTTGATAAC





TGGGTACCACC







LC-DNA
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1658




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGC





TTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAG





CCTGAAGATTTTGCAACTTATTACTGTCAACAGTTTAATAGTTACCTC





ACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGC





ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG





AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGC





CAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCC





AGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCT





CAGC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGGTCCAGCCTGGGGG
1659


1378

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAA





CTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGTTATTTATAGCGGTGGTAGCACATACTACGCAGACTCCGTGA





AGGGCCGATTCACCATCTCCAGACACAATTCCAAGAACACGCTGTAT





CTTCAAATGAACAGCCTGAGAGCTGAGGACACGGCCGTGTATTACTG





TGCGAGAGAAGGATATTGTACTAATGGTGTATGCTATAGGCATGCTTT





TGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGGGAGTG





CATCCGCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTC





GGATACGAGCAGCGTG







LC-DNA
CAGACTGTGGTGACCCAGGAGCCATCGTTCTCAGTGTCCCCTGGAGG
1660




GACAGTCACACTCACTTGTGGCTTGAGCTCTGGCTCAGTCTCTACTAG





TTACTACCCCAGCTGGTACCAGCAGACCCCAGGCCAGGCTCCACGCA





CGCTCATCTACAGCACAAACACTCGCTCTTCTGGGGTCCCTGATCGCT





TCTCTGGCTCCATCCTTGGGAACAAAGCTGCCCTCACCATCACGGGGG





CCCAGGCAGATGATGAATCTGATTATTACTGTGTGCTGTATATGGGTA





GTGGCATTTCGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1661


1379

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGAGATTACTATCAACTCCCTATGGACGTCTGGGGCCAAGGGAC





CACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCC





CCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGG





GCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGG





AACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA





CAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1662




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA





ATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC





CTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





CCTGAGTGGTCGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG





GTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTG





AGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGAC





TTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCC





CGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1663


1384

GTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACCTTCAGTAGCTA





TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TTTCATACATTAGTAGTAGTAGTAGTATCATATACTACGCAGACTCTG





TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA





CTGTGCGAGAGATTTCCTCGACTATAGCAGGTCGTATTCGTACGGTAT





GGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCA





CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT





CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC





GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT





GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
TCCTATGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGACAG
1664




ACGGCCAGGATTACCTGTGGGGGAGACAACATTGGAAGTAAAAATGT





GCACTGGTACCAGCAGAAGCCCGGCCAGGCCCCTGTGCTGGTCGTCT





TTGATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCC





GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGA





TCACTATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTC





AGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGG





AGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCT





ACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTC





AAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACA





AGTACGCGGCCAGCAGCTACC






S24-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCAGGGCG
1665


1476

GTCCCTGAGACTCTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTAT





GCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGT





AGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACACAATACGCCG





CCTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGC





ATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGT





GTATTACTGTACTAGAGTACGATATTGTACTAATGGTGTATGCTATGG





CTACCACTTTGACTACTGGGGCCAGGGAACCGTGGTCACCGTCTCCTC





AGCCTCCACC







LC-DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
1666




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAA





CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG





TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGTGG





ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGC





ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG





AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGC





CAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1667


1564

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGTCAGCCCCCAGGGAAGGGGCTGGAGTGGA





TTGGCTATGTCTATTACAGTGGGAACACCAAATACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGGGCTCTGTGACCGCCGCGGACACGGCCGTTTATTATTGT





GCGAGACATTCGAGGATAGAAGTGGCTGGTACTCTAGACTTTGACTA





CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGG





GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGG





GCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG





GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC





CTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1668




GACCGGGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGAAGCTA





TTTAAATTGGTATCAGCAGAAACGAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTC





CGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGC






S24-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1669


1636

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAACTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCCGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGGAGATTGTACTAATGGTGTATGCCATCCCCTTCTAA





TTTATTATGATAGTAGTGGTTTAGACTACTGGGGCCAGGGAACCCTGG





TCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG





CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGC





CTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC





AGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTC





CTCAGGA







LC-DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1670




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTA





CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG





CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCT





CCGATCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA





ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA





CAGCCTC






S24-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1671


1002

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCACTAGCTA





TGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATCATATGATGGAGGCAGTAAATACTACGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATT





ACTGTGCGAGGACTACACCGGGTATAACAGCAGCTGGAACAGGGACC





CTAGGGAGATACTACTACTACGGTATGGACGTCTGGGGCCAAGGGAC





CACGGTCACCGTCTCCTCAGGGAGTGCATCCGCCCCAACCCTTTTCCC





CCTCGTCTCCTGTGAGAATTCCCCGTCGGATACGAGCAGCGTG







LC-DNA
GCCATCCAGTTGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1672




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGCAGTGC





TTTAGCCTGGTATCAGCAGACACCAGGGAAAGCTCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCGTCAAGGTTCAGCG





GCAGTGGATCTGGGACAGATTTCTCTCTCACCATCGGCAGCCTGCAGC





CTGAAGATTTTGCAAGTTATTACTGTCAACAGTTTAATAGTTACCCTC





TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC





CCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC





CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA






S24-
HC-DNA
CAGGTCCAACTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1673


1301

CTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACACCCTCATTGAATT





ATCCATGCACTGGGTGCGACAGGCTCCTGGAAAAGGGCTTGAGTGGA





TGGGAGGTTTTGATCCTGAAGATGGTGAAACAATCTACGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCGAGGACACATCTACAGACACAGC





CTACATGGCGCTGAGCAGCCTGACATCTGAGGACACGGCCGTGTATT





ACTGTGCAACAGCCTACGCGTATTACTATGCTTCGGGGGGTTATTATA





CCCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCT





CCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA





CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC





CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG





CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGGCAGGGCTGACTCAGCCACCCTCGGTGTCCAAGGGCTTGAGACA
1674




GACCGCCACACTCACCTGCACTGGGAGCAGCAACAATGTTGGCAACC





AAGGAGCAGCTTGGTTGCAGCAGCACCAGGGCCACCCTCCCAAACTC





CTATCCTACAGGAATAACAACCGGCCCTCAGGGATCTCAGAGAGATT





CTCTGCATCCAGGTCAGGAAACACAGCCTCCCTGACCATTACTGGACT





CCAGCCTGAGGACGAGGCAGACTATTACTGCTCAGCATGGGACAGCA





GCCTCTCTAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTA






S24-
HC-DNA
CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACA
1675


223

GACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCACTCAACACTAG





TGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG





AGTGGCTTGCACTCATTTATTGGGATGATGATAAGCGCTACAGCCCAT





CTCTGAAGAGCAGGCTCACCATCACCAAGGACACCTCCAAAAACCAG





GTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACATA





TTACTGTGCACACCATACGATTGTTCCAATTTTTGACTACTGGGGCCA





GGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATCCGCCCCAACCCT





TTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGATACGAGCAGCGT





G







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1676




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAACTCATATACAAGCA





GCAGCACTCTCGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCC






S24-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1677


461

GACCCTGTCCCTCACGTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCCGGGAAGGGACTGGAGTGGA





TTGGGAATATCTATAACAGTGGGAGCACCAACTACAACCCCTCCCTC





AAGAGTCGACTCACCATATCAGTTGACACGTCCAAGAACCACTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGAGGAGGACTAGAGCACGACGGTGACTACGTCTACTACTACGG





TATGGACGTCTGGGGCCAAGGGACCACGATCACCGTCTCCTCAGCCT





CCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA





CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC





CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG





CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
TCCTATGAGCTGACACAGCCACCCTCGGTGTCAGTGTCCCTAGGACAG
1678




ATGGCCAGGATCACCTGCTCTGGAGAAGCATTGCCAAAAAAATATGC





TTATTGGTACCAGCAGAAGCCAGGCCAGTTCCCTATACTGGTGATATA





TAAAGACAGCGAGAGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAGCTCAGGGACAATAGTCACATTGACCATCAGTGGAGTCCAGGCA





GAAGACGAGGCTGACTATTACTGTCTATCAGAAGACAGCAGTGGTAC





TTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCA





AGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTC





AAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCG





GGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGC





GGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC





GCGGCCAGCAGCTA






S24-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1679


511

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATT





ACTGTGCGAAATATACGTCAACGGTAACTACGAACTACTACTACGGT





ATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCACC





CACCAAGGCTCCGGATGTGTTCCCCATCATATCAGGGTGCAGACACC





CAAAGGATAACAGCCCTGTGGTCCTGGCATGCTTGATAACTGGGTAC





CACC







LC-DNA
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAG
1680




ACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGATAAATATGC





TTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTA





TCAAGATAGCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCT





ATGGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCACTGT





GGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGG





CTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAG





CCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGA





GCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGG





AGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCG





GCCAGCAGCTACC






S24-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1681


788

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGGACGTTCCCCAGGTGGGGGCCACTACTACGGTATG





GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGGAGTGC





ATCCGCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCG





GATACGAGCAGCGTG







LC-DNA
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAG
1682




ACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGATAAATATGC





TTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTA





TCAAGATAGCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCT





ATGGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGCAGCTCTGT





GGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGG





CTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAG





CCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGA





GCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGG





AGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCG





GCCAGCAGCTA






S24-
HC-DNA
CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACA
1683


821

GACCCTCACACTGACCTGCACCTTCTCTGGGCTCTCACTCAGCAGTAG





TGGAATGTGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG





AGTGGCTTGCACGCATTGATTGGGATGATGATAAATACTACAGCACA





TCTCTGAAGACCAGGCTCACCATCTCCAAGGACACCTCCAAAAATCA





GGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACGT





ATTACTGTGCACGGATATGTACTATGGTTCGGGGACTCCATGATGCTT





TTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGGGAGT





GCATCCGCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGT





CGGATACGAGCAGCGTG







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1684




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGC





GGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCA





GCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTC





GTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGG





CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT





CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG





AGGCCAAAGTACAGTGGAAGGTGGATAACGC






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1685


67

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTACCACCT





ACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





GTGGGGATCATCTATCCTGATGACTCTGATACCAGATACAGCCCGTCC





TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCGGTACCGC





CTACCTGCAGTGGAGTAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGGGGCCAGTATTACGATTTTTGGAGCGGAGCCGGAGGT





GTGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTC





CACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCAC





CTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCC





CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC





GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1686




GAGGGTCACCATCTCTTGCACTGGGAGCAGGTCCAACATCGGGGCAG





GTTATGATGTACAGTGGTACCAGCAGGTTCCAGGAACAGCCCCCAAA





CTCCTCATCTCTGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC





AGCCTGAGTGGTCTGAGGGTATTCGGCGGAGGGACCAAGCTGACCGT





CCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTC





CTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAA





GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGC





AGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAG





CAACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGC





AGTGGAAGTCCCAC






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1687


69

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGCTTTACCAGCT





ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCC





TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCACTACCGCC





TACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATTA





CTGTGCGAGGACCCAGACTACGAACTGGTTCGACTCCTGGGGCCAGG





GAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCT





TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCC





CTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC





GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTG





TCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGTATCTGTAGGA
1688




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTGTTAGTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATTAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTTCTAC





ACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGC





ACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGG





AACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGC





CAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCC





AGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCT





CAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGGG
1689


94

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGACATTTACACGGTATGATGGAAGTAATAAGTTCTATGCAGACTCCG





TGAAGGGCCGATTCTCCATCTCCAGAGACAATTCCAAGAACACGTTG





TATCTGCAAATGAATAGTCTGAGAGCTGAGGACACGGCTGTATACTA





CTGCGCGAAAGAAAGTCGTGTGGCGTTTGGGGGAGCTATCGCCATCT





ACTACTTCGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTC





TCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGC





TCCAGGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA





GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCC





TGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
1690




GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGT





AATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC





TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC





TGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAA





TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA





GCTCTACAAACTCCTCAGTACACTTTTGGCCAGGGGACCAAGCTGGA





GATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATC





TGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAA





TAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACG





CCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGC





AAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGC





AGACTACGAGAA






S144-
HC-DNA
GAGGTGCAGTTATTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1691


113

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAACTA





TGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGCTATTCGTAATAGTGGTAGTAGCACATACTATGCTGACTCCG





TGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACTCGGCCGTATATTA





CTGTGCGAAAGTAGGGGGGACAGCAGCTGGTCATCCGTTTTATGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGACTC







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1692




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTGACCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATTAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGACTTACAGTGCCCCCA





CTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCA





CCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGA





ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCC





AAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCA





GGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC





AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1693


175

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGTCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGGCACAAACTTTGCACAGAGG





TTTCAGGGCAGGGTCTCCATGACCAGGGACACCTCCATCAGCACAGC





CTACATGGAACTGAGCAGCCTGAGATCTGACGACACGGCCGTATATT





ACTGTGCGAGAGGCGCAAAATTCGAGCACCTCCCTTTTGATATCTGGG





GCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCA





TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACA





GCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGAC





GGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCC





CGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTATGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1694




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA





ATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC





CTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





ACGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGC





CCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGC





TTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACC





CGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAG





GCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGT





ACGCGGCCAGCAGCTA






S144-
HC-DNA
CAGGTGCAACTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1695


208

CTCAGTGAAGGTCTCCTGCAAGTCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAATAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAACTGAGCAGGCTGAGATCTGACGACACGGCCGTATATT





ACTGTGCGAGAGGGGCCCGAGGTGGCGCGGGGTGCAGTGGCTGGTCA





TGTTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCC





TCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC





ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT





CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCG





GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
1696




TCAGTCACTATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTAT





AAGTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGACGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGATGAGGGTGATTATTACTGCTGCTCATATGCAGGCA





CCTACAGTTTGGTATTCGGCGGAGGGACCAAGGTGACCGTGACCGTC





CTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCC





TCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAG





TGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCA





GCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGC





AACAACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCA





GTGGAAGTCCCACA






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCGGGGG
1697


339

GGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACT





ATACCATGAACTGGGTCCGACAGGCTCCAGGGAAGGGACTGGAGTGG





GTCTCATCCATTACTAGAAGTAGTACTTACATCTACTACGCAGACTCA





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTCTATT





ACTGTGCGAGAGACCCCTATTACGATATTTTGACTGGTTATTGGAACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1698




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGTCTCCCAGGCTCCT





CATTTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAACAGACTG





GAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATCGTACCTCA





CCTCGAGGCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAAC





TGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTT





GAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCC





CAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGG





GTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCAC





CTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA





A






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1699


359

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTA





TGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCATCTATTAGAGGTAGTGGTGGTAGCACATACTACGCAGACTCCG





TGAAGGGCCGGTTCACCATCTCCAGAGACAACTCCAAGTACACGTTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTA





CTGTGCGAAAATAACTGGAGCCGTCGGGGGGGAGAACTGGTTCGACC





CCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1700




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAATTTACTACTGTCAACAGACTTCCCGTACCCCGC





TCACTTTCGGCGGAGGGACCAAGGTGGAGGTCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC





CCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC





CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
GAGGTGCGCCTGGTGCAGTCTGGGGGAGGCTTGGTAAAGCCCGGGGG
1701


460

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGCACCGC





CTGGGTGAGGTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGCG





TTGGCCGAATCAAAAGTAAAAATGACGGTGACAGAGCAGAGTACGCT





GCACCCGCGAGAGGCAGATTCATCATCTCAAGAGATGATGCAGAAAA





CATTCTGTATTTACAAATGAACAACCTGAAAACCGAGGACACAGCCT





TTTATTACTGTACCACGGATCAAGGAAATAGTAGTGCCTTCTACAGTG





CTGACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCATCCC





CGACCAGCCCCAAGGTCTTCCCGCTGAGCCTCGACAGCACCCCCCAA





GATGGGAACGTGGTCGTCGCATGCCTGGTCCAGGGCTTCTTCCCCCAG





GAGCCACTCAGTGTGACCTGGAGCGAAAGCGGACAGAACGTGACCGC





CAGAAACTTCCC







LC-DNA
GACATCCAGATGACCCAGTCTCCATCTGCCATGTCTGCATCTGTAGGA
1702




GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGACATTAACACCTT





TTTAACGTGGTTTCAGCAGAAACCAGGAAAAGTCCCTCAGCGCCTGA





TCTTTGCTGCATATCGTTTGCAAAGTGGGGTCCCTTCAAGGTTCAGTG





GCAGTGGATCTGGGACAGAATTCACTCTCACAATCAACAGCCTGCAG





CCTGAAGATGTTGCGACTTATTATTGTCTACACCATAAAACTTATCCG





TACACTTTTGGCCAGGGGACCAAACTGGAGATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1703


466

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAGGTTTACCAGAT





ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCTTGGTGACTCTGAAACCAGATACAGTCCGTCC





TTCCAAGGCCAGGTCACCATCTCAGCCGACAACTCCATCAGCACCGC





CTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGAAGTTCCAATTGGAATTACGGTGACTACTGGGGCCAG





GGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCGGTC





TTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCTGGGGGCACAGCGGC





CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC





GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTG





TCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTGGGA
1704




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTACTAGTTG





GTTGGCCTGGTATCAGCAGAAATCAGGGAAAGCCCCTAAACTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATCCT





TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1705


469

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTGA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGATATATGTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGT





GCGAGATGGGATAGGGGAAGCAGGCCTCACTACTACTACTATGGTAT





GGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCA





CCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT





CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC





GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT





GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGA
1706




GAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGT





AATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTC





TCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCC





TGACAGGTTCAGTGGCAGTGCATCAGGCACAGATTTTACACTGAAAA





TCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA





GCTCTACAAGCTTTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA





CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAG





CAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC





TATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCA





ATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC





AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTA





CGAGA






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1707


509

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGCATACACCTTTACCACCT





ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCC





TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGC





CTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGATTATTATTGGTGGCTGGTCCCTTTGACTACTGGGGCC





AGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCG





GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCG





GCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGT





GTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGG





CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG





TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATC





ACAAGCCCAGCAACACCAAGGTGGACA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1708




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATCCG





TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGC






S144-
HC-DNA
CAGGTGCAGCTGCTGCAGTCTGGGGCTGAAGTGAAGAAGCCTGGGGC
1709


516

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGGCACAAATTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGGCTGACATCTGACGACACGGCCGTGTATT





ACTGTGCGACCAAAACTGGAATTGATCGCTACTACTACTACTACATGG





ACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCAGCCTCCACC





AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCT





GGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA





ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC





ACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGAGGCCCCAGGGCA
1710




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA





CTGCTCATCTATGGTAACATTAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAAC





AGCCTGAATGGTTCGGTGTTCGGCGGAGGGACCAAACTGACCGTCCT





ACGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTC





TGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTG





ACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGC





CCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAA





CAACAAGTACGCGGCCAGCAGCTA






S144-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1711


568

GACCCTGTCCCTCACCTGCAGTGTCTCTGGTGGCTCCATCAGTGATTA





CTACTGGAGCTGGATCCGGCAGCCCCCTGGGAAGGGACTGGAGTGGA





TTGGATATATCTATAACAGTGGGAGTACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGCAGACCCGTCCAAGAACCAGTTCTCC





CTGAAGTTGAGCTCTGTGACCGCCGCAGACACGGCCGTATATTACTGT





GCGAGACCTCACGGCGGTGACTACGCTTTTGATATTTGGGGCCAAGG





GACAATGGTCACCGTCTCTTCAGCATCCCCGACCAGCCCCAAGGTCTT





CCCGCTGAGCCTCGACAGCACCCCCCAAGATGGGAACGTGGTCGTCG





CATGCCTGGTCCAGGGCTTCTTCCCCCAGGAGCCACTCAGTGTGACCT





GGAGCGAAAGCGGACAGAACGTGACCGCCAGAAACTTCCC







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1712




GAAAGAGCCACCCTCTCATGTAGGGCCAGTCAGAGTGTTAGCAGCAA





CTTCCTAGCCTGGTACCAGCAGAAACCTGGCCAGCCTCCCAGGCTCCT





CATCTATGGTGCATCCGTCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCACCAGACTG





GAGCCTGAAGATTTTGCAGTATATTACTGTCAGCAGTATGGTAGCTTA





CCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA





ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA





CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA






S144-
HC-DNA
CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGATGAAGCCTGGGTC
1713


576

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTA





TAGTATCACCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAAGGATCATCCCTATCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGGGTATAGTGGGAGCCCCTCGAATTTAGACGGTATG





GACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCCAC





CAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTC





TGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCG





AACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG





CACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGA
1714




CAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTGGTT





GGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCT





ATGATGCCTCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGC





AGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCC





TGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCTCC





GATCACCTTCGGCCAAGGGACACGACTCGAGATTAAACGAACTGTGG





CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT





CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG





AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC





TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA





GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1715


588

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAG





TAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG





AGTGGATTGGGAGTATCTATTATAGTGGGAGCACCTACTACAACCCG





TCCCTCAAGAGTCGATTCACCATATCCGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTA





TTACTGTGCGGCCTATCAGAGGAAACTAGGATATTGTCGTGGTAATA





GCTGCTTTTCCTGCTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCG





TCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCT





CCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC





AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGC





CCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG





A







LC-DNA
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAG
1716




ACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGATAAATATGC





TTGCTGGTATCAGCAAAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTA





TCAAGATACCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTC





CAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTA





TGGATGAGGCTGACTATTACTGTCAGGCGTGGGACAGTAGCACTGTG





TTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAGGC





TGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTTCAAGC





CAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAG





CCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCAAGGCGGGA





GTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGC





CAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACA






S144-
HC-DNA
GAGGTGCACCTGGTGCAGTCTGGAGCAGAGGTGAAACAGCCCGGGG
1717


628

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACAACTTTGCCACCT





ACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCC





TTCCAAGGCCAGGTCATCATCTCAGCCGACAAGTCCATCGGCACCGC





CTTCCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGGCGGGGGTATAGTAGCTCTAACTATCGCGTTGACGAA





TACTATTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCAC





CGTCTCCTCAGCATCCCCGACCAGCCCCAAGGTCTTCCCGCTGAGCCT





CTGCAGCACCCAGCCAGATGGGAACGTGGTCATCGCCTGCCTGGTCC





AGGGCTTCTTCCCCCAGGAGCCACTCAGTGTGACCTGGAGCGAAAGC





GGACAGGGCGTGACCGCCAGAAACTTCCCC







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAATGTCTGGGGCCCCAGGGCA
1718




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAGCAGCCCCCAAA





CTCCTCATCTATGGTGACACCAGTCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGACACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTTTGACAGA





AGTCTGAGTGGTCTCGTGATTTTCGGCGGAGGGACCAGGCTGACCGT





CCTCGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTC





CTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAA





GTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGC





AGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAG





CAACAACAAGTACGCGGCCAGCAGCTAAGATCGGAAGAGC






S144-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1719


740

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGACACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGATTGGGTAAAGGAATGGCAGCAGCCCGTACTGTCTTT





GACTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACC





AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCT





GGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA





ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC





ACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAGTTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1720




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCG





TCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTC





AGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACT





GGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTTTGGTAGCTC





TCCCACCTTCGGCCGAGGGACACGACTGGAGATTAAACGAACTGTGG





CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT





CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG





AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC





TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA





GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCACCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1721


741

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGAACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAACTGAGCAGGCTGAGATCTGACGACGCGGCCGTGTATT





ACTGTGCGAGAGCTGAGAGGTATAGCAGCAGCTGGTACAATCTTTAC





TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAA





GGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGG





GGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC





CGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC





ACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1722




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA





ATACTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAGCTC





CTCATCTATAGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





CCTGAATGGTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG





GTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTG





AGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGAC





TTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCC





CGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG





GAAGTCCCACA






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1723


803

AGTCTCTGAAGATCTCCTGTAAGGGTTCTAGATACAGCTTTACCAGAT





ACTGGATCGCCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCCTGGTGACTCTGATACCAGATACAGCCCGTCC





TTCCAAGGCCCGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGC





CTACCTGCAGTGGAGCAGCCTGAAGGCCTCGGACACCGCCATATATT





ACTGTGCGAGACTCCCGAACAGTAACTACGTTGACTACTGGGGCCAG





GGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTC





TTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGC





CCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTC





GTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTG





TCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC





CCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCAC





AAGCCCAGCAACACCAAGGTGGACAA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1724




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGTTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATATTTACCCG





TACACTTTTGGCCAGGGGACCAAGCTGGACATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGGG
1725


843

GTCCGTAAGACTCTCCTGTGCAGCGTCTGGATTCGACTTCACTAATAA





TGGCATGTATTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCATTTATACGGTATGATGGAAATAAACAAGACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAACACTCT





GTATCTGCAAATGAGCAGCCTTAGACCTGAGGACACGGCTGTATATT





ACTGTGCGAAAGGTGTTTATACTGAAAATTACGGCTGGGGCCAGGGA





ACCCTGGTCACCGTCTCCTCAGGGACCACGGTCACCGTCTCCTCAGCC





TCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGC





ACCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT





CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCG





GCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCC





TCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGGCACCCAGACC





TACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1726




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTGTTACCAGCAG





GTACTTAGCCTGGTATCAGCAGAAGCCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCACCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAATTCA





CCTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAAC





TGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTT





GAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCC





CAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGG





GTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCAC





CTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA





A






S144-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1727


877

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTACCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATCATATGATGGAAGTAATAAATATTATGCAGACTCCG





TGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTG





TATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTA





CTGTGCGAAACAGCAAGGCACCTATTGCAGTGGTGGTAACTGCTACT





CGGGATATTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCT





CAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCA





AGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC





TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC





CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTA





CTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCA





GACCTACATCTGCA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1728




GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTACGATGCATCGAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT





GGAAGTGGATCTGGGACAGATTTTAGTTTTAGTATCAGCAGCCTGCA





GCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATGTCCC





TCTTACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGG





CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT





CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG





AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC





TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA





GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
1729


952

CTCAGTGAAGGTCTCCTGCACGGCTTCTGGTTACACCGTTACCAGTTA





TGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAGCACTTACAATGGTAACACAAACTATGCACAGAAG





CTCCAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGC





CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGAATACAGCTATGGTTACCGACTGGCCTACTTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATCC





GCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGAT





ACGAGCAGCGTGGCCGTTGGCTGCCTCGCACAGGACTTCCTTCCCGAC





TCCATCACTTTCTCCTGGAAATACAAGAACAACTCTGACATCAGCAGC





ACCCGGGGCTTCCCATCAGTCCTGAGAGGGGGCAAGTACGCAGCCAC





CTCACAGGTGCTGCTGCCTTCCAAGGACGTCATG







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1730




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTAAACAG





CTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AGTATTATAGTACTCCTCAGACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT





GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT





AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC





CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCA





AGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA





GACTACGAGA






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1731


971

GTCCCTGAGAATCTCTTGTTCAGCCTCTGGATTCACCTTCAGTAGATA





TGCTATGCACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAATATG





TTTCAGCTATTAGGAGTAATGGGGGTAGCACATACTACGCAGACTCC





GTGAGGGGCAGATTCACCATCTCCAGAGACAATTCCAGGAACACGCT





GTATCTTCAAATGAGCAGTCTGAGAGCTGAGGACACGGCTGTGTATT





ACTGTGTGATAATAAACAATTTAGCAGCAGCTGGTACCCGTTTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1732




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAG





CTCCAACAATAAGAACTTCTTAACTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATATTATACTACTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT





GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT





AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC





CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCA





AGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA





GACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTACAGCAGTGGGGCGCAGGGCTGTTGAAGCCTTCGGA
1733


1036

GACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTA





CTTCTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGA





TTGGGGAAATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTC





AAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTC





CCTGAAGCTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTG





TGCGAGAGCGCCCTATTACGATTTCTTGCGGGAAGGAAACTGGTTCG





ACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACC





AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCT





GGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA





ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC





ACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCA





GCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT





GCAACGTGAATCACAAGCCCAGC







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1734




GAGAGGGCCACCATCAACTGCAACTCCAGCCAGAGTGTTTTATACAG





CTCCATCAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGCAC





AGCCTCCTAAGGTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATATTATAGGACTCCCTGGACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT





GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT





AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC





CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCA





AGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA





GACTACGAGAA






S144-
HC-DNA
CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1735


1079

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGACACCTTCGGCAGCTA





TAGTATCACCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGA





TGGGAAGGATCATCCCTGTCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGGGAGGGGGTTGTAGTGGTGGTAACTGCTACTCGTGGTAC





AACTGGTTCGACCCCTGGGGCCAGGGATCCCTGGTCACCGTCTCCTCA





GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG





AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTA





CTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCA





GCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1736




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAA





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGAGAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGGTCA





CCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA





ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACTTAC





AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1737


1299

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGGTATATCAATTACAGGGGGATCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACATGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCCGTGTATTCCTGT





GCGAGACTAGCAGTGGCTAGTCGAGGGACCGTTGACTACTGGGGCCA





GGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGT





CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGG





CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGT





CGTGGAACTCAGGCGCTCTGACCAGCGGCGTGCACACCTTCCCAGCT





GTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTG





CCCTCCAGCAACTTCGGCACCCAGACCTACACCTGCAACGTAGATCA





CAAGCCCAGCAACACCAAGGTGGAC







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1738




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTA





ATTATGTATACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC





CTCATCTATAGGAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





CCTGAGTGTTAATGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCC





TAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCT





CTGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGT





GACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAG





CCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCA





ACAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCTGAGCAG





TGGAAGTCCCACA






S144-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGACTGAGGTGAAGAAGCCTGGGGC
1739


1339

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTACCAGTGGTGGCACAAACTATCCACAGAAG





TTTCAGGGCAGTGTCACCATGACCAGGGACACGTCCCTCAGCACAGT





CTACATGGAACTGAGCGGGCTGAGATCTGACGACACGGCCGTCTATT





ATTGTGCGAGAGAGAGGGTTACTCTGATTCAGGGAAAGAACCACTAC





TACATGGACGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCAGC





CTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAG





CACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACT





TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC





GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1740




TCGATCACCATCTCCTGCACTGGAACCAACAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAGACT





CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTCTCGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTG





GAAGTCCCACA






S144-
HC-DNA
CAGGTCCAGCTTGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1741


1406

CTCAGTGAAGGTTTCCTGCAAGGCTTCTGGATATACCTTCACTACCTA





TGCTATGCATTGGGTGCGCCAGGCCCCCGGACAAAGGCTTGAGTGGA





TGGGATGGATCAACGCTGGCAATGGTAACACAAAATATTCACAGAAC





TTCCAGGGCAGAGTCACCATTACCAGGGACACATCCGCGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAAGACACGGCTGTGTATT





ACTGTGCGAGTCTCGTGGGTGGGGATAGCAGCAGCTGGTATGACTAC





ATGGACGTCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCAGCCTC





CACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCA





CCTCCGAGAGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC





CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGG





CGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCT





CAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCGG







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1742




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATCCG





TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1743


1407

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTA





TACTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGCCTTGAGTGGA





TGGGAAGGATCATCCCTGTCCGTGATATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGGACAGC





CTACATGGAGGTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGGCAACGGAGCTCCGCTCGGATGGTCTTGACATCTGGGGC





CAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATC





GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC





GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG





TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG





GCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1744




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCGTCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAATTATTCT





CCCATCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA





ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA





CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGC
1745


1569

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACACCTTTTCCAACTA





CGGTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAGCGCTTACAATGGTAACACTAAGTATCCACAAAAG





CTCCAGGGCAGAGTCACCATGAGCACAGACACATCCACGAGCACAGC





CTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGAGACGCGGTACGGTATGGACGTCTGGGGCCAAGGG





ACCACGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTC





CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCT





GGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGT





GGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC





CTACAGTCCTCAGGA







LC-DNA
CAGCCTGTGCTGACTCAGCCACCTTCTGCATCAGCCTCCCTGGGAGCC
1746




TCGGTCACACTCACCTGCACCCTGAGCAGCGGCTACAGTAATTATAA





AGTGGACTGGTACCAGCAGAGACCAGGGAAGGGCCCCCAGTTTGTGA





TGCGAGTGGGCACTGGTGGGATTGTGGGATCCAAGGGGGATGGCATC





CCTGATCGCTTCTCAGTCTTGGGCTCAGGCCTGAATCGGTACCTGACC





ATCAAGAACATCCAGGAAGAGGATGAGAGTGACTACCACTGTGGGGC





AGACCATGGCAGTGGGAGCAACTTCGTTCGGGTGTTCGGCGGAGGGA





CCAAGCTGACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACTC





TGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTGG





TGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGA





AGGCAGATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACC





CTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGCTACCTGAGCC





TGACGCCTGAGCAGTGGAAGTCCCAC






S144-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGG
1747


1641

AGTCTCTGAAGATCTCCTGTAAGGGTTCTGGATACACCTTTACCAGCT





ACTGGATCGGCTGGGTGCGCCAGATGCCCGGGAAAGGCCTGGAGTGG





ATGGGGATCATCTATCTTGGTGACTCTGATACGAGATACAGCCCGTCC





TTCCAAGGCCAGGTCACCATCTCAGCCGACAAGTCCATCAGCACCGC





CTACCTGCAGTGGAACAGCCTGAAGGCCTCGGACACCGCCATGTATT





ACTGTGCGAGACAGGTTACCGGAACTACGAGCTGGTTCGACCCCTGG





GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCC





ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCAC





AGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGA





CGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTC





CCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1748




GAGAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTAGGTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTTA





TCTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATCACTGCCACCAGTATAGTACTTATTCG





CTCACTTTCGGCGGAGGGACCAAGGTGGACATCAAACGAACTGTGGC





TGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATC





TGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGA





GGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACT





CCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAG





CCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGACGTGGTCCAGCCTGGGGG
1749


1827

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGAATTACCTTTAGTAACTA





TTGGATGACCTGGGTCCGCCAGGCTCCAGGGAAAGGGCTGGAGTGGG





TGGCCACCATAAAGAAGGATGGAGGGGAGCAGTACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAGGAATTCACT





GTATCTACAAATAAACAGCCTGAGGGCCGAGGATACGGCTGTCTATT





ACTGTGCGAGGGGTGGATCTAGCAGCAGCTACTACTGGATCTACTGG





GGCCAGGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATCCGCCCC





AACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGATACGAG





CAGCGTG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1750




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAACAG





CTACTTAGTCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCACCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCGTGGACGTTCGGCCAAGGGACCACGGTGGAAATCAAACGAACTGT





GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA





ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAG





AGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTA





ACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA





CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGG
1751


1848

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCGTCCATTAGTAGTAGTAGTAGTTACATATACTACGCAGACTCAG





TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAATTCACTG





TATCTGCAACTGAACAGCCTGAGAGCCGAGGACACGGCTGTGTACTA





CTGTGCGAGAGATCGGGACCAGTTGATATTCTCGGCCGCTTTTGATAT





CTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGG





GCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGG





GCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG





GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACAC





CTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1752




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGAACATA





ATTATGTATTCTGGTACCAGCAACTCCCAGGAACGGCCCCCAAACTCC





TCATCTATAGTAATAATCACCGGCCCTCAGGGGTCCCTGACCGATTCT





CTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCC





GGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGCCAGC





CTGAGTGGTCCTGTGGTATTCGCCGGAGGGACCAAGCTGACCGTCCT





AGGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTC





TGAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTG





ACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGC





CCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAA





CAACAAGTACGCGGCCAGCAGCTA






S144-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1753


1850

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTA





TGCCATGAGTTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCG





TGAAGGGCCGGTTCACCATCTCCAGAGCCAATTCCAAGAACACGCTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTA





CTGTGCGAAAGGCCCGCGCTTTAGTCGCGACTACTTTGACTACTGGGG





CCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCAT





CGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAG





CGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG





GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCC





GGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1754




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTACTAGCTG





GTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGATGCCTCCAATTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAATTATCTG





GGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGG





CTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT





CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAG





AGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC





TCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACA





GCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S144-
HC-DNA
CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1755


2234

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGAT





ATACTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGG





ATGGGAAGGATCATCCCTATACTTGGTACAGCAAACTACGCACAGAA





TTTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAG





CCTACATGGAGCTGAGTAGCCTGAGATCTGAGGACACGGCCGTGTAT





TACTGTGCGAGACACGGATACAGCTATGGTCCCTTTGACTACTGGGGC





CAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATC





GGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGC





GGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGG





TGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCG





GCTGTCCTACAGTCCTCAGGAG







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGACTGTGTCTCTGGGC
1756




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAG





CTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGCTCTGGGACAGATTTCACTCTCA





CCGTCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATATTATAGTACTCCTGGAACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCT





GATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT





AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGC





CCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCA





AGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA





GACTACGAGAA






S564-
HC-DNA
CAGGTGCGGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1757


105

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG





TAGTTACTACTGGAGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGG





AGTGGATTGGGCGTTTCCATACCAGTGGGAGCACCAACTACAATCCC





TCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCCGTGTA





TTACTGTGCGAGAGATTTAAAGGGAAAGACGTGGATACAGACCCCCT





TTGACTACTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCAGCCTCCA





CCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT





CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC





GAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGT





GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1758




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGCTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCACCTTCTTCGGAACTGGGACCACGGTCACCGTCCTAGGTCAGCCCA





AGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCC





AAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCG





GGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGC





GGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC





GCGGCCAGCAGCTAC






S564-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1759


14

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGACTCACCTTTAGTAGCTA





TTGGATGAGCTGGGCCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TGGCCAATATAAAGAAAGATGGAAGTGAGAAATACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





GTATCTGCAAATGAACAGCCTGAGAGTCGAGGACACGGCTGTGTATT





ACTGTGCGAGTGAACCTCCCCACTACGGTGGTAACTCCGGGGCTGAA





TACTTCCAGCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCA





CCCACCAAGGCTCCGGATGTGTTCCCCATCATATCAGGGTGCAGACA





CCCAAAGGATAACAGCCCTGTGGTCCTGGCATGCTTGATAACTGGGT





ACCACCC







LC-DNA
TCCTATGTGCTGACTCAGCCACCCTCAGTGTCAGTGGCCCCAGGAAAG
1760




ACGGCCAGGATTACCTGTGGGGGAAACAACATTGGAAGTAAAAGTGT





GCACTGGTACCAGCAGAGGCCAGGCCAGGCCCCTGTACTGGTCATCT





ATTATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCT





CCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAGGCC





GGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGA





TCACCATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTCA





GCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGA





GCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTTCTA





CCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCGTCA





AGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAA





GTACGCGGCCAGCAGCTA






S564-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1761


68

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACATCTTCACCGGCTA





TTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGGCACTAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCACCACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCTTTTATT





ACTGTGCGAGAGTCAAGAGGTTTTCGATTTTTGGAGTGGAGCTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAG
1762




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT





CCAGGCTGAGGATGAGGCTGATTATTTCTGCAGCTCATATGCAGACA





GCAACAATTTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTGCCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTACC






S564-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1763


98

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCC





CTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCCGTGTATTACTGT





GCGAGACATCAATCGCGGTGGAATATAGTGGCTACGATGGACTTTGA





CTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAA





GGGCCCATCGGTCTTCCCCCTGG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1764




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTCGCAGCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGCGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCGGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCTCCG





TGGCGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTC





CCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC





CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGA






S564-
HC-DNA
CAGGTGCGGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1757


105

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG





TAGTTACTACTGGAGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGG





AGTGGATTGGGCGTTTCCATACCAGTGGGAGCACCAACTACAATCCC





TCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCCGTGTA





TTACTGTGCGAGAGATTTAAAGGGAAAGACGTGGATACAGACCCCCT





TTGACTACTGGGGCCAGGGAATCCTGGTCACCGTCTCCTCAGCCTCCA





CCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCT





CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC





GAACCGGTGACGGTGTCGTGGAACTCAGGCGCTCTGACCAGCGGCGT





GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1758




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGCTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCACCTTCTTCGGAACTGGGACCACGGTCACCGTCCTAGGTCAGCCCA





AGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCC





AAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCG





GGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGC





GGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC





GCGGCCAGCAGCTAC






S564-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1765


134

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAACACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTACGAGAGTCGGGAGGTTTTCGATTTTTGGAGTGGAGCTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAACCTCCCTCCGCGTCCGGGTCTCCTGGACAG
1766




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAGCAACACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAATAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT





CCAGGCTGACGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA





GCAACAATTTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTA






S564-
HC-DNA
CAGGTGCTCCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1767


138

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATCTGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTATCAGTGGTGGCACAAACTATGCACAGAAT





TTTCAGGACAGGGTCACCATGACCAGGGACACGTCCATCATCACAGC





CTACATGGAACTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGACTTGCCTATTATTATGATAGTAGTGCTTACCGGGGTG





CTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCT





CCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA





CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC





CCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG





CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1768




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTC





AGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGG





AGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCT





ACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTC





AAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACA





AGTACGCGGCCAGCAGCTA






S564-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1769


152

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTTACTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATGGTATGATGGAAGTAATAAACACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTACT





ACTGTGCGAAAAATGCGGCCCCCTATTGTAGTGGTGGTAGCTGCTAC





GGTACCTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC





TCAGCCTCCACCAAGGGCCCATCTGTCTTCCCCCTGGCACCCTCCTCC





AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA





CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA





CCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1770




GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAACAACTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT





GGGAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCA





GCCTGAAGATATTGCAACATATTACTGTCAACAGTATGACAATGTCCC





TCCGCACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTG





TGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA





AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCA





GAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGT





AACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCT





ACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAA






S564-
HC-DNA
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTC
1771


218

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTA





TGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGAGGGATCATCCCTATCTTTGGTACAGCAAAGTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGGAAAAGATGGCTACAATCCCTGGGGCGCTTTTGAT





ATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGGGAGTGCATC





CGCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGA





TACGAGCAGCGTG







LC-DNA
CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAG
1772




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGCAGGCA





GCAACAATTTCGGGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTA





GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCT





GAGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGA





CTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCC





CCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCTGAGCAGTG





GAAGTCCCAC






S564-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCCGGGGG
1773


249

GTCCCTGAGACTCTCCTGCGTAGCCTCTGGATTCACCTTCAGTGACTA





TGCTATGCACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAATATA





TTGCAGCTATTAGTAGCAATGGGGGTAGGACATATTATGCAGACTCT





GTGAAGGACAAATTCACCATCTCCAGAGACAATTCCAAGAACATCTT





GTATCTTCACATGGGCAGCCTGAGAGCGGAGGACACGGCTGTGTATT





TCTGTGCGAGAGATCCCCAGTCATGGGTGACTTCCACCACAGCCCATT





TCCAGCACTGGGGCCAGGGCACCCTGGTCACCGTCTCCTCAGCATCCC





CGACCAGCCCCAAGGTCTTCCCGCTGAGCCTCTGCAGCACCCAGCCA





GATGGGAACGTGGTCATCGCCTGCCTGGTCCAGGGCTTCTTCCCCCAG





GAGCCACTCAGTGTGACCTGGAGCGAAAGCGGACAGGGCGTGACCGC





CAGAAACTTCCC







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1774




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACATTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT





CATCATTTCTGATGTCTCTAATCGGCCCTCAGGGGTTTCTAGTCGCTTC





TCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGACTC





CAGACTGAGGACGAGGCTCATTATTATTGCAGCTCGTTTAGAAGTGG





CATCACTCTCGGGGTATTCGGCGGGGGGACCAAGCTGACCGTCCTAG





GTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTG





AGGAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGAC





TTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCC





CGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAAC





AACAAGTACGCGGCCAGCAGCTA






S564-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1775


265

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGTCAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGCCATAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGTCGGGAGGTTTTCGATTTTTGGAGTGGAGCTTGATA





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAG





GGCCCATCTGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG





GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC





GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA





CCTTCCCGGCTGTCCTACAGTCCTCAGGA







LC-DNA
CAGTCTGCCCTGACTCAGCCTCCCTCCGCGTCCGGGTCTCCTGGACAG
1776




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTTTGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCGTCTCTGGGCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCAGCTCATATGGAGGCA





GCAACAATTTGATATTCGGCGGAGGGACCAGGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCTGAGCAGTGGA





AGTCCCAC






S564-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1777


275

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGTAGTTA





CTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGA





TTGGGTATATCTATTACAGTGGGAGCACCAAGTACAACCCCTCCCTCA





AGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAAGCAGTTCTCC





CTGAAGTTGAGCTCTGTGACCGCCGCAGACACGGCCGTGTATTACTGT





GCGAGACATATAAAGATAGGAGTGGTCGGAGGCCTTACTTTTGACTT





CTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATCCG





CCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGATA





CGAGCAGCGTG







LC-DNA
GACATTCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTATAGGA
1778




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCACCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAACTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGGCAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCGC





TCACTTTCGGCGGAGGGACGAAGGTGGAGATCAAACGAACTGTGGCT





GCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT





GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAG





GCCAAAGTACAGTGGAAGGTGGATAACGCC






S564-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1779


287

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGGCTGAGATGTGACGACACGGCCGTGTATT





ACTGTGCGAGAGCCTCAACTCCGTATAGCAGTGGCTCCTGGGCGGAC





TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGGAGTGCATC





CGCCCCAACCCTTTTCCCCCTCGTCTCCTGTGAGAATTCCCCGTCGGA





TACGAGCAGCGTG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1780




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATGCAAGCA





GCAGCACTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT





CAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCGCCCTCCTCTGAG





GAGCTTCAAGCCAACAAGGCCACACTGGTGTGTCTCATAAGTGACTT





CTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCCG





TCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAA





CAAGTACGCGGCCAGCAGCTATCTGAGCCTGACGCC






S166-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGG
1781


32

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTA





CTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TTTCATACATTAGTATTAGTGATACGACCATATACTACGCAGACGCTG





TGCAGGGCCGATTCACCATGTCCAGGGACAACGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAAGGCCGAGGACACGGCCGTGTATTA





CTGTGCGAGAGCTAGCCCATATTGTGGTGGTGATTGCTCTTTCGGCAA





TGCTTTTGATATCTGGGGCCTAGGGACAATGGTCACCGTCTCTTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA
1782




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTTTTAGCTGG





TTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGAT





CTATGATGCCTCCAGTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTGG





ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC






S305-
HC-DNA
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGAAG
1783


223

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGAAACTT





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCATTTATATGGACTGCTGAAAGTGATAAATTCTATGCAGACTCCG





TGAAGGGCCGATTCACCGTCTCCAGAGACAATTCGAAGAACACGCTG





TATTTGGAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA





CTGTACGAAAGCGATGGACGTCTGGGGCAGAGGGACCACGGTCACCG





TCTCCTCAG







LC-DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1784




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCACCTC





CTTAGCCTGGTACCAACAGAAATGTGGCCAGGCTCCCCGGCTCCTCAT





CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG





CCTGAAGATTTTGCAGTTTATTACTGTCAACAGCGTGGCAACTGGCCC





TTCACTTTCGGCCCTGGGACCAGAGTGGATATCAAAC






S305-
HC-DNA
CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1785


399

CTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACACCCTCACTGAATT





ATCCATGCACTGGGTGCGACAGGCTCCTGGAAAAGGGCTTGAGTGGA





TGGGAGGTTTTGATCCTGAAGATGGTGAAACAATCTACGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCGAAGACACATCTACAGACACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCAACAGGGGGATTGGGTTGTTCTAATGGGGTATGCAACAAC





TGGTTCGACCCCTGGGGCCTGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
1786




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTACTAGCAA





CTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAACCTGCAG





TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT





CTGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC






S305-
HC-DNA
CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1787


1456

CTCAGTGAAGGTCTCCTGCAAGGTTTCCGGATACACCCTCACTGAATT





ATCCATGCACTGGGTGCGGCAGGCTCCTGGAAAAGGGCTTGAGTGGA





TGGGAGGTTTTGATCCTGAAGATGCTGAAACAATCTACGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCGAGGACACATCTACAGACACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCAACAGGGGGCTTTCCCGTCAATAGCCTTTACGATATTTTGA





CTGGTTACCTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCT





CAG







LC-DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
1788




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAATGTTAGCAGCAA





CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCACCAGGGCCACTGGTATCCCGGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAG





TCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGCCT





CACACTTTCGGCCCTGGGACCAAAGTGGATATCAAAC






R125-
HC-DNA
CAGGTGCAGATGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGGG
1789


306

GTCCCTGAGACTCTCCTGTGCGGTCTCTGGCTTCACCTTCAACAACTTT





GGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGT





GGCATTTATTTCATATGAAGGAAGTAAAAAGTCTTATGCAGACTCCGT





GAAGGGCCGATTCACCATCTCCAGAGACAGTTCCAAGAACACGTTGT





ATCTGCAAATGAACAGCCTGAGACCTGAGGACACGTCTGTCTATTACT





GTGCGAAAGAATTAGCGATATTCATGATCTATGCAGGTCGCTACGGTT





TGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCA







LC-DNA
GTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTC
1790




GATCACCATCTCCTGCACTGGAATCTACAGTGATGTTGATGATTATAC





TTCTGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCACACTCAT





TATTTATGATGTCACTAAGCGGCCCTCAGGGGTTTCCAATCGTTTCTC





TGCCTCCAACTCTGACAATACCGCCTCCCTGACAATCTCTGGGCTCCA





GGCTGAGGACGAGGCTGAGTATTACTGCTGCTCACGTGGAAGTGCCA





CCAATTCTTATGTCTTCGGAACCGGGACCAAGGTCACTGTCCTA






R125-
HC-DNA
CAAGTGCAGCTGCAGGAATCGGGCCCAGGACTGGTGAAGCCTTCGGA
1791


444

GACCCTGTCCCTCACCTGCAATGTCTCAGGTGGCTCCGTCAAATTTTT





CTATTGGAGTTGGATCCGGCAGCCCCCCGGGAAGGGACTGGAGTGGA





TTGGATATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCA





AGAGTCGAGTGACCATGTCAGTGGACTCGCCCAACAACCAATTCTCC





CTGAAACTGAGGTCTGTGACTGCTGCAGACACGGCCGTATATTATTGT





GCGAGAGTGGGGGGGGACTGTAGCAGTGGAATATGCCGAACTTATGA





CTACTATGCTATGGATGTCTGGGGCCAAGGGACCACGGTCACTGTCTC





CTCA







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCGCTGTCTGGGGCCCCAGGGCA
1792




GAGGGTCACCATCTCCTGCACTGGGAGCCGCTCCAACATCGGGGCTG





GCTATGCTGTCCACTGGTACCAGCAACTTCCAGGAACAGCCCCCAAA





CTCCTCATCTCCGAGAACACCAATGGGCCCTCAGGAGTCCCTGACCG





ATTCTCTGGGTCCAAGTCTGACTCCTCGGCCTCCCTGGCCATCACCGA





CCTCCAGGCTGCGGATGAGGCTGATTATTACTGCCAGTCATACGACG





GCAGCCTGAGCGGTTGGGTGTTCGGCGGGGGGACCAAACTGACCGTC





CT






R3-
HC-DNA
CAGGTCACCTTGAAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGA
1793


428

GACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACCCAGCAATGC





TAGAATGGGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG





AATGGCTTGCACACGTGTATTCGAATGACGAGAAATCGTACAGCACA





TCTCTGAAGAGGAGGCTCACCATCTCCAAGGACACCTCCAAACGGCA





GGTGGTCCTTATTATGACCAACTTGGACCCTGCGGACACAGGCACAT





ATTACTGTGCACGGGCTCAAGACCCCCGGATACGGTTCGGGGAATTA





TTACCCGTCTACTTTGACAACTGGGGCCAGGGAACCCTGGTCACCGTC





TCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATTTGTGGGA
1794




GACAGAGTTACCATCAGTTGCCGGGCAAGTCAGAGCATTGTCAGCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTTTT





GTATAGTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGG





CAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACC





TGAAGATTTTGCAACTTACTACTGTCAACAGGGTTACACTACCCCGTG





GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC






R478
HC-DNA
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACTGCCTGGGGG
1795


910-

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCAGCTTTAGCAGCTA



171

TGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGGTATTAGTGGTCGTGGTACTAGCACATACTACGCAGACTCCG





TGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTA





TTGTGCGAAAGATCGGGTCAGCTATGGTTCCCCTTACTACTTTGACTA





CTGGGGCCAGGGAACGCTGGTCACCGTCTCCTCAG







LC-DNA
GACATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1796




GAAAGAGCCACCCTCTCCTGCGGGGCCAGTCAGAGTGTTAGCAGCAA





CTACTTAGCCTGGTACCAGCAGGAACCTGGCCTGGCGCCCAGGCTCCT





CATCTATGATGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





TCCACCTTCGGCCAAGGGACACGACTGGAGATTAAAC






R478
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1797


910-

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTA



23

TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGCTCCTGACTACTGGGGCCAGGGAACCCTGGTCACC





GTCTCCTCAG







LC-DNA
GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1798




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGA





TTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGC





CTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCGT





ACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAAC






R478
HC-DNA
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1799


910-

GTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACCGTTAGTAACTA



25

TGGCCTGAGCTGGGTCCGCCAGGGTCCAGGGAAGGGGCTAGAGTGGG





TCGCAGCTATTAGTGGTAGTGGTGGTAGGACATACTATGCAGACTCC





GTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTTTCTGCAATTGAACAGCCTGAGAGCCGAGGACACGGCCGTATATT





ACTGTGCGAAAGGTCGAGATGAACTGGTGGTAGGTGCTACTCAGGAC





TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGG
1800




GACAGAGTCACCATCACTTGCCGGGCAAATCAGAACATTAGGAGCTA





TTTAAATTGGTATCAGCAGACACCAGGGAAAGCCCCTAAACTCCTGA





TCTATGCTACATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCAGTCTGCAA





CCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTATCCCA





TTCGATTTCGGCCCTGGGACCAAAGTGGATATCAAAC






R478
HC-DNA
GAGGTGCAGCTGTTGGAGTCTGGGGGAGACTTAGTACAGCCTGGGGG
1801


910-3

GTCCCTGAGACTCTCCTGTGTAGCCTCTGGATTCACCTTTAGGAGTTA





TGCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAAGTATTAGTGGTAGTGGTGGCGGCACATACTACGCAGACTCC





GTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTTTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATT





ACTGTGCGAGAGGGAGGGAGGACTGGTTATTAAGCCTAACATATGGC





TACTGGGGCCAGGGAGCCCTGGTCACCGTCTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1802




GACAGAGTCCCCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTA





TTTAAATTGGTATCAGCAGAGACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACACTATCCCTC





CGACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAC






R478
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1803


910-

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGGTAGCTA



421

TTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TGGCCAACATAAACGAAGATGGAAGTGAGAAATACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





ATATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGGACATTCTCTGGGTGAGTGGGGCCAGGGATCCCCG





GTCACCGTCTCCTCAG







LC-DNA
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG
1804




ACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTCTGC





AAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCT





ATATTAAAAACAAACGACCCTCAGGGATCCCAGACCGATTCTCTGGC





TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGC





GGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTG





ACCATCTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






R478
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1805


910-8

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





TAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TTTCATACATTAGTAGTAGTAGTAGTACCATATACTACGCAGACTCTG





TGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTA





CTGTGCGAGGGCCAACTGGAACGACATGTACTTCGATCTCTGGGGCC





GTGGCACCCTGGTCACTGTCTCCTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1806




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCTTTTGGCCAGGGGACCAAGCTGGAGATCAAAC






S195-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1807


637

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCAA





TGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGG





TGGCAGTTATATCATATGATGGAGATAATAAATACTACGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAATACGCT





GTATCTGCAAATGAACAGCCTGAGAACTGAGGACACGGCTGTGTATT





ACTGTGCGAGGTCGTTGGGCGGAAACTACTTCTACGGTATGGACGTCT





GGGGCCAAGGGACCACGGTCACCGTCTCCTCA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1808




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCGCTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTTTGGTGGCTCT





TGGACGTTCGGCCCAGGGACCAAGGTGGAAATCAAAC






S380-
HC-DNA
GAGGTGCAACTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1809


1191

GTCCCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTCAGTGGCTA





TATCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGG





TTTCATCCATCAGTGGTGGTAGTATTTCCATATCCTACGCAGGCTCTG





TGAAGGGCCGATTCACCATCTCCCGAGACAATGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAGAGCCGGGGACTCGGCTGTTTATTA





CTGTGCTCTTACGACTTTTGGAGTGGTTACCTCTTATCCCTCCTTTGAC





TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTC







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1810




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA





CTCCTCATCTATGGTAACAGTAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC





AGCTTGAGTGGTTATGTGTTCGGCGGAGGGACCGAGCTGACCGTCCT





AG






S451-
HC-DNA
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGATC
1811


101

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTA





TGCTATCAGCTGGGTGCGACAGGCCCCTGGACCAGGGCTTGAGTGGA





TGGGAGGGATCATCCCTTTCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGGGCCCCCGGGTATAGTAGTGTAGGGTCGACAAACTAC





TTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1812




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAACTTCCAGGAGCAGCCCCCAAA





CTCCTCATCTATGCAAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC





AGCCTGAGTGGTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA





G






S451-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGGAGCCTTCACA
1813


11

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG





TGGTTACTACTGGAGTTGGATCCGCCAGCACCCAGGGAAGGGCCTGG





AGTGGATCGGGTACATCTCTTACAGTGGTGGAAGCACCTACTACAAC





CCGTCCCTCAAGAGTGTAGTTACCATATCACTAGACACGTCTAAGAAT





CAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTG





TATTACTGTGCGAGAGTTTCCTATGGTTCGGGGAGTTTTCGTTTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
1814




TCAGTCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTAT





AACTATTTCTCCTGGTACCAACACCACGCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGCCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCA





CCTACACTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S451-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1815


1101

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAATAGTTA





CTCCTGGAGCTGGATCCGGCAGCCCGCCGGGAAGGGACTGGAGTGGA





TTGGGCGTATCTCTACCAGTGGGAGCACCAACAACAACCCCTCCCTCA





AGAGTCGAGTCACCATGTCAGTAGACACGTCCAAGGACCAGTTCTCC





CTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCCGTGTATTACTGT





GCGAGAATTAATGGGGCAGCAGCTGGGACGCCCTTTGACTACTGGGG





CCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1816




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAACTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGGACATTCG





GCCAAGGGACCAAGGTGGAAATCAAAC






S451-
HC-DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCCGGCAG
1817


1439

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTTT





GCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGT





CTCAGGTATTAGTTGGAATGGTGGTATCATAGGCTATGCGGACTCTGT





GAAGGCCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGT





ATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTAC





TGTGCAAAGACCAGGGGGGATTATGATTACGTTTGGGGGAGCCGTTC





TTCGAATTACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACGGT





CTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1818




GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTA





TTTAAATTGGTATCAGAAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTACGATGCAACCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT





GGAAGTGGATCTGGGACAGAGTTTACTTTCACCATCAGCAGCCTGCA





GCCTGAAGATATTGCAACATATTATTGTCAACAGTATGATAATGTCCC





TCCAATCACTTTCGGCCCTGGGACCAAAGTGGATATGAAAC






S451-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1807


1451

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCAA





TGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTAGAGTGGG





TGGCAGTTATATCATATGATGGAGATAATAAATACTACGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAATACGCT





GTATCTGCAAATGAACAGCCTGAGAACTGAGGACACGGCTGTGTATT





ACTGTGCGAGGTCGTTGGGCGGAAACTACTTCTACGGTATGGACGTCT





GGGGCCAAGGGACCACGGTCACCGTCTCCTCA







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1808




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCGCTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTTTGGTGGCTCT





TGGACGTTCGGCCCAGGGACCAAGGTGGAAATCAAAC






S451-
HC-DNA
GAGCCGCAGCTGGTGGAATCTGGGGGAGGCTTGGTACAGCCGGGGGG
1819


1477

GTCCCTGAGACTCTCCTGTGCAGGCTCTGGATTCGGCTTCATATCTTA





CCCCATGAACTGGGTCCGCCAGGCTCCAGGAAAGGGGCCGGAGTGGA





TTTCAAATATTAGGACAACCGCTGAAGGTGGAACCTTTTACGCAGACT





CTGTGAAGGGCCGATTCACCATGTCCAGAGACGACGGCAAGACTTCA





ATATATCTTCAAATGAACAGCCTGAGAGACGAGGACACGGCTACATA





TTACTGTGCGAGAGACTCTTCCTACGGATTTGATCTCTGGGGCCAGGG





GACAGTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
1820




TCAGTCACCATCTCCTGCACTGGAACCAGTAGTGATGTTGGTGGTTAT





AACTATGTCTCCTGGTATCAACAACGCCCAGGGAAAGCCCCCGAATT





GATGATTTATCATGTCAGTGAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAATCTGGCAACACGGCCTCCCTGACCATCTCTAGGCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCA





GCCACTTTTGGGTGTTCGGCGGAGGGACCAAGTTGACCGTCCTAG






S451-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1803


1503

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGGTAGCTA





TTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TGGCCAACATAAACGAAGATGGAAGTGAGAAATACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





ATATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGGACATTCTCTGGGTGAGTGGGGCCAGGGATCCCCG





GTCACCGTCTCCTCAG







LC-DNA
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG
1804




ACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTCTGC





AAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCT





ATATTAAAAACAAACGACCCTCAGGGATCCCAGACCGATTCTCTGGC





TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGC





GGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTG





ACCATCTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S451-
HC-DNA
GAGGTGCAACTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1809


1522

GTCCCTGAGACTCTCCTGTGCGGCCTCTGGATTCACCTTCAGTGGCTA





TATCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGG





TTTCATCCATCAGTGGTGGTAGTATTTCCATATCCTACGCAGGCTCTG





TGAAGGGCCGATTCACCATCTCCCGAGACAATGCCAAGAACTCACTG





TATCTGCAAATGAACAGCCTGAGAGCCGGGGACTCGGCTGTTTATTA





CTGTGCTCTTACGACTTTTGGAGTGGTTACCTCTTATCCCTCCTTTGAC





TACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTC







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1810




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAGCTTCCAGGAACAGCCCCCAAA





CTCCTCATCTATGGTAACAGTAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC





AGCTTGAGTGGTTATGTGTTCGGCGGAGGGACCGAGCTGACCGTCCT





AG






S451-
HC-DNA
CAGGTGCAACTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1821


1921

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG





TGATTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG





AGTGGCTTGGGTACATCTATTACAGTGGGAGCACCTTCTACAACCCGT





CCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCCAAGAACCAG





TTCTCCCTGAGGCTGACCTCTGTGACTGCCGCAGACACGGCCGTGTAT





TTCTGTGCCAGAGAGGAGAATAAATTCAACTATGGCCATCATCCCCTC





AATGGAGTCTTTGCCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC





TCAG







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1822




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTGTACAG





CCCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAACCTGCTCATCTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAACAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATCTTATAATACTCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAAC






S451-
HC-DNA
CAGGTCACCTTGAAGGAGTCTGGTCCTGTGCTGGTGAAACCCACAGA
1823


337

GACCCTCACGCTGACCTGCACCGTCTCTGGGTTCTCACTCATCAATGC





TAGGTTGGGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG





AGTGGCTTGCACACATTTTTTCGGATGACGAGAAATCCTACAGCACAT





CTCTGAAGAGCAGGCTCACCATCTCCAAGGACACCTCCAAGAGCCAG





GTGGTCCTTACCATGACCAACATGGACCCTGTGGACACAGCCACATA





TTACTGTGCACGGATATCTTGGCCCCCTTATGGTTCGGGGACTTATTA





TATTAAGGCTTTTGATATCTGGGGCCAAGGGACACTGGTCACCGTCTC





TTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGTCTCCGTGTCTGGGTCTCCTGGACAG
1824




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTCTGAGGTCAGTAATCGACCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATGCAAGCA





GCAGCACCCTTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCT






S451-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1825


650

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGCCTCCATCAGTAATTTC





TACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGACTGGAGTGGAT





TGGGTATATCTATTATAGTGGGAGCACCAACTACAACCCCTCCCTCAA





GAGTCGAGTCACCATGTCACTAGACACGTCCAAGAACCAGTTCTCCCT





GAATCTGAGCTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGC





GAGAATCCCCAATTTCTGGTTCGGGGAGTTATTATTTGACTTCTGGGG





CCACGGAACGCTGGTCACCGTCTCCTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1826




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAA





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAAC






S626-
HC-DNA
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGATC
1811


362

CTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTA





TGCTATCAGCTGGGTGCGACAGGCCCCTGGACCAGGGCTTGAGTGGA





TGGGAGGGATCATCCCTTTCCTTGGTATAGCAAACTACGCACAGAAG





TTCCAGGGCAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGGGCCCCCGGGTATAGTAGTGTAGGGTCGACAAACTAC





TTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCA
1812




GAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAG





GTTATGATGTACACTGGTACCAGCAACTTCCAGGAGCAGCCCCCAAA





CTCCTCATCTATGCAAACAGCAATCGGCCCTCAGGGGTCCCTGACCGA





TTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGG





CTCCAGGCTGAGGATGAGGCTGATTATTACTGCCAGTCCTATGACAGC





AGCCTGAGTGGTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA





G






S626-
HC-DNA
GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCCGGCAG
1817


651

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTTT





GCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGT





CTCAGGTATTAGTTGGAATGGTGGTATCATAGGCTATGCGGACTCTGT





GAAGGCCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGT





ATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTAC





TGTGCAAAGACCAGGGGGGATTATGATTACGTTTGGGGGAGCCGTTC





TTCGAATTACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACGGT





CTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1818




GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTA





TTTAAATTGGTATCAGAAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTACGATGCAACCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT





GGAAGTGGATCTGGGACAGAGTTTACTTTCACCATCAGCAGCCTGCA





GCCTGAAGATATTGCAACATATTATTGTCAACAGTATGATAATGTCCC





TCCAATCACTTTCGGCCCTGGGACCAAAGTGGATATGAAAC






S626-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1827


692

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACGCCTTCACCAGTTA





TGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGA





TGGGATGGATGAACCCTAACAGTGGTGACACATTCTATGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCAGGAGCACCTCCATAAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGGGAGGGTAGGGGCGGATTATGTTTCGGGGAACCGT





GGATACTACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCAC





GGTCACCGTCTCCTCA







LC-DNA
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG
1828




ACAGTCAGGATCACATGCCAAGGAGAGAACCTCAGAAGCTACTATGC





AACCTGGTACCAGCAGAAGCCAGGACAGGCCCCTATACTTGTCATCT





ATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGC





TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGC





GGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTA





ACCATCTAAGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S626-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1827


7

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACGCCTTCACCAGTTA





TGATATCAACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGA





TGGGATGGATGAACCCTAACAGTGGTGACACATTCTATGCACAGAAG





TTCCAGGGCAGAGTCACCATGACCAGGAGCACCTCCATAAGCACAGC





CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ACTGTGCGAGAGGGAGGGTAGGGGCGGATTATGTTTCGGGGAACCGT





GGATACTACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCAC





GGTCACCGTCTCCTCA







LC-DNA
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG
1828




ACAGTCAGGATCACATGCCAAGGAGAGAACCTCAGAAGCTACTATGC





AACCTGGTACCAGCAGAAGCCAGGACAGGCCCCTATACTTGTCATCT





ATGGTAAAAACAACCGGCCCTCAGGGATCCCAGACCGATTCTCTGGC





TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGC





GGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTA





ACCATCTAAGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S626-
HC-DNA
GAGCCGCAGCTGGTGGAATCTGGGGGAGGCTTGGTACAGCCGGGGGG
1819


747

GTCCCTGAGACTCTCCTGTGCAGGCTCTGGATTCGGCTTCATATCTTA





CCCCATGAACTGGGTCCGCCAGGCTCCAGGAAAGGGGCCGGAGTGGA





TTTCAAATATTAGGACAACCGCTGAAGGTGGAACCTTTTACGCAGACT





CTGTGAAGGGCCGATTCACCATGTCCAGAGACGACGGCAAGACTTCA





ATATATCTTCAAATGAACAGCCTGAGAGACGAGGACACGGCTACATA





TTACTGTGCGAGAGACTCTTCCTACGGATTTGATCTCTGGGGCCAGGG





GACAGTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTCGCTCAGTGTCCGGGTCTCCTGGACAG
1820




TCAGTCACCATCTCCTGCACTGGAACCAGTAGTGATGTTGGTGGTTAT





AACTATGTCTCCTGGTATCAACAACGCCCAGGGAAAGCCCCCGAATT





GATGATTTATCATGTCAGTGAGCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAATCTGGCAACACGGCCTCCCTGACCATCTCTAGGCT





CCAGGCTGAGGATGAGGCTGATTATTACTGCTGCTCATATGCAGGCA





GCCACTTTTGGGTGTTCGGCGGAGGGACCAAGTTGACCGTCCTAG






S626-
HC-DNA
CAGGTGCAACTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1821


75

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGG





TGATTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGCCTGG





AGTGGCTTGGGTACATCTATTACAGTGGGAGCACCTTCTACAACCCGT





CCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCCAAGAACCAG





TTCTCCCTGAGGCTGACCTCTGTGACTGCCGCAGACACGGCCGTGTAT





TTCTGTGCCAGAGAGGAGAATAAATTCAACTATGGCCATCATCCCCTC





AATGGAGTCTTTGCCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC





TCAG







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGC
1822




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTGTACAG





CCCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGAC





AGCCTCCTAACCTGCTCATCTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAACAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGC





AATCTTATAATACTCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAA





ATCAAAC






S626-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1829


8

GTCCCTGAGACTCTCCTGTGTATCCTCTGAAGTCACCTTCAATAGATA





TACTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCATCTATATCATTTGAAGGAAGTGTTAAAACCTATGTAGACTCCG





TGAAGGGCCGATTCACCATCTCCAGAGACGATTCCAAGAAAACGCTG





TTTCTGCAGTTGAACAGCCTGAGAGATGAGGACACGGCTATGTATTA





CTGTGCGCGAGGTCAGTGGCCATCCGGGGGTGACTACTGGGGCCGGG





GAACGCTGGTCACCGTCTCCTCAG







LC-DNA
GATGTTGTGCTGACTCAGTCTCCACTCTCCCTGTCCGTCACCCTTGGA
1830




CAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCTCGTTTACAGT





GATGGAAGCACCTACTTGAATTGGTTTCATCAGAGGCCAGGCCAATC





TCCAAGGCGCCTAATTTATAAGGTTTCTAACCGGGACTCTGGGGTCCC





AGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAA





TCACCAGGGTGGCGGCTGAGGATGTTGGGGTTTATTACTGCATGCAA





GGTACATACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAAT





CAAAC






S68-
HC-DNA
GAGGTGCAGCTGGTGCAGTCTGGAGCAGAAATCAAAAAGCCGGGGG
1831


253

AGTCTCTGAAGATCTCCTGCCAGGGTTCTGGATACATCTTTACCAACA





ACTGGATCGGCTGGGTCCGCCAGCAGCCCGGCAAAGGACTGGAGTGG





ATGGGCATCATCTATCCTGGTGACTCTGATGCCAGATATAGCCCGTCC





TTCCAAGGCCACGTCAGCTTCTCTGCCGACAAGTCCATCAACACCGCC





TTCCTGCAGTGGCACAGCCTGAAGGCCTCGGACACCGCCATGTATTAT





TGTGCGAGAATCCGGAGAAGGGGACAGGGAGCTACTGCTGCTTTCGA





TATCTGGGGCCCGGGGACAAAGGTCACCGTCTCTTCAG







LC-DNA
GACATCGTGATGACCCAGTCTCCAGACTCCCTGACTGTGTCTCTGGGC
1832




GAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAATATTTTAACCAC





CTCCAACAATAAGAATTACTTGGCTTGGTACCAACAAAAGCCAGGAC





AGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGG





TCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCA





CCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAAC





AATATTTTAATTCTCCTCCGTACACTTTTGGCCAGGGGACCAAGCTGG





AGATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1833


1502

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGCTCACCAGCCACTGCTGTACGGGTTGGGCTACTACT





TTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1834




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTCTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S728-
HC-DNA
GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGCCTGGGGG
1835


1789

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





CTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGG





TCTCACGTATTAATAGTGATGGGAGTAGCACAAGCTACGCGGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACACGCT





GTATCTGCAAATGAACAGTCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCAAGAGATCGGTATAGCAGCCTTGACTACTGGGGCCAGGGA





ACCCTGGTCACCGTCTCCTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1836




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCCGCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1833


1806

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGCTCACCAGCCACTGCTGTACGGGTTGGGCTACTACT





TTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1834




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCAGCTCATATACAAGCA





GCAGCACTCTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S728-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1837


1981

CTCAGTGAAGGTTTCCTGCAAGACATCTGGATACACGTTCACCAACTA





CTTTATGCACTGGGTGCGACAGGCCCCCGGACAAGGCCTTGAGTGGA





TGGGAATAATCAACCCTAGTGGTGGTAGCGCAAGCTACGCACAGAAG





TTCCAGGGCAGAATCACCATGACCAGCGACACGTCCACGAGCACAGT





GTACATGGAACTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ATTGTGCGAGAGAGGATATTATCGTGGTGGTTCCTGCTAGGCCTCTTG





ACTACTGGGGCCACGGAACCCTGGTCACCGTCTCCTC







LC-DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1838




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTTTTAGCAACTA





CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG





CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCT





CCGCTGCTCACTTTCGGCGGAGGGACCAAGGTTGAGATCAAAC






S728-
HC-DNA
CAGGTGCACCTGGTGCAGTCTGGGGCTGAGATCAGGAAGCCTGGGGC
1839


2036

CTCAGTGATGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTA





CTATATACACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGGTGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAA





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGAACAGC





CTACATGGAACTGAGCAGGCTGAGATCTGACGACGCGGCCGTTTATT





ACTGTGCGAGAGAAGGAATTTCAATGCTTCGGGGAGTTAGATCCTGG





TTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAATCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1840




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGGAGTTAT





AATCTTGTCTCCTGGTACCAACAGCACCCAGGCAAGGTCCCCAAACTC





ATAATTTATGAGGTCACTAAGCGGCCCTCAGGGGTTTCTAATCGCTTC





TCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCTC





CAAACTGAGGACGAGGCTGATTATTACTGCTGCTCATATGCAGGTTTT





AGCGCTTGGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTAG






S728-
HC-DNA
GAGGTGCAGCTGGTGGAGTCCGGGGGAGGCTTAGTTCAGCCTGGGGG
1835


2111

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTA





CTGGATGCACTGGGTCCGCCAAGCTCCAGGGAAGGGGCTGGTGTGGG





TCTCACGTATTAATAGTGATGGGAGTAGCACAAGCTACGCGGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACACGCT





GTATCTGCAAATGAACAGTCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCAAGAGATCGGTATAGCAGCCTTGACTACTGGGGCCAGGGA





ACCCTGGTCACCGTCTCCTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1836




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCCGCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG
1797


2148

GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTA





TGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGG





TGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCC





GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT





GTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGCTCCTGACTACTGGGGCCAGGGAACCCTGGTCACC





GTCTCCTCAG







LC-DNA
GCCATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1798




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGA





TTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGCACAGATTTCACTCTCACCATCAGCAGCCTGCAGC





CTGAAGATTTTGCAACTTATTACTGTCTACAAGATTACAATTACCCGT





ACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAAC






S728-
HC-DNA
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1841


656

GTCCCTGAGACTCTCATGTGCAGCCTCTGGATTCACCTTTAGTAGTTA





TGTCTTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGG





TCTCAGCTATTAGTGGTAGTGGTGGTATCACATATTACGCAGACTCCG





TGAAGGGCCGCTTCACCATCTCCAGAGACAATTCCAAGAACACACTG





TATCTGCAAATGAACAGTCTGAGAGCCGAGGACACGGCCGTATATTA





CTGTGCGATTCGAATTACGATTTCTGGAGTGTTTACTCCCGCTTGGGA





CTCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1842




GACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCACCTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAAC





CTGAAGATTTTGCAACTTACTTCTGTCAACAGAGTTACAGTTCCCCAT





TCACTTTCGGCCCTGGGACCAAAGTGGATATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1837


723

CTCAGTGAAGGTTTCCTGCAAGACATCTGGATACACGTTCACCAACTA





CTTTATGCACTGGGTGCGACAGGCCCCCGGACAAGGCCTTGAGTGGA





TGGGAATAATCAACCCTAGTGGTGGTAGCGCAAGCTACGCACAGAAG





TTCCAGGGCAGAATCACCATGACCAGCGACACGTCCACGAGCACAGT





GTACATGGAACTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATT





ATTGTGCGAGAGAGGATATTATCGTGGTGGTTCCTGCTAGGCCTCTTG





ACTACTGGGGCCACGGAACCCTGGTCACCGTCTCCTC







LC-DNA
GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGG
1838




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTTTTAGCAACTA





CTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAG





CCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCT





CCGCTGCTCACTTTCGGCGGAGGGACCAAGGTTGAGATCAAAC






S728-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1803


826

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGGTAGCTA





TTGGATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TGGCCAACATAAACGAAGATGGAAGTGAGAAATACTATGTGGACTCT





GTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACT





ATATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATT





ACTGTGCGAGAGGACATTCTCTGGGTGAGTGGGGCCAGGGATCCCCG





GTCACCGTCTCCTCAG







LC-DNA
TCTTCTGAGCTGACTCAGGACCCTGCTGTGTCTGTGGCCTTGGGACAG
1804




ACAGTCAGGATCACATGCCAAGGAGACAGCCTCAGAAGCTATTCTGC





AAGCTGGTACCAGCAGAAGCCAGGACAGGCCCCTGTACTTGTCATCT





ATATTAAAAACAAACGACCCTCAGGGATCCCAGACCGATTCTCTGGC





TCCAGCTCAGGAAACACAGCTTCCTTGACCATCACTGGGGCTCAGGC





GGAAGATGAGGCTGACTATTACTGTAACTCCCGGGACAGCAGTGGTG





ACCATCTGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S728-
HC-DNA
CAGGTGCACCTGGTGCAGTCTGGGGCTGAGATCAGGAAGCCTGGGGC
1839


959

CTCAGTGATGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTA





CTATATACACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGGTGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAA





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGAACAGC





CTACATGGAACTGAGCAGGCTGAGATCTGACGACGCGGCCGTTTATT





ACTGTGCGAGAGAAGGAATTTCAATGCTTCGGGGAGTTAGATCCTGG





TTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAATCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1840




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGGAGTTAT





AATCTTGTCTCCTGGTACCAACAGCACCCAGGCAAGGTCCCCAAACTC





ATAATTTATGAGGTCACTAAGCGGCCCTCAGGGGTTTCTAATCGCTTC





TCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCTC





CAAACTGAGGACGAGGCTGATTATTACTGCTGCTCATATGCAGGTTTT





AGCGCTTGGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTAG






S210-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1843


530

CTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTA





CTTTATTCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAATATAT





GGGATGGATCAACCCTAATAGTGCTGGCACAAACTATGCACAGAAGT





TTCAGGGCAGGGTCACCATGACCGGGGACACGTCCATCAGCACAGTC





TACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCATGTATTA





CTGTGCGAGAGTATTTTTTGACTGGTTATTGCCGTTTGACTACTGGGG





CCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1844




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGGAGTTAT





AACCTTGTCTCCTGGTATCAACAGCACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAAGCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCTGCTCATATGCAGGTA





GTAATTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAG






S210-
HC-DNA
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG
1845


1129

GTCCCTGAGACTCTCCTGTGTAGCCTCTAGATTCACCTTTAGCGACTA





CGCCATGAGCTGGGTCCGCCAGCCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAAGTATTAGTGGTAGTGGTGGTATTACTTACTACGCAGACTCCG





TGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACACTG





TATCTGCAAATAAAGAGCCTGAGAGCCGAGGACACGGCCATATATTA





CTGTGCGAAGGAACGATCTAACTGGAACTACGTGGAAAACTTTGACT





ACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGACTGTGGTGACTCAGGAGCCCTCACTGACTGTGTCCCCAGGAGG
1846




GACAGTCACTCTCACCTGTGCTTCCAGTACTGGAACAGTCACCAGTGC





TTTCTTTCCAAACTGGTTCCAGCAGAAACCTGGACAAGCACCCAGGG





CACTGATTTATAGTACAACCAACAAATACTCCTGGACCCCTGCCCGGT





TCTCAGGCTCCCTCCTTGGGGGCAAAGCTGCCCTGACACTGTCAGGTG





TGCAGCCTGAGGACGAGGCTGACTATTACTGCCTGCTCTTCTATGGTG





GTGCTCGGCCCCATGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTC





CTAG






S451-
HC-DNA
CAGGTGCAGCTACAGCAGTGGGGCGCGGGACTGTTGAAGCCTTCGGA
1847


5

GACCCTGTCCCTCACCTGCGCTGTCTATGGTGCGTCCGTCAGTGGTTA





CTTCTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGA





TTGGAGAAATCAATCGTTTTGGAAGCACCAACTACAACCCGTCCCTCA





AGAGTCGAGTCACCTTATCAGTGGACACGTCCAGGAACCAGTTCTCC





CTGAAGCTGGGCTCTGTGACCGCCGCGGACACGGCAATGTATTACTG





TGCGAGAGGCAGTCAGGCCAACCCCCTCGTACGATTTTTTGACAGCCC





CGTCACGGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTC





TTCAG







LC-DNA
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGG
1848




GAAAGGGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAAGAGCAA





CTTAGCCTGGTACCAACAAAAACCTGGCCAGGCTCCCAGGCTCCTCAT





CTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTG





GCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCCGCCTGCAG





TCTGAAGATTTTGCACTTTATTACTGTCAGCAGTATGATAACTGGCCT





CCGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAAC






S451-
HC-DNA
CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACA
1849


506

GACCCTCACGCTGACCTGCACCTTCTCTGGGTTCTCATTCACCAGTAG





TGGAGTGGGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCATGG





AGTGGCTTGCACTCATTTATTGGGATGATGATAAGCGTTACAGCCCAT





CTCTGAAGAGCAGGCTCACCATCACCAAGGACACCTCCAAAAACCAG





GTGGTCCTTAAAATGACCAATATGGACCCTGTGGACACAGCCACATA





TTACTGTGCACGCCATACAGTGGCTACGATTGTTGACTACTGGGGCCA





GGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCAGGACAG
1850




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAACACCCAGGCAAAGCCCCCAAACT





CATGATTTATGAGGTCAGTAATCGGCCCTCAGGGGTCCCTGATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACCATCTCTGGGCT





CCAGGCTGAGGACGAGGCTGATTATTACTGCGGCTCATATACAACCA





GCAGCACTCCTGTGGTTTTCGGCGGAGGGACCAAGCTGACCGTCCTA





G






S451-
HC-DNA
GAGGTGCAGCTGGTGGAGACTGGAGGAGGCTTGATCCAGCCTGGGGG
1851


1140

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGGATCACCGTCAGTAGCAA





CTACATGAACTGGGTCCGCCTGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCACTCATTTATAGCGGTGGTAGCACATTCTACGCAGACTCCGTGA





AGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT





CTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTATTG





TGCGAGAGAAGGTTTAGTGGGAGCTACGACGGCTTTTGACTACTGGG





GCCAGGGAACGCTGGTCACCGTCTCCTCAG







LC-DNA
GACATCCAGTTGACCCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGA
1852




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTA





TTTAGCCTGGTATCAGCTACAACCAGGGAAAGCCCCTAAGCTCCTGAT





CTATGCTGCATCCACTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGG





CAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAGCCTGCAGC





CTGAAGATTTTGCAACTTATTACTGTCAACAGCTTAATGGTCACCCCC





AGGGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC






S451-
HC-DNA
CAGGTCACCTTGAGGGAGTCTGGTCCTGCGCTGGTGAAACCCACACA
1853


1190

GACCCTCACACTGACCTGCACCTTCTCTGGGTTCTCACTCACCACTAG





TGGAATGTGTGTGAGCTGGATCCGTCAGCCCCCAGGGAAGGCCCTGG





AGTGGCTTGCACGCATTGATTGGGATGATGATAAATACTACAGCACA





TCTCTGAAGGCCAGGCTCACCATCTCCAAGGACACCTCCAAAAACCA





GGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCCACGT





ATTACTGTGCACGGACTTCAGTGGGAGGTACCAAGTACTACTTTGACT





ACTGGGGCCAGGGAACGCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCA
1854




GAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGAA





ATACTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCAAACTC





CTCATCTATAGTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTC





TCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTC





CAGTCTGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAG





CCTGAATGGGGGGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S626-
HC-DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1855


84

GGCCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCACTAG





TAATTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG





AGTGGATTGGGAGTATCTATTATCGTGGGGGCACCCACTACAACCCG





TCCCTCAAGACTCGAGTCACCATATCCGTAGACACGTCCAAGAACCA





GTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTA





TTACTGTGCGAGACATACCTATTTCTATGATATCGTGGGGGCAGCGGT





TTGGGAACCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTC





TTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1856




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





CTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTCTGATGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGTAGCTCA





CCTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC






S626-
HC-DNA
CAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGA
1857


161

GACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAA





TAATTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGG





AGTGGATTGGGAGTATCTATTATAGTGGCAGCACCTACTACAACCCGT





CTCTCAAGAGTCGAGTCACCATGTCCGTAGACACGTCCAAGAACCAG





TTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTAT





CACTGTGCGAGACAAGGACCGAATTACTATGATAGAAGTGGTTATTA





TTACGTCGGCCCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGT





CTCTTCAG







LC-DNA
CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACA
1858




GAAGGTCACCATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATA





ATTCTGTATCCTGGTACCAGCACCTCCCAGGAACAGCCCCCAAACTCC





TCATCTATGAAAATAATGAGCGACCCTCAGGGATTCCTGACCGATTCT





CTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCGGACTCC





AGACTGGGGACGAGGCCGATTATTACTGCGAAACATGGGATAGGAGC





CTGAGTGCTTCCTTCGGAACTGGGACCAAGGTCACCGTCCTAG






S626-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1859


664

CTCAGTGAAGGTCTCCTGCAGGGTTTCTGGATACACCTTCACCGGCTA





CTATATACACTGGGTGCGGCAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCACCACAGC





CTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATT





ACTGTGCGAGAGTCCCTATGATCCTAGTGGTTGATCATTGGGGTTCCT





ACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG







LC-DNA
CAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAG
1860




TCGATCACCATCTCCTGCACTGGAACCAGCAGTGATGTTGGTGGTTAT





AACTATGTCTCCTGGTACCAACAATACCCAGGCAAAGCCCCCAAACT





CATGATTTATGATGTCAGTAAGCGGCCCTCAGGGGTTTCTAATCGCTT





CTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGACAATCTCTGGGCT





CCAGGCAGAGGACGAGGCTGATTATTACTGCTGCTCATATGCAGGTA





GTAGCGCTTTAGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S728-
HC-DNA
CAGATCACCTTGAAGGAGTCTGGTCCTACGCTGGTGAAACCCACACA
1861


209

GACCCTCACACTGACCTGCACCCTCTCTGGATTCTCACTCAGCACTAG





TGGAGTTAGTGTGGGCTGGATCCGTCAGCCCCCAGGAAAGGCCCTGG





AATGGCTTGCAGTCATTTTTTGGGATGATGATAAGCGCTACAACCCAT





CTCTGAAGAGCAGGCTCACCATCGCCAAGGACACCTCCAAAAGCCAG





GTGGTCCTTACAATGACCAACCTGGACCCTGTGGACACTGGCACATAT





TACTGTGTGTCGGGCAGCTCGTATTACTACTACTACTACATGGACGTC





TGGGGCAAAGGGACCACGGTCACCGTCTCCTCA







LC-DNA
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTATTGGA
1862




GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGATATTAGCACCTG





GTTAGCCTGGTATCAGCAAAAACCAGGGAGAGCCCCTAACCTCCTGA





TCTATGGTGCATCCAGCTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAG





CCTGAAGATTTTGCAACTTATTATTGTCAACAGGCTACCAGTTTCCCT





CTCACTTTCGGCGGAGGGACCAAGGTCGAGATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA
1863


369

GACCCTGTCTCTCACCTGCTCTGTCTCTGGTGGCTCCATCAGCAGTGG





TGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGG





AGTGGATTGGGTACATGTATTACAGTGGGAGCACTTATTATAACCCGT





CCCTCAAGAGTCGAGTTACCATATTCGTGGACACGTCTAAGAACCACT





TCTCCCTGAAACTGACCTCTGTTACTGCCGCGGACACGGCCGTTTATT





ACTGTGCGAGAGATTCGTACGAAAATTACTATGGTTCGGGGAGCCTG





GAGCCCAACTACCACCACTACAATATGGACGTCTGGGGCCAAGGGAC





CACGGTCACCGTCTCCTCA







LC-DNA
GACGTCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTATAGGA
1864




GACAGAGTCACCATCACTTGCCGGGCCAGTCAGAGTATTAGTGGCTG





GTTGGCCTGGTATCAGCAGAGACCAGGGAAAGCCCCTAAACTCCTGA





TCTATAGGGCGTCTAGTTTAGATTTTGGGGTCCCATCAAGGTTCAGCG





GCAATGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAG





CCTGATGATTTTGCAACTTATTACTGCCAACAGTATCATACTTATCGG





ACGTTCGGCCAAGGGACCAAGGTGGAAGTCAAAC






S728-
HC-DNA
GAGGTGCAGCTGGTGGAGTCTGGAGGAGGCTTGATCCAGCCTGGGGG
1865


430

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGGTTCACCGTCAGTAGCAA





CTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGG





TCTCAGTTATTTATAGCGGTGGTAGTACATACTACGCAGACTCCGTGA





AGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTAT





CTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTG





TGCGAGAACCCCGAGGGGCAGCAGGCGGGGGGCTTTTGATATCTGGG





GCCAAGGGACAATGGTCACCGTCTCTTCAG







LC-DNA
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA
1866




GACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCGACTA





TTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGA





TCTACGATGCATCCAATTTGGAAACAGGGGTCCCATCAAGGTTCAGT





GGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCA





GCCTGAAGATATTGCAACATATTACTGTCAACAGTATGATAATCTCCC





TCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAC






S728-
HC-DNA
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGC
1867


537

CTCAGTGAAAGTCTCCTGTAAGACTTCTGGATACACCTTCACCGGCTT





CTATTTGCACTGGCTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGA





TGGGACGAATCAACCCTAACACCGGTGACACAGACTATGCACAGAAG





TTTCAGGGCAGGGTCACCATGACCAGGGACACCTCCATCAGCACAGC





CTACATGGAACTGAGCAGGCTGAGAGCTGACGACACGGCCGTGTATT





ATTGTGCGAGAACGCCCGGGCAAACACGACAACTGTTCGTGGGGACT





AATGTTCTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA





G







LC-DNA
GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGG
1868




GACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTG





GTTAGCCTGGTATCAACAGAAACCAGGGAAAGCCCCTAAGGTCCTCA





TTTTTGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCG





GCAGTGGATCTGGGACAGATTTCACTCTCACCATCACCAGCCTGCAGC





CTGAAGATTTTGCAACTTACTTTTGTCAACAGACTAACAGTTTCCCTC





CCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAAC






S728-
HC-DNA
GAGGTGCAACTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG
1869


1157

GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTACTCGTCAGTAGAAA





TTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGG





TCTCAATTATTTATAGTGGTGGCAGCACATTCTACGCAGACTCCGTGG





AGGGCCGATTCACCATCTCCAGAGACGAGTCCAAGAACACACTGTAT





CTTCAAATGAACAGTCTGAGAACTGACGACACGGCTGTGTATTACTGT





GCGAGAGATCTCTCCGACTACGGTGGGATTGACTGCTGGGGCCAGGG





AACCCTGGTCACCGTCTCCTCAG







LC-DNA
CCTATGAACTGACTCAGCCACTCTCAGTGTCAATGGCCCTGGGACAG
1870




ACGGCCAGGATTTCCTGTGGGGGAGACAACGTGGGAAGTCAAAATGT





GCACTGGTACCAGCAGAGGCCAGGCCAGGCCCCTGTGCTGGTCATCT





ATAGGGATAGCAACCGGCCCTCTGGGATCCCTGAGCGATTCTCTGGCT





CCAAGTCGGGGAACACGGCCACCCTGACCATCAGCAGAGCCCAAGCC





GGGGATGAGGCTGACTATTACTGTCAGGTGTGGGACAGCAGCACTGT





GGCTTTCGGCGGAGGGACCAAGCTGACCGTCCTAG






S728-
HC-DNA
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGG
1871


1261

GACCCTGTCCCTCACCTGCGCTGTCTCTGGTGGCTCCATCAGTAATAA





TAACTGGTGGATTTGGGTCCGCCAGCCCCCAGGGAAGGGGCTGGAGT





GGATTGGGGAAATCCATCATAGTGGGAGCACCGACTACAACCCGTCC





CTCAAGAGTCGAGTCACCATATCAATAGACAAGTCCAAGAACCAGTT





CTCCCTGAGGCTGAGCTCTGTGACCGCCGCGGACACGGCCGTGTATTA





CTGTGCGAGAAAGCCAGAACCGTACTACTACTACTACTACATGGACG





TCTGGGGCAAAGGGACCACGGTCACCGTCTCCTCA







LC-DNA
GAGACTGTGTTGACACAGTCTCCAGGCACCCTGTCTTTGTCTCCGGGG
1872




GAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAG





TTATATAACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGTAGACTG





GAGCCTGAAGATTTCGCAGTGTATTACTGTCAGCAATATCGTAGCCCC





TGGGGGCTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAAC






S728-
HC-DNA
CAGGTCCAGCTGGTGCAGTCTGGGGCTGAGGTGGTGAAGCCTGGGTC
1873


1690

CTCGGTGAAGGTCTCCTGCAAGGCCTCTGGAGGCACCTTCACCAGGT





ACGCTATTAGCTGGGTGCGACAGGCCCCCGGACAAGGGCCTGAGTGG





ATGGGAAGGATCATCCCTATGTTTGGAATAGCAAACTACGCACAGAG





GTTCCAGGGCAGAGTCACGATGACCGCGGACAAATCCACGAGCACTG





CCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTCTAT





TACTGTGCGACATGCCAGTATTATTATGACAGTAGTGGTTATGGGTCC





CTTGACTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCAG







LC-DNA
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGG
1874




GAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCAA





CTTCTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT





CATCTCTGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCA





GTGGCGGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTG





GAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATCATAGCTCA





CCGCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAAC
















TABLE 3







Summary of SEQ ID NOS.





























HC








LC













vari-
HC
HCD
HC
HFR
HFR
HFR
HFR

vari-
LCD
LCD
LCD
LFR
LFR
LFR
LFR
HC-
LC-


Clone
HC
able
DR1
R2
DR3
1
2
3
4
LC
able
R1
R2
R3
1
2
3
4
DNA
DNA






























S20-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1603
1604


15


S20-
19
20
21
22
23
24
25
26
9
27
28
29
30
31
32
33
34
35
1605
1606


22


S20-
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
1607
1608


31


S20-
54
55
56
57
58
24
25
59
60
61
62
63
64
65
66
67
68
69
1609
1610


40


S20-
70
71
72
73
74
75
7
76
60
77
78
79
80
81
82
83
84
85
1611
1612


58


S20-
86
87
3
88
89
24
90
91
44
92
93
63
94
95
96
67
97
69
1613
1614


74


S20-
98
99
100
101
102
103
104
105
106
107
108
63
64
65
66
67
68
18
1615
1616


86


S24-
109
110
56
111
112
113
114
115
60
116
117
118
119
120
121
122
123
69
1617
1618


68


S24-
124
125
126
127
128
129
130
131
60
132
133
134
135
136
50
137
138
53
1619
1620


105


S24-
139
140
141
142
143
144
145
146
147
148
149
150
151
152
66
153
68
18
1621
1622


178


S24-
154
155
156
157
158
159
160
161
147
162
163
63
164
165
66
67
166
167
1623
1624


188


S24-
168
169
170
171
172
173
174
175
147
176
177
178
179
180
181
182
183
184
1625
1626


202


S24-
185
186
187
188
189
190
160
191
147
192
193
194
135
195
50
182
196
85
1627
1628


278


S24-
197
198
199
200
201
202
203
204
60
205
206
207
208
209
210
182
211
53
1629
1630


339


S24-
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
69
1631
1632


472


S24-
229
230
231
232
233
190
160
234
60
235
236
237
135
238
50
239
196
85
1633
1634


490


S24-
240
241
242
243
244
245
7
115
9
246
247
248
249
250
251
252
253
85
1635
1636


494


S24-
254
255
199
256
257
258
203
259
60
260
261
262
263
264
265
266
267
53
1637
1638


566


S24-
268
269
270
271
272
129
145
273
60
274
275
276
277
278
279
280
281
69
1639
1640


636


S24-
282
283
284
285
286
190
287
288
60
289
290
291
30
292
32
33
293
85
1641
1642


740


S24-
294
295
296
297
298
24
7
299
44
300
301
302
135
303
304
182
305
53
1643
1644


791


S24-
306
307
308
157
309
310
160
161
147
311
312
313
314
315
316
317
318
69
1645
1646


902


S24-
319
320
321
322
323
324
7
325
44
326
327
328
249
329
330
252
253
53
1647
1648


921


S24-
331
332
56
333
334
24
7
335
60
336
337
338
135
303
50
182
339
53
1649
1650


1063


S24-
340
341
342
343
344
345
160
346
60
347
348
349
350
351
352
353
354
355
1651
1652


1224


S24-
356
357
358
359
360
361
130
362
60
363
364
365
366
367
368
369
370
69
1653
1654


1271


S24-
371
372
358
373
374
361
130
375
147
376
377
338
135
378
50
379
196
380
1655
1656


1339


S24-
381
382
242
243
383
245
7
115
60
384
385
386
387
388
389
252
253
85
1657
1658


1345


S24-
390
391
358
392
393
361
130
375
44
394
395
276
396
397
279
280
281
69
1659
1660


1378


S24-
398
399
56
4
400
24
7
115
147
401
402
403
404
405
121
122
406
69
1661
1662


1379


S24-
407
408
126
409
410
411
130
273
147
412
413
414
13
415
15
416
17
69
1663
1664


1384


S24-
417
418
199
419
420
202
203
259
421
422
423
207
208
424
210
182
211
53
1665
1666


1476


S24-
425
426
56
427
428
24
7
429
60
430
431
432
249
433
251
434
253
53
1667
1668


1564


S24-
435
436
437
142
438
144
145
146
60
439
440
178
441
442
181
182
183
443
1669
1670


1636


S24-
444
445
446
447
448
449
145
146
147
450
451
386
387
452
389
453
454
85
1671
1672


1002


S24-
455
456
457
458
459
460
42
461
60
462
463
464
465
466
467
468
469
69
1673
1674


1301


S24-
470
471
472
473
474
475
476
477
60
478
479
63
64
480
66
67
68
69
1675
1676


223


S24-
481
482
56
483
484
24
7
485
486
487
488
489
490
491
492
493
494
69
1677
1678


461


S24-
495
496
141
497
498
144
145
499
147
500
501
502
503
504
368
369
370
69
1679
1680


511


S24-
505
506
141
142
507
144
145
146
147
508
509
502
503
510
368
369
370
69
1681
1682


788


S24-
511
512
513
514
515
516
476
517
44
518
519
520
521
522
523
252
524
53
1683
1684


821


S144-
525
526
527
528
529
530
531
532
147
533
534
535
350
536
537
538
539
69
1685
1686


67


S144-
540
541
542
543
544
530
174
545
60
546
547
548
387
549
550
252
524
380
1687
1688


69


S144-
551
552
141
553
554
555
556
557
147
558
559
262
263
560
265
266
267
380
1689
1690


94


S144-
561
562
563
564
565
566
130
567
60
568
569
570
249
571
251
572
573
85
1691
1692


113


S144-
574
575
187
576
577
190
160
578
44
579
580
403
404
581
582
122
406
69
1693
1694


175


S144-
583
584
187
585
586
587
160
588
60
589
590
591
592
593
594
67
595
596
1695
1696


208


S144-
597
598
599
600
601
602
130
273
60
603
604
605
135
606
50
607
138
85
1697
1698


339


S144-
608
609
610
611
612
613
130
614
60
615
616
248
249
617
251
252
618
619
1699
1700


359


S144-
620
621
622
623
624
625
626
627
60
628
629
630
631
632
633
634
635
380
1701
1702


460


S144-
636
637
638
639
640
641
174
642
60
643
644
645
387
646
523
647
524
53
1703
1704


466


S144-
648
649
650
88
651
24
7
115
147
652
653
262
263
654
265
266
655
443
1705
1706


469


S144-
656
657
658
543
659
660
174
661
60
662
663
520
387
646
523
664
524
53
1707
1708


509


S144-
665
666
187
585
667
668
160
669
670
671
672
673
674
675
676
122
539
69
1709
1710


516


S144-
677
678
679
680
681
682
7
683
44
684
685
686
687
688
50
689
690
53
1711
1712


568


S144-
691
692
693
157
694
695
160
161
147
696
697
520
698
699
700
252
524
701
1713
1714


576


S144-
702
703
242
243
704
245
7
705
60
706
707
502
366
708
368
369
370
69
1715
1716


588


S144-
709
710
527
543
711
712
174
713
147
714
715
673
716
717
718
719
720
721
1717
1718


628


S144-
722
723
187
724
725
190
160
588
60
726
727
338
135
728
729
730
196
731
1719
1720


740


S144-
732
733
734
585
735
736
160
737
60
738
739
740
119
741
121
122
123
69
1721
1722


741


S144-
742
743
744
543
745
746
174
747
60
748
749
520
387
750
523
252
524
751
1723
1724


803


S144-
752
753
754
755
756
757
145
758
60
759
760
761
208
762
50
182
196
380
1725
1726


843


S144-
763
764
765
497
766
144
145
499
60
767
768
769
770
771
251
252
772
85
1727
1728


877


S144-
773
774
775
776
777
778
160
779
60
780
781
782
30
783
32
33
293
53
1729
1730


952


S144-
784
785
786
787
788
789
790
791
60
792
793
794
30
795
32
33
293
53
1731
1732


971


S144-
796
797
798
799
800
801
7
115
60
802
803
804
30
805
32
806
293
53
1733
1734


1036


S144-
807
808
693
809
810
811
160
812
813
814
815
816
135
817
50
182
818
380
1735
1736


1079


S144-
819
820
56
821
822
24
7
823
60
824
825
403
404
826
121
122
406
69
1737
1738


1299


S144-
827
828
829
830
831
832
160
833
834
835
836
837
64
838
66
839
68
69
1739
1740


1339


S144-
840
841
842
843
844
190
287
845
670
846
847
520
387
646
523
252
524
53
1741
1742


1406


S144-
848
849
850
851
852
310
160
853
44
854
855
520
387
856
523
252
857
380
1743
1744


1407


S144-
858
859
860
861
862
863
160
864
147
865
866
867
868
869
870
871
872
69
1745
1746


1569


S144-
873
874
542
875
876
877
174
878
60
879
880
881
387
882
883
252
884
885
1747
1748


1641


S144-
886
887
888
889
890
891
145
892
60
893
894
895
208
303
50
182
196
896
1749
1750


1827


S144-
897
898
126
899
900
602
130
901
44
902
903
904
905
906
121
122
406
907
1751
1752


1848


S144-
908
909
610
910
911
613
130
912
60
913
914
645
915
916
523
252
524
53
1753
1754


1850


S144-
917
918
919
920
921
310
160
161
60
922
923
291
30
924
925
33
926
53
1755
1756


2234


S564-
927
928
929
930
931
932
25
115
220
933
934
935
151
936
66
67
68
937
1757
1758


105


S564-
938
939
270
940
941
942
943
944
60
945
946
12
947
948
949
950
17
18
1759
1760


14


S564-
951
952
187
953
954
955
160
956
60
957
958
63
94
959
96
67
960
69
1761
1762


68


S564-
961
962
56
4
963
24
7
115
60
964
965
432
249
966
251
252
967
53
1763
1764


98


S564-
927
928
929
930
931
932
25
115
220
933
934
935
151
936
66
67
68
937
1757
1758


105


S564-
968
969
187
953
970
190
160
971
60
972
973
63
974
975
96
67
976
69
1765
1766


134


S564-
977
978
979
980
981
982
160
983
44
984
985
63
151
986
66
67
987
18
1767
1768


138


S564-
988
989
990
991
992
144
145
499
60
993
994
995
770
996
251
252
997
380
1769
1770


152


S564-
998
999
308
1000
1001
310
160
1002
44
1003
1004
63
94
1005
96
67
1006
69
1771
1772


218


S564-
1007
1008
1009
1010
1011
1012
1013
1014
60
1015
1016
1017
64
1018
66
1019
1020
69
1773
1774


249


S564-
1021
1022
187
1023
1024
190
160
1025
60
1026
1027
1028
94
1029
96
67
1006
721
1775
1776


265


S564-
1030
1031
56
333
1032
24
7
1033
60
1034
1035
1036
249
1037
1038
252
1039
85
1777
1778


275


S564-
1040
1041
187
953
1042
190
160
1043
60
1044
1045
63
64
1046
66
67
68
69
1779
1780


287


S166-
1047
1048
1049
1050
1051
1052
1053
1054
1055
1056
1057
1058
387
1059
523
252
524
53
1781
1782


32


S305-
1060
1061
1062
1063
1064
1065
145
1066
1067
1068
1069
1070
441
1071
181
1072
183
1073
1783
1784


223


S305-
1074
1075
457
458
1076
1077
42
1078
1079
1080
1081
1082
208
1083
210
182
1084
53
1785
1786


399


S305-
1085
1086
457
1087
1088
1077
42
1078
60
1089
1090
1091
208
1092
210
182
211
443
1787
1788


1456


R125
1093
1094
1062
1095
1096
1097
145
1098
147
1099
1100
1101
1102
1103
1104
1105
1106
18
1789
1790


-306


R125
1107
1108
1109
4
1110
1111
7
1112
147
1113
1114
1115
1116
1117
1118
1119
1120
69
1791
1792


-444


R3-
1121
1122
1123
1124
1125
1126
476
1127
60
1128
1129
1130
1131
1132
1133
1134
253
53
1793
1794


428


R478
1135
1136
610
1137
1138
1139
130
499
60
1140
1141
1142
1143
1144
1145
1146
196
701
1795
1796


910-


171


R478
1147
1148
141
142
1149
144
145
146
60
1150
1151
1152
249
1153
1154
252
253
380
1797
1798


910-


23


R478
1155
1156
1157
1158
1159
1160
1161
1162
60
1163
1164
1165
1166
1167
251
453
1168
443
1799
1800


910-


25


R478
1169
1170
1171
1172
1173
1174
130
1175
1176
1177
1178
248
249
1179
1180
1181
253
85
1801
1802


910-3


R478
1182
1183
1184
1185
1186
1187
145
273
1188
1189
1190
1191
1192
1193
1194
1195
1196
69
1803
1804


910-


421


R478
1197
1198
126
127
1199
613
130
273
9
1200
1201
338
135
1202
50
182
196
380
1805
1806


910-8


S195-
1203
1204
1205
1206
1207
144
145
1208
147
1209
1210
338
1211
1212
50
182
196
1213
1807
1808


637


S380-
1214
1215
1216
1217
1218
613
130
1219
60
1220
1221
673
350
1222
537
122
539
1223
1809
1810


1191


S451-
1224
1225
1226
1227
1228
310
1229
161
60
1230
1231
673
1232
1222
537
719
539
18
1811
1812


101


S451-
1233
1234
1235
1236
1237
1238
1239
1240
60
1241
1242
1243
592
1244
594
1245
1246
69
1813
1814


11


S451-
1247
1248
1249
1250
1251
324
25
1252
60
1253
1254
570
249
1255
251
252
253
53
1815
1816


1101


S451-
1256
1257
1258
1259
1260
1261
130
1262
60
1263
1264
769
1265
1266
251
1267
1268
1269
1817
1818


1439


S451-
1203
1204
1205
1206
1207
144
145
1208
147
1209
1210
338
1211
1212
50
182
196
1213
1807
1808


1451


S451-
1270
1271
1272
1273
1274
1275
1276
1277
421
1278
1279
63
1280
1281
594
1282
1283
69
1819
1820


1477


S451-
1182
1183
1184
1185
1186
1187
145
273
1188
1189
1190
1191
1192
1193
1194
1195
1196
69
1803
1804


1503


S451-
1214
1215
1216
1217
1218
613
130
1219
60
1220
1221
673
350
1222
537
122
539
1223
1809
1810


1522


S451-
1284
1285
72
1286
1287
1288
1289
1290
60
1291
1292
1293
30
1294
32
1295
1296
53
1821
1822


1921


S451-
1297
1298
1299
1300
1301
1302
476
1303
60
1304
1305
63
151
1306
1307
1308
68
69
1823
1824


337


S451-
1309
1310
1311
4
1312
1313
7
1314
1315
1316
1317
816
135
1318
50
182
196
701
1825
1826


650


S626-
1224
1225
1226
1227
1228
310
1229
161
60
1230
1231
673
1232
1222
537
719
539
18
1811
1812


362


S626-
1256
1257
1258
1259
1260
1261
130
1262
60
1263
1264
769
1265
1266
251
1267
1268
1269
1817
1818


651


S626-
1319
1320
1321
1322
1323
1324
1325
1326
670
1327
1328
1329
1330
1331
1194
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1196
69
1827
1828


692


S626-
1319
1320
1321
1322
1323
1324
1325
1326
670
1327
1328
1329
1330
1331
1194
1332
1196
69
1827
1828


7


S626-
1270
1271
1272
1273
1274
1275
1276
1277
421
1278
1279
63
1280
1281
594
1282
1283
69
1819
1820


747


S626-
1284
1285
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1286
1287
1288
1289
1290
60
1291
1292
1293
30
1294
32
1295
1296
53
1821
1822


75


S626-
1333
1334
1335
1336
1337
1338
145
1339
9
1340
1341
1342
1343
1344
1345
1346
1347
53
1829
1830


8


S68-
1348
1349
1350
1351
1352
1353
1354
1355
1356
1357
1358
1359
30
1360
925
33
293
380
1831
1832


253


S728-
1361
1362
187
585
1363
190
160
588
60
1364
1365
63
151
1366
66
67
68
69
1833
1834


1502


S728-
1367
1368
1369
1370
1371
613
1372
1373
60
1374
1201
338
135
1375
50
182
196
85
1835
1836


1789


S728-
1361
1362
187
585
1363
190
160
588
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1364
1365
63
151
1366
66
67
68
69
1833
1834


1806


S728-
1376
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1379
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160
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1383
1384
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441
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181
182
183
85
1837
1838


1981


S728-
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953
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60
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66
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69
1839
1840


2036


S728-
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1371
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60
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135
1375
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182
196
85
1835
1836


2111


S728-
1147
1148
141
142
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144
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146
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1150
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249
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252
253
380
1797
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2148


S728-
1400
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130
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656


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1376
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85
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723


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1182
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69
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69
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959


S210-
1410
1411
1412
1413
1414
190
1415
1416
60
1417
1418
1395
94
1419
66
67
68
18
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1844


530


S210-
1420
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199
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1424
104
1425
60
1426
1427
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1429
1430
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1432
1433
69
1845
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1129


S451-
1434
1435
798
1436
1437
1438
7
1439
44
1440
1441
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208
1443
210
182
1444
380
1847
1848


5


S451-
1445
1446
1447
473
1448
1449
1450
1451
60
1452
1453
63
151
1454
66
67
1246
69
1849
1850


506


S451-
1455
1456
1457
1458
1459
1460
1461
146
60
1462
1463
1464
1465
1466
1467
1468
1469
53
1851
1852


1140


S451-
1470
1471
1472
1473
1474
1475
476
517
60
1476
1477
1478
119
1479
121
122
123
69
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1190


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1480
1481
1482
1483
1484
1485
7
115
44
1486
1487
338
1143
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50
1489
196
53
1855
1856


84


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1490
1491
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243
1493
245
7
1494
44
1495
1496
1497
1498
1499
1500
1501
1502
18
1857
1858


161


S626-
1503
1504
1505
953
1506
1507
160
1508
60
1509
1510
63
592
1511
66
1512
68
69
1859
1860


664


S728-
1513
1514
1515
1516
1517
1518
476
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670
1520
1521
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1524
1525
1526
253
85
1861
1862


209


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1527
1528
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1530
1531
1239
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147
1533
1534
1535
1536
1537
1538
1181
1539
1540
1863
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369


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1541
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358
392
1543
1544
130
146
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1546
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770
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251
252
997
85
1865
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430


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1564
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1566
1567
1568
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1570
1571
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1574
1575
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69
1869
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1157


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1577
1578
1579
1580
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217
218
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182
196
443
1871
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1588
1589
1590
1591
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1593
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1596
1597
1598
1599
135
1600
1601
1489
1602
53
1873
1874


1690









1. Variant Polypeptides

The following is a discussion of changing the amino acid subunits of a protein to create an equivalent, or even improved, second-generation variant polypeptide or peptide. For example, certain amino acids may be substituted for other amino acids in a protein or polypeptide sequence with or without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines that protein's functional activity, certain amino acid substitutions can be made in a protein sequence and in its corresponding DNA coding sequence, and nevertheless produce a protein with similar or desirable properties. It is thus contemplated by the inventors that various changes may be made in the DNA sequences of genes which encode proteins without appreciable loss of their biological utility or activity.


The term “functionally equivalent codon” is used herein to refer to codons that encode the same amino acid, such as the six different codons for arginine. Also considered are “neutral substitutions” or “neutral mutations” which refers to a change in the codon or codons that encode biologically equivalent amino acids.


Amino acid sequence variants of the disclosure can be substitutional, insertional, or deletion variants. A variation in a polypeptide of the disclosure may affect 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more non-contiguous or contiguous amino acids of the protein or polypeptide, as compared to wild-type. A variant can comprise an amino acid sequence that is at least 50%, 60%, 70%, 80%, or 90%, including all values and ranges there between, identical to any sequence provided or referenced herein. A variant can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more substitute amino acids.


It also will be understood that amino acid and nucleic acid sequences may include additional residues, such as additional N- or C-terminal amino acids, or 5′ or 3′ sequences, respectively, and yet still be essentially identical as set forth in one of the sequences disclosed herein, so long as the sequence meets the criteria set forth above, including the maintenance of biological protein activity where protein expression is concerned. The addition of terminal sequences particularly applies to nucleic acid sequences that may, for example, include various non-coding sequences flanking either of the 5′ or 3′ portions of the coding region.


Deletion variants typically lack one or more residues of the native or wild type protein. Individual residues can be deleted or a number of contiguous amino acids can be deleted. A stop codon may be introduced (by substitution or insertion) into an encoding nucleic acid sequence to generate a truncated protein.


Insertional mutants typically involve the addition of amino acid residues at a non-terminal point in the polypeptide. This may include the insertion of one or more amino acid residues. Terminal additions may also be generated and can include fusion proteins which are multimers or concatemers of one or more peptides or polypeptides described or referenced herein.


Substitutional variants typically contain the exchange of one amino acid for another at one or more sites within the protein or polypeptide, and may be designed to modulate one or more properties of the polypeptide, with or without the loss of other functions or properties. Substitutions may be conservative, that is, one amino acid is replaced with one of similar chemical properties. “Conservative amino acid substitutions” may involve exchange of a member of one amino acid class with another member of the same class. Conservative substitutions are well known in the art and include, for example, the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; and valine to isoleucine or leucine. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics or other reversed or inverted forms of amino acid moieties.


Alternatively, substitutions may be “non-conservative”, such that a function or activity of the polypeptide is affected. Non-conservative changes typically involve substituting an amino acid residue with one that is chemically dissimilar, such as a polar or charged amino acid for a nonpolar or uncharged amino acid, and vice versa. Non-conservative substitutions may involve the exchange of a member of one of the amino acid classes for a member from another class.


2. Considerations for Substitutions

One skilled in the art can determine suitable variants of polypeptides as set forth herein using well-known techniques. One skilled in the art may identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. The skilled artisan will also be able to identify amino acid residues and portions of the molecules that are conserved among similar proteins or polypeptides. Areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without significantly altering the biological activity or without adversely affecting the protein or polypeptide structure.


In making such changes, the hydropathy index of amino acids may be considered. The hydropathy profile of a protein is calculated by assigning each amino acid a numerical value (“hydropathy index”) and then repetitively averaging these values along the peptide chain. Each amino acid has been assigned a value based on its hydrophobicity and charge characteristics. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cysteine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5). The importance of the hydropathy amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte et al., J. Mol. Biol. 157:105-131 (1982)). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein or polypeptide, which in turn defines the interaction of the protein or polypeptide with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and others. It is also known that certain amino acids may be substituted for other amino acids having a similar hydropathy index or score, and still retain a similar biological activity. In making changes based upon the hydropathy index, the substitution of amino acids whose hydropathy indices are within ±2 is included. Those that are within ±1 may be included, or those within ±0.5 may be included.


It also is understood in the art that the substitution of like amino acids can be effectively made based on hydrophilicity. U.S. Pat. No. 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein. The greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, may correlate with its immunogenicity and antigen binding, that is, as a biological property of the protein. The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5±1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); and tryptophan (−3.4). In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within +2 may be included, or those which are within +1 may be included, or those within +0.5 may be included. In some instances, one may also identify epitopes from primary amino acid sequences based on hydrophilicity. These regions are also referred to as “epitopic core regions.” It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still produce a biologically equivalent and immunologically equivalent protein.


Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides or proteins that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues important for activity or structure in similar proteins. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues.


One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar proteins or polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with respect to its three-dimensional structure. One skilled in the art may choose not to make changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules. Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each desired amino acid residue. These variants can then be screened using standard assays for binding and/or activity, thus yielding information gathered from such routine experiments, which may allow one skilled in the art to determine the amino acid positions where further substitutions should be avoided either alone or in combination with other mutations. Various tools available to determine secondary structure can be found on the world wide web at expasy.org/proteomics/protein_structure.


The amino acid substitutions may be made that: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter ligand or antigen binding affinities, and/or (5) confer or modify other physicochemical or functional properties on such polypeptides. For example, single or multiple amino acid substitutions (e.g. conservative amino acid substitutions) may be made in the naturally occurring sequence. Substitutions can be made in that portion of the antibody that lies outside the domain(s) forming intermolecular contacts. Conservative amino acid substitutions can be used that do not substantially change the structural characteristics of the protein or polypeptide (e.g., one or more replacement amino acids that do not disrupt the secondary structure that characterizes the native antibody).


VII. Nucleic Acids

Nucleic acid sequences can exist in a variety of instances such as: isolated segments and recombinant vectors of incorporated sequences or recombinant polynucleotides encoding peptides and polypeptides of the disclosure, or a fragment, derivative, mutein, or variant thereof, polynucleotides sufficient for use as hybridization probes, PCR primers or sequencing primers for identifying, analyzing, mutating or amplifying a polynucleotide encoding a polypeptide, anti-sense nucleic acids for inhibiting expression of a polynucleotide, and complementary sequences of the foregoing described herein. Nucleic acids encoding fusion proteins that include these peptides are also provided. The nucleic acids can be single-stranded or double-stranded and can comprise RNA and/or DNA nucleotides and artificial variants thereof (e.g., peptide nucleic acids).


The term “polynucleotide” refers to a nucleic acid molecule that either is recombinant or has been isolated from total genomic nucleic acid. Included within the term “polynucleotide” are oligonucleotides (nucleic acids 100 residues or less in length), recombinant vectors, including, for example, plasmids, cosmids, phage, viruses, and the like. Polynucleotides include regulatory sequences, isolated substantially away from their naturally occurring genes or protein encoding sequences. Polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be RNA, DNA (genomic, cDNA or synthetic), analogs thereof, or a combination thereof. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide.


In this respect, the term “gene,” “polynucleotide,” or “nucleic acid” is used to refer to a nucleic acid that encodes a protein, polypeptide, or peptide (including any sequences required for proper transcription, post-translational modification, or localization). As will be understood by those in the art, this term encompasses genomic sequences, expression cassettes, cDNA sequences, and smaller engineered nucleic acid segments that express, or may be adapted to express, proteins, polypeptides, domains, peptides, fusion proteins, and mutants. A nucleic acid encoding all or part of a polypeptide may contain a contiguous nucleic acid sequence encoding all or a portion of such a polypeptide. It also is contemplated that a particular polypeptide may be encoded by nucleic acids containing variations having slightly different nucleic acid sequences but, nonetheless, encode the same or substantially similar protein.


Also included are polynucleotide variants having substantial identity to the sequences disclosed herein; those comprising at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or higher sequence identity, including all values and ranges there between, compared to a polynucleotide sequence provided herein using the methods described herein (e.g., BLAST analysis using standard parameters). The isolated polynucleotide may comprise a nucleotide sequence encoding a polypeptide that has at least 90%, preferably 95% and above, identity to an amino acid sequence described herein, over the entire length of the sequence; or a nucleotide sequence complementary to said isolated polynucleotide.


The nucleic acid segments, regardless of the length of the coding sequence itself, may be combined with other nucleic acid sequences, such as promoters, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, other coding segments, and the like, such that their overall length may vary considerably. The nucleic acids can be any length. They can be, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 125, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1000, 1500, 3000, 5000 or more nucleotides in length, and/or can comprise one or more additional sequences, for example, regulatory sequences, and/or be a part of a larger nucleic acid, for example, a vector. It is therefore contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant nucleic acid protocol. In some cases, a nucleic acid sequence may encode a polypeptide sequence with additional heterologous coding sequences, for example to allow for purification of the polypeptide, transport, secretion, post-translational modification, or for therapeutic benefits such as targeting or efficacy. As discussed above, a tag or other heterologous polypeptide may be added to the modified polypeptide-encoding sequence, wherein “heterologous” refers to a polypeptide that is not the same as the modified polypeptide.


A. Hybridization

The nucleic acids that hybridize to other nucleic acids under particular hybridization conditions. Methods for hybridizing nucleic acids are well known in the art. See, e.g., Current Protocols in Molecular Biology, John Wiley and Sons, N. Y. (1989), 6.3.1-6.3.6. As defined herein, a moderately stringent hybridization condition uses a prewashing solution containing 5× sodium chloride/sodium citrate (SSC), 0.5% SDS, 1.0 mM EDTA (pH 8.0), hybridization buffer of about 50% formamide, 6×SSC, and a hybridization temperature of 55° C. (or other similar hybridization solutions, such as one containing about 50% formamide, with a hybridization temperature of 42° C.), and washing conditions of 60° C. in 0.5×SSC, 0.1% SDS. A stringent hybridization condition hybridizes in 6×SSC at 45° C., followed by one or more washes in 0.1×SSC, 0.2% SDS at 68° C. Furthermore, one of skill in the art can manipulate the hybridization and/or washing conditions to increase or decrease the stringency of hybridization such that nucleic acids comprising nucleotide sequence that are at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to each other typically remain hybridized to each other.


The parameters affecting the choice of hybridization conditions and guidance for devising suitable conditions are set forth by, for example, Sambrook, Fritsch, and Maniatis (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters 9 and 11 (1989); Current Protocols in Molecular Biology, Ausubel et al., eds., John Wiley and Sons, Inc., sections 2.10 and 6.3-6.4 (1995), both of which are herein incorporated by reference in their entirety for all purposes) and can be readily determined by those having ordinary skill in the art based on, for example, the length and/or base composition of the DNA.


B. Mutation

Changes can be introduced by mutation into a nucleic acid, thereby leading to changes in the amino acid sequence of a polypeptide (e.g., an antigenic peptide or polypeptide) that it encodes. Mutations can be introduced using any technique known in the art. One or more particular amino acid residues may be changed using, for example, a site-directed mutagenesis protocol. One or more randomly selected residues may be changed using, for example, a random mutagenesis protocol. However it is made, a mutant polypeptide can be expressed and screened for a desired property.


Mutations can be introduced into a nucleic acid without significantly altering the biological activity of a polypeptide that it encodes. For example, one can make nucleotide substitutions leading to amino acid substitutions at non-essential amino acid residues. Alternatively, one or more mutations can be introduced into a nucleic acid that selectively changes the biological activity of a polypeptide that it encodes. See, eg., Romain Studer et al., Biochem. J. 449:581-594 (2013). For example, the mutation can quantitatively or qualitatively change the biological activity. Examples of quantitative changes include increasing, reducing or eliminating the activity. Examples of qualitative changes include altering the antigen specificity of an antibody.


C. Probes

Nucleic acid molecules may be suitable for use as primers or hybridization probes for the detection of nucleic acid sequences. A nucleic acid molecule can comprise only a portion of a nucleic acid sequence encoding a full-length polypeptide, for example, a fragment that can be used as a probe or primer or a fragment encoding an active portion of a given polypeptide.


The nucleic acid molecules may be used as probes or PCR primers for specific nucleic acid sequences. For instance, a nucleic acid molecule probe may be used in diagnostic methods or a nucleic acid molecule PCR primer may be used to amplify regions of DNA that could be used, inter alia, to isolate nucleic acid sequences for use in producing the engineered cells of the disclosure. The nucleic acid molecules may be further defined as oligonucleotides.


Probes based on the desired sequence of a nucleic acid can be used to detect the nucleic acid or similar nucleic acids, for example, transcripts encoding a polypeptide of interest. The probe can comprise a label group, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used to identify a cell that expresses the polypeptide.


VIII. Polypeptide Expression

Also provided are nucleic acid molecule encoding polypeptides, antibodies, or antigen binding fragments of the disclosure. The nucleic acid molecules may be used to express large quantities of polypeptides. If the nucleic acid molecules are derived from a non-human, non-transgenic animal, the nucleic acid molecules may be used for humanization of the antibody or TCR genes.


A. Vectors

Contemplated are expression vectors comprising a nucleic acid molecule encoding a polypeptide of the desired sequence or a portion thereof (e.g., a fragment containing one or more CDRs or one or more variable region domains). Expression vectors comprising the nucleic acid molecules may encode the heavy chain, light chain, or the antigen-binding portion thereof. Also provided are expression vectors comprising nucleic acid molecules may encode fusion proteins, modified antibodies, antibody heavy and/or light chain, antibody fragments, and probes thereof. In addition to control sequences that govern transcription and translation, vectors and expression vectors may contain nucleic acid sequences that serve other functions as well.


To express the polypeptides or peptides of the disclosure, DNAs encoding the polypeptides or peptides are inserted into expression vectors such that the gene area is operatively linked to transcriptional and translational control sequences. A vector that encodes a functionally complete human CH or CL immunoglobulin sequence with appropriate restriction sites may be engineered so that any VH or VL sequence can be easily inserted and expressed. A vector that encodes a functionally complete human TCR alpha or TCR beta sequence with appropriate restriction sites may be engineered so that any variable sequence or CDR1, CDR2, and/or CDR3 can be easily inserted and expressed. Typically, expression vectors used in any of the host cells contain sequences for plasmid or virus maintenance and for cloning and expression of exogenous nucleotide sequences. Such sequences, collectively referred to as “flanking sequences” typically include one or more of the following operatively linked nucleotide sequences: a promoter, one or more enhancer sequences, an origin of replication, a transcriptional termination sequence, a complete intron sequence containing a donor and acceptor splice site, a sequence encoding a leader sequence for polypeptide secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element. Such sequences and methods of using the same are well known in the art.


B. Expression Systems

Numerous expression systems exist that comprise at least a part or all of the expression vectors discussed above. Prokaryote- and/or eukaryote-based systems can be employed to produce nucleic acid sequences, or their cognate polypeptides, proteins and peptides. Commercially and widely available systems include in but are not limited to bacterial, mammalian, yeast, and insect cell systems. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. Those skilled in the art are able to express a vector to produce a nucleic acid sequence or its cognate polypeptide, protein, or peptide using an appropriate expression system.


C. Methods of Gene Transfer

Suitable methods for nucleic acid delivery to effect expression of compositions are anticipated to include virtually any method by which a nucleic acid (e.g., DNA, including viral and nonviral vectors) can be introduced into a cell, a tissue or an organism, as described herein or as would be known to one of ordinary skill in the art. Such methods include, but are not limited to, direct delivery of DNA such as by injection (U.S. Pat. No. 5,994,624, 5,981,274, 5,945,100, 5,780,448, 5,736,524, 5,702,932, 5,656,610, 5,589,466 and 5,580,859, each incorporated herein by reference), including microinjection (Harland and Weintraub, 1985; U.S. Pat. No. 5,789,215, incorporated herein by reference); by electroporation (U.S. Pat. No. 5,384,253, incorporated herein by reference); by calcium phosphate precipitation (Graham and Van Der Eb, 1973; Chen and Okayama, 1987; Rippe et al., 1990); by using DEAE dextran followed by polyethylene glycol (Gopal, 1985); by direct sonic loading (Fechheimer et al., 1987); by liposome mediated transfection (Nicolau and Sene, 1982; Fraley et al., 1979; Nicolau et al., 1987; Wong et al., 1980; Kaneda et al., 1989; Kato et al., 1991); by microprojectile bombardment (PCT Application Nos. WO 94/09699 and 95/06128; U.S. Pat. Nos. 5,610,042; 5,322,783, 5,563,055, 5,550,318, 5,538,877 and 5,538,880, and each incorporated herein by reference); by agitation with silicon carbide fibers (Kaeppler et al., 1990; U.S. Pat. Nos. 5,302,523 and 5,464,765, each incorporated herein by reference); by Agrobacterium mediated transformation (U.S. Pat. Nos. 5,591,616 and 5,563,055, each incorporated herein by reference); or by PEG mediated transformation of protoplasts (Omirulleh et al., 1993; U.S. Pat. Nos. 4,684,611 and 4,952,500, each incorporated herein by reference); by desiccation/inhibition mediated DNA uptake (Potrykus et al., 1985). Other methods include viral transduction, such as gene transfer by lentiviral or retroviral transduction.


IX. Pharmaceutical Compositions

The present disclosure includes methods for treating disease and modulating immune responses in a subject in need thereof. The disclosure includes cells that may be in the form of a pharmaceutical composition that can be used to induce or modify an immune response.


Administration of the compositions according to the current disclosure will typically be via any common route. This includes, but is not limited to parenteral, orthotopic, intradermal, subcutaneous, orally, transdermally, intramuscular, intraperitoneal, intraperitoneally, intraorbitally, by implantation, by inhalation, intraventricularly, intranasally or intravenous injection. Compositions of the present disclosure (e.g., compositions comprising SARS-CoV-2 protein-binding polypeptides) may be administered to a subject intravenously.


Typically, compositions and therapies of the disclosure are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically effective and immune modifying. The quantity to be administered depends on the subject to be treated. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner.


The manner of application may be varied widely. Any of the conventional methods for administration of pharmaceutical compositions comprising cellular components are applicable. The dosage of the pharmaceutical composition will depend on the route of administration and will vary according to the size and health of the subject.


In many instances, it will be desirable to have multiple administrations of at most or at least 3, 4, 5, 6, 7, 8, 9, 10 or more. The administrations may range from 2-day to 12-week intervals, more usually from one to two week intervals.


The phrases “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in immunogenic and therapeutic compositions is contemplated. The pharmaceutical compositions of the current disclosure are pharmaceutically acceptable compositions.


The compositions of the disclosure can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions and the preparations can also be emulsified.


Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.


Sterile injectable solutions are prepared by incorporating the active ingredients (e.g., polypeptides of the disclosure) in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.


An effective amount of a composition is determined based on the intended goal. The term “unit dose” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the composition calculated to produce the desired responses discussed herein in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and/or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above.


The compositions and related methods of the present disclosure, particularly administration of a composition of the disclosure may also be used in combination with the administration of additional therapies such as the additional therapeutics described herein or in combination with other traditional therapeutics known in the art.


The therapeutic compositions and treatments disclosed herein may precede, be co-current with and/or follow another treatment or agent by intervals ranging from minutes to weeks. In instances where agents are applied separately to a cell, tissue or organism, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the therapeutic agents would still be able to exert an advantageously combined effect on the cell, tissue or organism. For example, in such instances, it is contemplated that one may contact the cell, tissue or organism with two, three, four or more agents or treatments substantially simultaneously (i.e., within less than about a minute). One or more therapeutic agents or treatments may be administered or provided within 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more, and any range derivable therein, prior to and/or after administering another therapeutic agent or treatment.


The treatments may include various “unit doses.” Unit dose is defined as containing a predetermined-quantity of the therapeutic composition. The quantity to be administered, and the particular route and formulation, is within the skill of determination of those in the clinical arts. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. A unit dose may comprise a single administrable dose.


The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. It is contemplated that doses in the range from 10 mg/kg to 200 mg/kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 μg/kg, mg/kg, μg/day, or mg/day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and/or on multiple days, weeks, or months.


The therapeutically effective or sufficient amount of the immune checkpoint inhibitor, such as an antibody and/or microbial modulator, that is administered to a human may be in the range of about 0.01 to about 50 mg/kg of patient body weight whether by one or more administrations. The therapy used may be about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg administered daily, for example. A therapy described herein may be administered to a subject at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg on day 1 of 21-day cycles. The dose may be administered as a single dose or as multiple doses (e.g., 2 or 3 doses), such as infusions. The progress of this therapy is easily monitored by conventional techniques.


The effective dose of the pharmaceutical composition may be one which can provide a blood level of about 1 μM to 150 μM. The effective dose may provide a blood level of about 4 μM to 100 μM; or about 1μ M to 100μ; or about 1μ M to 50μ; or about 1μ M to 40μ; or about 1 μM to 30 μM; or about 1 μM to 20 μM; or about 1 μM to 10 μM; or about 10 μM to 150 μM; or about 10 μM to 100 μM; or about 10 μM to 50 μM; or about 25 μM to 150 μM; or about 25 μM to 100 μM; or about 25 μM to 50 μM; or about 50 μM to 150 μM; or about 50 μM to 100 μM (or any range derivable therein). The dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μM or any range derivable therein. The therapeutic agent may be administered to a subject and may be metabolized in the body to a metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent.


Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.


It will be understood by those skilled in the art and made aware that dosage units of μg/kg or mg/kg of body weight can be converted and expressed in comparable concentration units of μg/ml or mM (blood levels), such as 4 μM to 100 μM. It is also understood that uptake is species and organ/tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.


X. Detectable Labels

It will be useful to detectably or therapeutically label an antibody or antigen binding fragment. Methods for conjugating polypeptides to these agents are known in the art. For the purpose of illustration only, polypeptides can be labeled with a detectable moiety such as a radioactive atom, a chromophore, a fluorophore, or the like. Such labeled polypeptides can be used for diagnostic techniques, either in vivo, or in an isolated test sample or in methods described herein.


As used herein, the term “label” intends a directly or indirectly detectable compound or composition that is conjugated directly or indirectly to the composition to be detected, e.g., polynucleotide or protein such as an antibody so as to generate a “labeled” composition. The term also includes sequences conjugated to the polynucleotide that will provide a signal upon expression of the inserted sequences, such as green fluorescent protein (GFP) and the like. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable. The labels can be suitable for small scale detection or more suitable for high-throughput screening. As such, suitable labels include, but are not limited to radioisotopes, fluorochromes, chemiluminescent compounds, dyes, and proteins, including enzymes. The label may be simply detected or it may be quantified. A response that is simply detected generally comprises a response whose existence merely is confirmed, whereas a response that is quantified generally comprises a response having a quantifiable (e.g., numerically reportable) value such as an intensity, polarization, and/or other property. In luminescence or fluorescence assays, the detectable response may be generated directly using a luminophore or fluorophore associated with an assay component actually involved in binding, or indirectly using a luminophore or fluorophore associated with another (e.g., reporter or indicator) component.


Examples of luminescent labels that produce signals include, but are not limited to bioluminescence and chemiluminescence. Detectable luminescence response generally comprises a change in, or an occurrence of, a luminescence signal. Suitable methods and luminophores for luminescently labeling assay components are known in the art and described for example in Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6.sup.th ed.). Examples of luminescent probes include, but are not limited to, aequorin and luciferases.


Examples of suitable fluorescent labels include, but are not limited to, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosin, coumarin, methyl-coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade Blue™, and Texas Red. Other suitable optical dyes are described in the Haugland, Richard P. (1996) Handbook of Fluorescent Probes and Research Chemicals (6.sup.th ed.).


The fluorescent label may be functionalized to facilitate covalent attachment to a cellular component present in or on the surface of the cell or tissue such as a cell surface marker. Suitable functional groups, including, but not are limited to, isothiocyanate groups, amino groups, haloacetyl groups, maleimides, succinimidyl esters, and sulfonyl halides, all of which may be used to attach the fluorescent label to a second molecule. The choice of the functional group of the fluorescent label will depend on the site of attachment to either a linker, the agent, the marker, or the second labeling agent.


Attachment of the fluorescent label may be either directly to the cellular component or compound or alternatively, can by via a linker. Suitable binding pairs for use in indirectly linking the fluorescent label to the intermediate include, but are not limited to, antigens/polypeptides, e.g., rhodamine/anti-rhodamine, biotin/avidin and biotin/strepavidin.


The coupling of polypeptides to low molecular weight haptens can increase the sensitivity of the antibody in an assay. The haptens can then be specifically detected by means of a second reaction. For example, it is common to use haptens such as biotin, which reacts avidin, or dinitrophenol, pyridoxal, and fluorescein, which can react with specific anti-hapten polypeptides. See, Harlow and Lane (1988) supra.


XI. Sample Preparation

Methods can involve obtaining or evaluating a sample from a subject. The sample may include a sample obtained from any source including but not limited to blood, sweat, hair follicle, buccal tissue, tears, menses, feces, or saliva. Any medical professional such as a doctor, nurse or medical technician may obtain a biological sample for testing. Yet further, the biological sample can be obtained without the assistance of a medical professional.


A sample may include but is not limited to, tissue, cells, or biological material from cells or derived from cells of a subject. The biological sample may be a heterogeneous or homogeneous population of cells or tissues. The biological sample may be obtained using any method known to the art that can provide a sample suitable for the analytical methods described herein. The sample may be obtained by non-invasive methods including but not limited to: scraping of the skin or cervix, swabbing of the cheek, saliva collection, urine collection, feces collection, collection of menses, tears, or semen.


The sample may be obtained by methods known in the art. The samples may be obtained by biopsy. The sample may be obtained by swabbing, endoscopy, scraping, phlebotomy, or any other methods known in the art. In some cases, the sample may be obtained, stored, or transported using components of a kit of the present methods. In some cases, multiple samples, such as multiple esophageal samples may be obtained for diagnosis by the methods described herein. In other cases, multiple samples, such as one or more samples from one tissue type (for example esophagus) and one or more samples from another specimen (for example serum) may be obtained for diagnosis by the methods. In some cases, multiple samples such as one or more samples from one tissue type (e.g. esophagus) and one or more samples from another specimen (e.g. serum) may be obtained at the same or different times. Samples may be obtained at different times are stored and/or analyzed by different methods. For example, a sample may be obtained and analyzed by routine staining methods or any other cytological analysis methods.


The biological sample may be obtained by a physician, nurse, or other medical professional such as a medical technician, endocrinologist, cytologist, phlebotomist, radiologist, or a pulmonologist. The medical professional may indicate the appropriate test or assay to perform on the sample. A molecular profiling business may consult on which assays or tests are most appropriately indicated. The patient or subject may obtain a biological sample for testing without the assistance of a medical professional, such as obtaining a whole blood sample, a urine sample, a fecal sample, a buccal sample, or a saliva sample.


In other cases, the sample is obtained by an invasive procedure including but not limited to: biopsy, needle aspiration, endoscopy, or phlebotomy. The method of needle aspiration may further include fine needle aspiration, core needle biopsy, vacuum assisted biopsy, or large core biopsy. Multiple samples may be obtained by the methods herein to ensure a sufficient amount of biological material.


General methods for obtaining biological samples are also known in the art. Publications such as Ramzy, Ibrahim Clinical Cytopathology and Aspiration Biopsy 2001, which is herein incorporated by reference in its entirety, describes general methods for biopsy and cytological methods. In some cases, the fine needle aspirate sampling procedure may be guided by the use of an ultrasound, X-ray, or other imaging device.


The molecular profiling business may obtain the biological sample from a subject directly, from a medical professional, from a third party, or from a kit provided by a molecular profiling business or a third party. In some cases, the biological sample may be obtained by the molecular profiling business after the subject, a medical professional, or a third party acquires and sends the biological sample to the molecular profiling business. In some cases, the molecular profiling business may provide suitable containers, and excipients for storage and transport of the biological sample to the molecular profiling business.


A medical professional may need not be involved in the initial diagnosis or sample acquisition. An individual may alternatively obtain a sample through the use of an over the counter (OTC) kit. An OTC kit may contain a means for obtaining said sample as described herein, a means for storing said sample for inspection, and instructions for proper use of the kit. In some cases, molecular profiling services are included in the price for purchase of the kit. In other cases, the molecular profiling services are billed separately. A sample suitable for use by the molecular profiling business may be any material containing tissues, cells, nucleic acids, genes, gene fragments, expression products, gene expression products, or gene expression product fragments of an individual to be tested. Methods for determining sample suitability and/or adequacy are provided.


The subject may be referred to a specialist such as an oncologist, surgeon, or endocrinologist. The specialist may likewise obtain a biological sample for testing or refer the individual to a testing center or laboratory for submission of the biological sample. In some cases the medical professional may refer the subject to a testing center or laboratory for submission of the biological sample. In other cases, the subject may provide the sample. In some cases, a molecular profiling business may obtain the sample.


XII. Host Cells

As used herein, the terms “cell,” “cell line,” and “cell culture” may be used interchangeably. All of these terms also include both freshly isolated cells and ex vivo cultured, activated or expanded cells. All of these terms also include their progeny, which is any and all subsequent generations. It is understood that all progeny may not be identical due to deliberate or inadvertent mutations. In the context of expressing a heterologous nucleic acid sequence, “host cell” refers to a prokaryotic or eukaryotic cell, and it includes any transformable organism that is capable of replicating a vector or expressing a heterologous gene encoded by a vector. A host cell can, and has been, used as a recipient for vectors or viruses. A host cell may be “transfected” or “transformed,” which refers to a process by which exogenous nucleic acid, such as a recombinant protein-encoding sequence, is transferred or introduced into the host cell. A transformed cell includes the primary subject cell and its progeny.


Transfection can be carried out on any prokaryotic or eukaryotic cell. Electroporation can involve transfection of a human cell. Electroporation can involve transfection of an animal cell. Transfection can involve transfection of a cell line or a hybrid cell type. The cells or cell lines can be A549, B-cells, B16, BHK-21, C2C12, C6, CaCo-2, CAP/, CAP-T, CHO, CHO2, CHO-DG44, CHO-K1, COS-1, Cos-7, CV-1, Dendritic cells, DLD-1, Embryonic Stem (ES) Cell or derivative, H1299, HEK, 293, 293T, 293 FT, Hep G2, Hematopoietic Stem Cells, HOS, Huh-7, Induced Pluripotent Stem (iPS) Cell or derivative, Jurkat, K562, L5278Y, LNCaP, MCF7, MDA-MB-231, MDCK, Mesenchymal Cells, Min-6, Monocytic cell, Neuro2a, NIH 3T3, NIH3T3L1, K562, NK-cells, NS0, Panc-1, PC12, PC-3, Peripheral blood cells, Plasma cells, Primary Fibroblasts, RBL, Renca, RLE, SF21, SF9, SH-SY5Y, SK-MES-1, SK-N-SH, SL3, SW403, Stimulus-triggered Acquisition of Pluripotency (STAP) cell or derivate SW403, T-cells, THP-1, Tumor cells, U2OS, U937, peripheral blood lymphocytes, expanded T cells, hematopoietic stem cells, or Vero cells.


XIII. Kits

Also described are kits containing compositions of the disclosure or compositions to implement methods of the disclosure. Kits can be used to detect the presence of a SARS-CoV-2 virus in a sample. A kit can contain, contain at least or contain at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 100, 500, 1,000 or more probes, primers or primer sets, synthetic molecules or inhibitors, or any value or range and combination derivable therein. A kit can contain one or more polypeptides capable of binding to a SARS-CoV-2 spike protein, including polypeptides disclosed herein. For example, a kit may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more Fabs disclosed herein for detecting a SARS-CoV-2 spike protein. A kit may comprise a detection pair. A kit may comprise an enzyme. A kit may comprise a substrate for an enzyme.


Kits may comprise components, which may be individually packaged or placed in a container, such as a tube, bottle, vial, syringe, or other suitable container means.


Individual components may also be provided in a kit in concentrated amounts; a component may be provided individually in the same concentration as it would be in a solution with other components. Concentrations of components may be provided as 1×, 2×, 5×, 10×, or 20× or more.


Kits for using probes, synthetic nucleic acids, nonsynthetic nucleic acids, and/or inhibitors of the disclosure for prognostic or diagnostic applications are included as part of the disclosure. Negative and/or positive control nucleic acids, probes, and inhibitors may be included in some kits.


Kits may further comprise instructions for use. For example, a kit comprises instructions for detecting a SARS-CoV-2 virus in a sample.


It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different aspects may be combined. The claims originally filed are contemplated to cover claims that are multiply dependent on any filed claim or combination of filed claims.


XIV. EXAMPLES

The following examples are included to demonstrate certain aspects of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments and aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.


Example 1-Cross Neutralization of Emerging SARS-CoV-2 Variants of Concern by Antibodies Targeting Distinct Epitopes on Spike
A. Results

1. Convalescent Sera have Reduced Antibody Titers but Retain Neutralization Capabilities against Circulating SARS-CoV-2 VOCs


To investigate whether antibodies from subjects naturally infected with WT SARS-CoV-2 lost binding or neutralization activity against VOCs, the inventors collected blood samples from 10 convalescent donors at a median of 49 days post-symptom onset26, 27 (Supplementary Table 1) forin-depth analysis of specificity of individual memory B cells. As an initial estimate of antibody activity from these patients, serum antibody reactivity was measured comparing reactivity to WTtrimeric SARS-CoV-2 spike and spike proteins from the D614G, B.1.1.7, B. 1.351, P.1, B.1.617.2, B.1.526, and B.1.617.1 variants. While serum antibody IgG titers from these 10 patients against WT and D614G spike antigens were similar, titers were significantly reduced against the spike proteins of B.1.1.7 (1.4-fold), B.1.351 (1.5-fold), P.1 (3.8-fold), B.1.617.2 (1.5-fold), B.1.526 (1.3-fold), and B.1.617.1 (2.3-fold) relative to WT spike protein (FIG. 1a). Similarly, IgG titers against the RBD of B.1.1.7 (1.7-fold), B.1.351 (2.8-fold) and P.1 (2.6-fold) were reduced compared to WT RBD. However, the inventors noted that there was less than a 2-fold decrease in antibody binding against single mutants of the RBD (FIG. 1b). Despite reductions in serum binding activity, the sera retained similar neutralizing titers against the WT, B.1.1.7 and P.1 SARS-CoV-2 variants. However, the inventors found a significant reduction in neutralization against B.1.617.1 and B.1.617.2 compared to WT (FIG. 1c). Although antibody titers were lower against the VOCs and VUMs, these data indicate that serum antibodies elicited by natural WT infection were able to neutralize B.1.1.7, P.1 and WT virus equally, while most donors lost neutralizing potential against B.1.617-lineage viruses.


2. Generation of Mabs Against Distinct Domains of the Sars-Cov-2 Spike

The inventors next sought to determine the specificities of antibodies that could cross-neutralize these viral variants by generating mAbs from spike-binding B cells isolated from 10 convalescent subjects collected between April and July of 202026, 27. The inventors sort-purified B cells binding to spike and/or RBD fluorophore- and oligo-conjugated probes, and performed single-cell RNA-sequencing and B cell receptor sequencing. As the antigen probes included a DNA oligonucleotide sequence, the inventors were able to track the antigen-specificity of isolated B cells. In total, the inventors obtained 1,703 paired immunoglobulin heavy and light chains from non-RBD- and RBD-binding B cells specific for the spike. Overall, the percentage of spike non-RBD-binding B cells was 4-fold higher than RBD-binding B cells (FIG. 2a-c), indicating that natural WT infection preferentially induced B cell response toward epitopes on the spike outside of the RBD28.29. Overall, B cells targeting the RBD or epitopes outside of the RBD utilized similar V (D) J genes, had overlapping heavy and light chain pairings, and possessed similar numbers of mutations and complementarity determining region 3 (CDR3) lengths (FIG. 5a-i).


Based on the acquired antibody sequences and probe-binding intensities, the inventors generated 43 mAbs from all 10 donors specific to the WT spike protein (Supplementary Table 2). To investigate specific domain targeting, mAbs were tested for binding to the RBD and monomeric S1 and S2 recombinant spike antigens. Based on binding to these discrete antigens, spike-reactive mAbs were categorized into 4 groups: NTD-A-reactive mAbs (n=5) that bound strongly to S1 but not RBD, NTD-B-reactive mAbs (n=7) that weakly bind S1 but not RBD, S2-reactive mAbs (n=2), and RBD-reactive mAbs (n=29) (FIG. 2d-e). Additionally, NTD-A and NTD-B-classified antibodies targeted distinct epitopes as shown by competition ELISA (FIG. 6a). The inventors further determined whether antibodies with different binding specificities differ in their neutralization capacity against WT SARS-CoV-2. Of the 43 mAbs, 18 (42%) were neutralizing. Notably, only mAbs binding the RBD and NTD-B were neutralizing, whereas all mAbs binding NTD-A and S2 were non-neutralizing (FIG. 2d-f). Moreover, 52% of RBD-targeting mAbs were neutralizing, with eight mAbs being potently neutralizing antibodies (50% inhibitory concentration, IC50, of <500 ng/ml), and three out of seven NTD-B mAbs having moderate neutralization potency (5,000-7,500 ng/ml) (FIG. 2g-h). Of the 10 convalescent donors, seven had at least one neutralizing mAb among the antibodies cloned for this study, although the potencies of the mAbs varied by donor (FIG. 2i). Together, these data reveal that mAbs against the RBD are the predominate source of neutralizing antibodies induced by WT SARS-CoV-2 infection.


3. Binding and Neutralizing Breadth of Non-RBD Spike Antibodies

To understand the effects of viral variants on mAb binding to epitopes on the spike outside of the RBD, the inventors tested non-RBD-targeting mAbs for binding to a panel of SARS-CoV-2 variants, including D614G and the emerging variants B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.526 and


B.1.617.1 (FIG. 3a-g). All non-RBD spike-reactive antibodies showed similar binding to the D614G spike. Furthermore, all mAbs targeting NTD-A and S2 maintained similar binding to the spike of the B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.526 and B.1.617.1 variants (FIG. 3h). Although mAbs against NTD-A and S2 retain binding to VOCs, they are non-neutralizing, implying that NTD-A- and S2-reactive antibodies may provide limited immune pressure to mutate these epitopes. Of interest, NTD-B mAbs showed significantly reduced binding to the spike of B.1.1.7, B.1.351, B.1.617.2 and B.1.617.1 while showing similar binding to B.1.526, and a minor reduction in binding to the spike of P.1 (FIG. 3h). Two of the three neutralizing NTD-B binding mAbs (S166-32 and S305-1456), which were isolated from two different subjects, retained neutralization potential against B.1.1.7 and P.1 at moderate neutralizing potency (FIG. 3h). The third neutralizing NTD-B-binding mAb (S24-1301) also had moderate neutralizing potency against the WT strain with weak cross-neutralization activity against the P.1 variant and no neutralization activity against B.1.1.7, consistent with its binding profile (FIG. 3h). However, all three neutralizing NTD-B mAbs failed to neutralize B.1.617.1 and B.1.617.2. Together, our data indicate that antibodies against NTD-B show cross-neutralization capacity and thus may provide protection against some emerging VOCs, such as B.1.1.7 and P.1. However, antibodies targeting the NTD-B epitope may be driving spike evolution, particularly the mutations and deletions found within B.1.1.7, B.1.351, B.1.617.1 and B.1.617.2, leaving the future of this epitope as a reliable target for cross-reactive antibodies uncertain.


4. A Subset of RBD-Binding mAbs Retain Neutralization Activity Against VOCs


Viral escape mutations occurring within the RBD may result in reduction in neutralization capacity of RBD-targeting antibodies30-32. To understand the impacts of RBD mutations on mAb binding, the inventors tested RBD-targeting mAbs for binding to RBD mutants that possessed a single mutation found in circulating SARS-CoV-2 VOCs, VOIs, VUMs or artificial mutants at key contact residues of the RBD-ACE2 interaction30-35, as well as full-length spike constructs containing multiple mutations in the RBD (Supplementary Table 3). In addition, the inventors tested mAb binding to the RBDs of SARS-CoV-1 and Middle Eastern Respiratory Syndrome (MERS)-CoV to investigate cross-reactivity to other coronaviruses. Notably, RBD-binding mAbs have been classified into four classes, classes 1-4 or receptor binding site (RBS) A-D, based on structural analysis and antibody binding features36, 37. More recently, classification of four key antigenic regions of the RBD can also be defined by determining the loss of binding to RBD mutants (class 1-3 epitopes) or binding to cryptic epitopes on the RBD that are conserved across SARS-CoV-1 and MERS-CoV RBDs (class 4 epitope, FIG. 4a-b) 30.38. Based on the binding profiles of class 1˜4 binding mAbs, the inventors were able to segregate 23 out of 29 mAbs into one of the four classes (FIG. 4c and Supplementary FIG. 2b). Notably, no class 1 mAbs were found and six mAbs could not be classified as they either lost binding to multiple mutant classes or bound equally to all RBD mutants but did not bind to SARS-CoV-1 or MERS-CoV.


Class 2 RBD-binding mAbs showed reduced binding to at least one of the RBD class 2 single escape mutants, notably E484K and F490K, and the majority of these mAbs lost binding to the RBD mutants found in the B.1.351, P.1, B.1.526 and B.1.617.1 (FIG. 4c). Of the 12 class 2 mAbs, 11 were potently neutralizing against WT SARS-CoV-2. Of the neutralizing class 2 mAbs, all but one neutralized B.1.1.7 at concentrations comparable to neutralization of the WT strain. By contrast, six neutralized B.1.617.2 at lower potency compared to WT and B.1.1.7. Seven of the class 2 mAbs retained their neutralization activity against at least two VOCs (FIG. 4c). Of note, 10 out of 11 neutralizing class 2 mAbs were unable to neutralize the variants that harbored a mutation at E484, P.1 and B.1.617.1. This is in line with previous studies, which have shown that the E484K and E484Q mutations are the key escaping residue responsible for neutralization resistance by P.1, P.2, B.1.351 and B.1.617.1 VOCs2, 4, 39. Of greatest interest, S144-1406, which retained binding to E484K and to all spike variants, neutralized B.1.1.7 and P.1 variants with high neutralization potency. Similar to another E484K-binder, S24-1224 neutralized three out of four VOCs tested, including B.1.617.1 (FIG. 4c). These data indicate that some class 2 antibodies can cross-neutralize VOCs. Additionally, the epitope targeted by S144-1406 partially overlapped with S24-1224 and other class 2 mAbs that failed to neutralize P.1 and B.1.617.1 (FIG. 6c), suggesting class 2 mAbs target similar but slightly different RBD epitopes.


Only one mAb (S24-821) specifically lost binding to the class 3 mutants, particularly to N439K and N440K, which are associated with circulating SARS-CoV-2 variants35, 40 and have been reported as in vitro escape sites for class 3 epitope-binding mAbs30, 31, 35 (FIG. 4b and Supplementary Table 3). Moreover, the inventors classified five more mAbs as class 3-like as they strongly competed for RBD binding with S24-821 but did not compete with class 2 mAbs (FIG. 6b). Importantly, all class 3 and class 3-like mAbs maintained binding to L452R, another mutation associated with class 3 antibodies that is present in B.1.427/B.1.42919, 41 and B.1.617 variants20 (FIG. 4c). However, there was 2-3-fold reduction of class 3 and class 3-like mAbs in binding against B.1.617.2 which carry T487K and L452R substitutions in RBD region. Of the four neutralizing class 3 and class 3-like mAbs, all four retained neutralization activity against B.1.1.7 and three were neutralizing against P.1 (FIG. 4b). In contrast to class 2 mAbs, B.1.617.2 was resistant to all class 3-neutralizing mAbs. Only one mAb (S24-821) retained modest neutralization potency to B.1.617.1, indicating antibodies binding class 3 epitopes could neutralize some VOCs even though they bound L452R single mutation and all spike variants.


All of the mAbs that were categorized into class 4 (n=5) maintained binding to all RBD mutants and spike variants and displayed cross-reactivity to the SARS-CoV-1 RBD. However, all class 4 mAbs were non-neutralizing against WT virus, suggesting antibodies against this epitope are likely not strong drivers of antigenic drift. Notably, three antibodies in the class 4 group utilized the same heavy chain gene, VH5-51, as CR3022 and competed with CR3022 for binding to the RBD, indicating the class 4 antibodies in our study likely target the same or a similar epitope as CR3022 (Supplementary Table 2 and FIG. 6d). This is consistent with a previous study showing CR3022 cross-reacts with SARS-CoV-1, suggesting class 4 antibodies are common across subjects and studies 17.30.


With the classification of mAbs against distinct epitopes, the inventors next tested the relative abundance of serum antibodies against these distinct epitopes of the RBD and NTD by performing competition assays. Notably, donors had significantly higher titers of serum antibodies targeting class 3 (S24-821) and class 3-like (S20-74) epitopes, whereas subjects largely had undetectable titers against class 2 and NTD-B epitopes, suggesting WT SARS-CoV-2 infection predominately induces polyclonal antibodies targeting RBD class 3 epitopes that can neutralize emerging VOCs B.1.1.7 and P.1. (FIG. 6e). These data are consistent with the observed anti-B.1.1.7 and anti-P.1 serum neutralizing titers shown in FIG. 1c, suggesting the retention of serum neutralization activity could be due to abundant class 3 antibody responses. Loss of neutralization capabilities to B.1.617-lineage viruses may be due to insufficient levels of class 2 serum antibodies. A comparison of the neutralization capabilities of mAbs targeting different epitopes revealed class 2 RBD-reactive mAbs were the most potently neutralizing followed by mAbs targeting class 3 RBD epitopes and NTD-B (FIG. 7a). It is important to note that none of neutralizing mAbs induced by natural WT infection were able to neutralize all emerging SARS-CoV-2 variants. Nonetheless, the inventors identified at least one mAb that could neutralize each VOC, suggesting the convalescent donors generated a diverse cross-neutralizing antibody response (FIG. 7b). Therefore, antibodies targeting multiple epitopes on the spike are a valuable source of neutralizing antibodies against emerging VOCs. Additionally, the inventors found majority of antibodies isolated from donors who had high antibody titers exhibited lower neutralizing potency than antibodies derived from donors who had lower serological titers and less severity (FIG. 7b and Supplementary Table 1). However, there was no difference between high and low responders in generating of cross-neutralizing antibodies against VOCs and VUMs. Moreover, the cross-neutralizing RBD-targeting mAbs used V (D) J gene features similar to other published RBD-binding mAbs (Supplementary Table 3)+2-++. However, the mAbs in our studies utilized distinct heavy and light chain pairings, indicating these clones are not public with other known neutralizing SARS-CoV-2 antibodies. Despite this, the data indicate that cross-neutralizing antibodies use a diverse antibody repertoire against multiple distinct epitopes. Therefore, driving a polyclonal antibody response against these three epitopes may provide cross-neutralizing protection against existing and future variants.


B. Discussion

This study shows WT SARS-CoV-2-convalescent individuals possess antibodies that can effectively cross-neutralize against emerging VOCs, with cross-neutralizing antibodies targeting multiple epitopes of the spike protein. In total, the inventors identified 12 mAbs that potently neutralize current circulating VOCs, including B.1.1.7, the alpha variant that has been reported to be more infectious8, 19, P.1, the gamma variant that partially escapes both natural and vaccine-induced humoral immunity2, 12, 45, and B.1.617.2, the delta variant that is more transmissible than the alpha variant and has led to a surge of more hospitalizations in India and can evade partial immunity induced by one vaccine dose4, 15, 23. Convalescent subjects in our cohort had sufficient serum titers to neutralize both B.1.1.7 and P.1 but not B.1.617, suggesting that the cross-neutralizing mAbs identified in this study may play an important role in polyclonal neutralization for some of VOCs.


Using high-throughput antigen probing at the single B cell level, the inventors found that B cells isolated from convalescent subjects largely targeted non-RBD epitopes rather than potently neutralizing epitopes on the RBD. Similarly, mRNA vaccines also largely induce antibodies against non-neutralizing epitopes, suggesting epitopes outside of the RBD are immunodominant46. Despite this, vaccination has been shown to induce cross-neutralizing antibodies1, suggesting both natural WT infection and currently approved vaccines can elicit protective humoral immunity against emerging variants. As the inventors identified 12 antibodies cross-neutralizing to VOCs derived from seven different convalescent COVID-19 donors, these study suggests most people generate a cross-neutralizing antibody response. Notably, these antibodies largely target three distinct epitopes, including two sites on the RBD and the one on the NTD. Several recent studies have demonstrated that antibodies against the NTD and S2 are neutralizing47-49. Although the anti-S2 mAbs identified in our study were non-neutralizing, S2-binding antibodies exhibit broad reactivity with spike proteins from SARS-CoV-2 variants, related beta coronaviruses such as SARS-CoV-1 and MERS-CoV, and distantly related endemic coronaviruses. Moreover, anti-spike serum antibodies can mediate protection via Fc-mediated functions, suggesting a combination of neutralizing antibodies and polyfunctional antibodies will provide optimal protection against infection with variants of SARS-CoV-250.


This study also showed that anti-RBD mAbs are primarily class 2 mAbs, consistent with other reports30, 37, 43, 51. The majority of class 2 mAbs retained their neutralization activity against B.1.1.7 and B.1.617.2, but were largely non-neutralizing against P.1, suggesting class 2 mAbs may have driven the evolution of P.1 mutants. In contrast, neutralizing class 3 mAbs retained their neutralization activity against both B.1.1.7 and P.1, but did not neutralize the B.1.617 variants. Notably, none of the neutralizing mAbs could cross-neutralize B.1.1.7, P.1 and B.1.617.2, the most prevalent VOCs at this time. Therefore, vaccination approaches to increase affinity and frequencies of antibodies to the S1 domain may enhance the breadth of protection against emerging SARS-CoV-2 VOCs, including epitopes on the RBD and NTD. It is likely that targeting multiple epitopes will provide optimal protection so as to avoid generating escape mutants that can evade antibodies against any one epitope. Moreover, vaccinating previously infected subjects has been shown to substantially improve neutralization titers3 and may allow for refinement of memory B cells against neutralizing epitopes.


In conclusion, this study shows SARS-CoV-2 infection induces cross-neutralizing immunity against circulating VOCs, which is likely attributed to polyclonal antibodies targeting multiple epitopes of the spike protein. This work emphasizes the need for the induction of cross-neutralizing antibodies that bind distinct sites on the spike with various mechanisms that can synergize to provide protection against SARS-CoV-2 variants as well as limit the virus from escaping any single antibody target.


C. Materials & Methods
1. Study Cohort and Spike-Specific B Cells Sorting

All studies were performed with the approval of the University of Chicago institutional review board IRB20-0523 and University of Chicago, University of Wisconsin-Madison. Informed consent was obtained after the research applications and possible consequences of the studies were disclosed to study subjects. The details of PBMC collection from leukoreduction filters were described elsewhere27. For spike-specific B cells sorting, PBMC were thawed in 37° C. water bath and B cells were enriched using human pan B cell EasySep™ enrichment kit (STEMCELL). B cells were stained with anti-CD19-PE-Cy7 (Biolegend) and anti-CD3-BV510 (BD Biosciences) and antigen probes (PE) for 30 minutes on ice in 1×PBS supplemented with 0.2% BSA and 2 mM Pierce Biotin. Probe generation was performed as previously described27. Cells were subsequently washed with 1×PBS with 0.2% BSA and stained with Live/Dead BV510 (Thermo Fisher) in 1×PBS for 15 minutes. Cells were washed again and re-suspended at a maximum of 4 million cells/mL in 1×PBS supplemented with 0.2% BSA and 2 mM Pierce Biotin for downstream cell sorting using the MACSQuantTyto cartridge sorting platform (Miltenyi). Viable/CD19+/antigen-PE+ cells were sorted as probe positive. Cells were then collected from the cartridge sorting chamber and used for downstream processing with the chromium controller (10× Genomics).


2. Single-Cell RNA-Seq and B Cell Receptor Sequencing

The human B cell V (D) J, 5′ gene expression, feature barcode libraries were prepared according to manufacturer's instructions. Libraries were pooled and sequenced using an Illumina NextSeq 550 or an Illumina NextSeq 500 at the University of Chicago. Cell Ranger (version 3.0.2) was used to perform raw sequencing processing, sample de-multiplexing, barcode processing, single-cell 5′ transcripts counting and B cell receptor repertoire sequences assembly. The reference genome assembly for transcriptome is GRCh38-1.2.0, and reference genome assembly for V (D) J is cellranger-vdj-GRCh38-alts-ensembl-2.0.0. The data obtained from Cell Ranger were subsequently performed downstream analysis using Seurat toolkit (version 3.2.0, an R package, for transcriptome, cell surface protein and antigen probe analysis) 52 and IgBlast (version 1.15) for immunoglobulin gene analysis53. Cell quality control (QC), normalization, data scaling, and linear dimensional reduction, clustering, differential expression analysis, batch effects correction, and data visualization were processed using Seurat (version 3.2.0). The QC of cells were performed further to exclude cells with less than 200 and more then 2500 detected genes and cells expressing high percentage of mitochondrial genes. Transcriptome RNA data was analyzed using conventional log normalization. The inventors performed principal component analysis (PCA) and used the top 15 principal components (PCs) in linear dimensional reduction and clustering. Only filtered, high-quality cells were clustered in this analysis using Louvain algorithm implemented in Seurat under the resolution of 0.6 for clustering. Batch effects across different datasets were normalized using an Anchor method implemented in Seurat.


3. Monoclonal Antibody Production

B cells were selected for mAb generation based on antigen probe intensity visualized by JMPPro 15, as previous described27. Antibody heavy and light chain genes obtained by 10× Genomics V(D)J sequencing analysis were synthesized by Integrated DNA Technologies. The synthesized fragments for heavy and light chain with 5′ and 3′ Gibson overhangs were then cloned into human IgG1 and human kappa or lambda light chain expression vectors by Gibson assembly as previously described54. The heavy and light chains of a corresponding mAb were co-transfected into HEK293T cells. After 4 days, secreted mAbs in the medium supernatant were harvested and purified using protein A agarose beads (Thermo Fisher).


4. Recombinant Proteins

The recombinant WT SARS-CoV-2 full-length (FL) spike, D614G FL spike, WT RBD, K417T/R/A RBD, N501Q/A RBD, and SARS-CoV-1 RBD and MERS-CoV were generated in-house either by using gBlock fragment synthesized by Integrated DNA Technologies or by performing single-site mutagenesis, and expressed by Expi293F cells (Thermo Fisher). The recombinant FL spikes derived from variants of B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.526, and were kindly provided by Dr. Noah Sather laboratory at Seattle Children's Research Institute. The recombinant RBD found in VOCs, B.1.351 or P.1 variants, and RBD with single mutation or multiple mutations (N439: Y453F, E406Q, K417E, K417V, Y453F, F486A, N487R, F490K, Q493R, N439K, N440K, N501Y) were generously provided from the Krammer laboratory at Icahn School of Medicine at Mount Sinai. The recombinant S1 and S2 subunit, and RBD with single mutation of K417N, E484K and L452R were obtained from Sino Biological. The protein sequences and resources for each antigen are listed in Extended Data Table 3.


5. Virus Neutralization Assay

Virus neutralization assays were performed with different variants of SARS-CoV-2 on Vero E6/TMPRSS2 (Extended Data Table 4). Virus (˜100 plaque-forming units) was incubated with an equal volume of two-fold diluted of serum or mAbs for 1 hour. Plasma samples were diluted in calcium free media, while antibodies were diluted in growth media. In addition, plasma was heat treated for 30 minutes at 37° C. prior to use. The antibody/virus mixture was added to confluent Vero E6/TMPRSS2 cells that were plated at 30,000 cells per well the day prior in 96-well plates. The cells were incubated for 3 days at 37° C. and then fixed and stained with 20% methanol and crystal violet solution. Virus neutralization titers were determined as the reciprocal of the highest serum dilution that completely prevented cytopathic effects. The 50% inhibitory concentrations for mAbs (IC50) was determined using log (inhibitor) versus normalized response (variable slope) performed by Prism (Graphpad Version 9.0). All plasma and mAbs were tested in duplicate and each experiment was performed twice.


6. Enzyme-Linked Immunosorbent Assay (ELISA)

High-protein binding microtiter plates (Costar) were coated with 50 μl of recombinant proteins (either full-length spike or RBD) at 2 μg/ml in 1×PBS solution overnight at 4° C. The plates were washed 3 times the next day with 1×PBS supplemented with 0.05% Tween 20 and blocked with 175 μl of 1×PBS containing 20% FBS for 1 hour at 37° C. MAbs were serially diluted 1:3 starting at 10 μg/ml and incubated for 1 hour at 37° C. The plates were then washed 3 times and incubated with horseradish peroxidase (HRP)-conjugated goat anti-human IgG antibody (Jackson ImmunoResearch) diluted 1:1000 for 1 hour at 37° C., and plates were subsequently developed with Super AquaBlue ELISA substrate (eBioscience). Absorbance was measured at 405 nm on a microplate spectrophotometer (Bio-Rad). To standardize the assays, control antibodies with known binding characteristics were included on each plate and the plates were developed when the absorbance of the control reached 3.0 OD405 units. All mAbs were tested in duplicate and each experiment was performed twice.


7. Competition ELISAs

To determine the classification of certain mAbs, competition ELISAs were carried out using the mAbs with known epitope binding property as competitor mAbs. The competitor mAbs were biotinylated overnight at 4° C. with EZ-Link™ Sulfo-NHS-Biotin (Thermo Scientific). The excess free biotin of biotinylated mAbs were removed by 7k MWCO Zeba™ spin desalted columns (Thermo Scientific). Plates were coated with 50 μl of 2 μg/ml RBD antigen overnight at 4° C. After 1 hour of blocking the plates with PBS 20% FBS, the 2-fold dilution of undetermined classmAbs or serum were added (starting at 20 μg/ml of mAbs and 1:50 of serum) into coated well. After incubated for 2 hours at room temperature, biotinylated competitor mAb was added at a concentration of 2× Kd and incubated another 2 hours at room temperature together with mAbs or serum that were previously added. The plates were washed 3 times and incubated with 100 μl HRP-conjugated streptavidin (Southern Biotech) dilution of 1:1000 for 1 hour at 37° C. The plates were developed with Super AquaBlue ELISA substrate (eBioscience). To standardize the assays, competitor biotinylated mAb was added in well that without any competing mAbs or serum as control well. The data were recorded when the absorbance of the control well reached 1 to 1.5 OD405 units. All mAbs were tested in duplicate and each experiment was performed twice. The percent competition was then calculated by dividing a sample's observe OD by the OD reached by the positive control, subtracting this value from 1, and multiplying by 100. For the serum data, ODs were log transformed and analyzed by non-linear regression to determine EC50 values using Prism software (Graphpad Version 9.0).


8. Biolayer Interferometry (BLI)

To determine the classification of certain mAbs, competition assays were performed using the mAbs with known epitope binding property as competitor mAbs with mAb binding unknown epitopes using BLI with a Octet K2 instrument (Forte Bio). The RBD of SARS-CoV-2 was biotinylated, desalted and loaded at a concentration of 10 μg/ml onto streptavidin probes for 300 seconds followed by PBS for 60 seconds. The probe was moved to associate with mAbs of interest (10 μg/ml) for 300 seconds followed by PBS for 60 seconds and then associations with control mAbs (10 μg/mL) for 300 seconds. The final volume for all the solutions was 200 ml/well. All of the assays were performed with PBS buffer at 30° C.


9. SARS-CoV-2 Spike and RBD Protein Models

FL mutations were visualized on the WT spike protein (PDB: 7KJ2) using PyMOL (Schrödinger). The model of RBD mutations and RBD classes were visualized on the WT RBD protein (PDB: 7KDL) using PyMOL (Schrödinger). The models were further processed by Adobe Illustrator 2021 and Adobe Photoshop.


10. Statistical Analysis

All statistical analyses were performed using Prism software (Graphpad Version 9.0). Sample sizes (n) for the number of mAbs tested are indicated in corresponding figures or in the center of pie graphs. Number of biological repeats for experiments and specific tests for statistical significance used are indicated in the corresponding figure legends. P values less than or equal to 0.05 were considered significant. * P≤0.05, ** P≤0.01, *** P≤0.001, **** P<0.0001.


D. Tables








SUPPLEMENTARY TABLE 1







COVID-19 convalescent subjects. Responder group and


Severity were categorized by previous study26.



















Symptom







SARS-
Duration of
start to


Subject


CoV-2
symptoms
donation
Responder
Severity


ID
Age
Sex
PCR Test
(days)
(days)
Category26
Category26

















24
34
M
Mar. 23, 2020
12
41
High
Severe


20
31
M
Mar. 31, 2020
19
48
High
Critical


564
24
F
Mar. 19, 2020
32
60
Low
Severe


144
56
M
Mar. 16, 2020
23
54
Low
Moderate


305
43
F
Apr. 17, 2020
4
47
Low
Moderate


166
42
F
Mar. 25, 2020
17
55
Low
Moderate


210
47
M
Apr. 4, 2020
7
41
Low
Moderate


451
46
M
Apr. 4, 2020
11
49
High
Severe









(hospitalized)


626
44
M
Mar. 31, 2020
19
56
High
Moderate


728
62
F
Mar. 15, 2020
53
130
High
Severe
















SUPPLEMENTARY TABLE 2







Characteristics of SARS-CoV-2 spike binding mAbs. Cross-neutralizing


mAbs against WT, B.1.1.7 and P.1 or B.1.617.2 are bolded.














mAb
Epitope


# VH
#VL
CDRH3
CDRL3


ID
specificity
VH gene
VL gene
SHM
SHM
length
length

















S20-58
Spike RBD
IGHV4-
IGKV2-
5
2
15
9



Class 2
30-4*08
24*01



S20-74
Spike RBD
IGHV4-
IGLV2-
7
3
15
11



Class 3-like
59*11
8*01


S24-
Spike RBD
IGHV2-
IGLV2-
1
3
11
11


223
undetermined
5*02
14*01



S24-
Spike RBD
IGHV2-
IGKV1-
3
0
16
9



821

Class 3
70*15
5*03


S24-
Spike RBD
IGHV1-
IGLV7-
0
0
15
8


902
undetermined
69*04
46*01


S24-
Spike RBD
IGHV3-
IGKV1-
4
5
25
9


1002
Class 2
30-3*01
13*02



S24-
Spike RBD
IGHV1-
IGLV1-
8
7
20
11



1224

Class 2
46*01
40*01


S24-
Spike RBD
IGHV3-
IGLV3-
7
6
22
9


1271
undetermined
66*01
1*01


S24-
Spike
IGHV1-
IGLV10-
6
4
18
11


1301
NTD-B
24*01
54*01


S24-
Spike RBD
IGHV3-
IGLV3-
3
4
17
12


1384
Class 4
48*04
21*02



S24-
Spike RBD
IGHV3-
IGKV3-
3
0
18
8



1476

Class 2
49*03
15*01


S144-
Spike RBD
IGHV5-
IGLV1-
8
5
17
12


67
Class 3-like
51*01
40*01


S144-
Spike RBD
IGHV5-
IGKV1-
3
3
11
8


69
Class 4
51*01
5*01


S144-
Spike RBD
IGHV5-
IGKV1-
7
6
11
9


466
Class 4
51*01
5*01


S144-
Spike RBD
IGHV5-
IGKV1-
3
1
12
9


509
Class 4
51*01
5*01


S144-
Spike RBD
IGHV1-
IGKV3-
9
3
19
9


1079
Class 2
69*02
20*01



S144-
Spike RBD
IGHV1-
IGLV2-
15
5
18
11



1339

Class 2
2*06
14*01



S144-
Spike RBD
IGHV1-
IGKV1-
4
0
11
17



1406

Class 2
3*01
5*01


S144-
Spike RBD
IGHV1-
IGKV1-
9
2
12
10


1407
Class 2
69*02
5*01


S144-
Spike RBD
IGHV3-
IGKV1-
2
3
13
9


1850
undetermined
23*04
5*01



S166-
Spike
IGHV3-
IGKV1-
10
2
19
8



32

NTD-B
11*01
5*01


S166-
Spike
IGHV4-
IGLV3-
3
5
16
12


2395
NTD-B
4*07
21*02


S210-
Spike
IGHV4-
IGLV4-
11
4
10
9


1262
NTD-A
39*01
69*01


S305-
Spike RBD
IGHV3-
IGKV3-
18
8
6
9


223
Class 2
33*06
11*01


S305-
Spike RBD
IGHV1-
IGKV3-
4
4
18
9


399
undetermined
24*01
15*01



S305-
Spike
IGHV1-
IGKV3-
3
3
20
9



1456

NTD-B
24*01
15*01


S451-
Spike
IGHV3-
IGKV3D-
8
3
15
8


11
NTD-A
23*01
20*01


S451-
Spike
IGHV4-
IGKV3-
10
1
15
10


337
NTD-B
59*01
20*01


S451-
Spike S2
IGHV3-
IGKV3-
6
4
14
8


650

30*01
20*01


S451-
Spike
IGHV4-
IGLV2-
9
5
14
10


1451
NTD-A
31*01
11*01


S451-
Spike
IGHV2-
IGLV2-
8
5
20
11


1522
NTD-B
26*01
14*01


S564-
Spike RBD
IGHV3-
IGLV3-
6
3
18
12


14
Class 3-like
7*01
21*04



S564-
Spike RBD
IGHV1-
IGLV2-
6
2
15
10



68

Class 2
2*02
8*01



S564-
Spike RBD
IGHV1-
IGLV2-
2
6
15
10



134

Class 2
2*02
8*01


S564-
Spike RBD
IGHV1-
IGLV2-
10
1
18
10


138
Class 2
2*02
14*01


S564-
Spike RBD
IGHV3-
IGKV1-
4
4
20
10


152
Class 4
33*06
33*01



S564-
Spike RBD
IGHV1-
IGLV2-
4
3
15
10



265

Class 2
2*02
8*01


S626-8
Spike S2
IGHV1-
IGLV3-
7
5
24
12




8*01
19*01


S626-
Spike RBD
IGHV3-
IGLV1-
18
3
16
11


362
undetermined
48*01
40*01


S626-
Spike RBD
IGHV1-
IGLV1-
6
4
17
11


651
Class 3-like
69*04
40*01



S626-
Spike RBD
IGHV3-
IGKV1-
6
6
22
10



747

Class 3-like
9*01
33*01


S728-
Spike
IGHV1-
IGKV3-
17
3
16
11


1981
NTD-A
46*01
11*01


S728-
Spike
IGHV1-
IGLV2-
14
12
17
10


2036
NTD-A
2*02
23*02
















SUPPLEMENTARY TABLE 3







Antigen information and source. VOC refers to variant


of concern and VUM refers to variant under monitoring.


















Mutation



Antigen
S1 NTD
RBD
S1 CTD
S2
detected in
Source











Spike FL, 2-P, trimer














WT
—
—
—
—
—
In-house


D614G
—
—
D614G
—
VOC
In-house


B.1.1.7 (alpha)
H69del,
N501Y
A570D,
T716I,
VOC
Sather lab



V70del,

D614G,
S982A,



Y144del

P681H
D1118H


B.1.351 (beta)
L18F,
K417N,
D614G
A701V
VOC
Sather lab



D80A,
E484K.



D215G,
N501Y



del241-243,



R246I


P.1 (gamma)
L18F,
K417T,
D614G,
T1027I,
VOC
Sather lab



T20N,
E484K,
H655Y
V1176F



P26S,
N501Y



D138Y,



R190S


B.1.617.2 (delta)
T19R,
L452R,
D614G,
D950N
VOC
Sather lab



G142D,
T478K,
P681R



del156-157,



R158G


B.1.526 (iota)
L5F, T95I,
E484K
D614G
A701V
VUM
Sather lab



D253G


B.1.617.1
T95I,
L452R,
D614G,
Q1071H
VUM
Sather lab


(kappa)
G142D,
E484Q
P681R



E154K








S1 monomeric














WT
—
—
—
—
—
SinoBiological


S2 monomeric


WT
—
—
—
—
—
SinoBiological


RBD


WT
—
—
—
—
—
In-house


E406Q
—
E406Q
—
—
Circulating
Krammer lab







variant, In vitro







escape


K417N
—
K417N
—
—
VOC, In vitro
SinoBiological


(B.1.351)




escape


K417T (P.1)
—
K417T
—
—
VOC, In vitro
In-house







escape


K417E
—
K417E
—
—
In vitro escape
Krammer lab


K417V
—
K417V
—
—
In vitro escape
Krammer lab


K417A
—
K417A
—
—
RBD-ACE2
In-house







contacting


Y453F (B.1.427,
—
Y453F
—
—
VOC, In vitro
Krammer lab


B.1.429)




escape


F486A
—
F486A
—
—
In vitro escape
Krammer lab


N487R
—
N487R
—
—
In vitro escape
Krammer lab


E484K (P.1,
—
E484K
—
—
VOC, In vitro
Krammer lab


B.1.526,




escape


B.1.351,


B.1.1.318,


B.1.525, R.1,


B.1.526.2, B.1.1,


B.1.621, B.1,


B.1.1.7)


F490K
—
F490K
—
—
In vitro escape
Krammer lab


Q493R
—
Q493R
—
—
In vitro escape
Krammer lab


N439K
—
N439K
—
—
VOC, In vitro
Krammer lab







escape


N440K (B.1.36)
—
N440K
—
—
Circulating
Krammer lab







variant, In vitro







escape


L452R
—
L452R
—
—
VOC, In vitro
SinoBiological


(B.1.526.1,


B.1.429,


B.1.427,




escape


B.1.617.2, B.1,


B.1.617.1, C.36,


A.2.5)


N501Y (B.1.1.7)
—
N501Y
—
—
VOC
Krammer lab


N501Q
—
N501Q
—
—
RBD-ACE2
Krammer lab







contacting


N501A
—
N501A
—
—
RBD-ACE2
Krammer lab







contacting


B.1.351

K417N,


VOC
Krammer lab




E484K,




N501Y


P.1
K417T,



VOC
Krammer lab



E484K,



N501Y








Other coronaviruses










SARS-CoV-1 RBD WT
—
In-house


MERS-CoV RBD WT
—
In-house
















SUPPLEMENTARY TABLE 4







SARS-CoV-2 virus information and source.












Antigen
S1 NTD
RBD
S1 CTD
S2
Source





WT
—
—
—
—
SARS-CoV-2/UT-







NCGM02/Human/2020/Tokyo







from BEI


B.1.1.7
L5F, H69del,
N501Y
A570D,
T716I,
hCoV-



V70del,

D614G,
S982A,
19/Japan/QHN001/2020 from



Y144del

P681H
D1118H
BEI


P.1
L18F, T20N,
K417T,
D614G,
T1027I,
hCoV-19/Japan/TY7-



P26S, D138Y,
E484K,
H655Y
V1176F
501/2021 from BEI



G181V, R190S
N501Y


B.1.617.1
G142D, E154K
L452R,
D614G,
Q1071H,
hCoV-19/USA/CA-Stanford-




E484Q
P681R
H1101D
15_S02/2021 from BEI


B.1.617.2
T19R, T95I,
L452R,
D614G,
D950N
hCoV-19/USA/WI-UW-



G142D, E156G,
T478K
P681R

5250/2021



F157del,



R158del









E. References

The following references and the references cited throughout the specification, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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Example 2: A Broadly Protective Antibody to Emerging SARS-CoV-2 Variants Binds an Epitope More Readily Accessible on Hexaproline Spike Antigen Constructs

The rapid evolution of SARS-CoV-2 Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, the inventors identify S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) and derived from an individual previously infected with SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrates broad cross-neutralization of all dominant variants including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5). Furthermore, it protected hamsters against in vivo challenges with wildtype, Delta, and BA.1 viruses. Structural analysis reveals that this antibody targets a class 1 epitope via multiple hydrophobic and polar interactions with its CDR-H3, in addition to common class 1 motifs in CDR-H1/CDR-H2. Importantly, this epitope is more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared to diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential, and may inform target-driven vaccine design against future SARS-CoV-2 variants.


A. Introduction

Since the start of the pandemic in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has led to over 576 million cases of coronavirus disease 2019 (COVID-19) and over six million deaths globally. Although the rapid development and distribution of vaccines and therapeutics has curbed the impact of COVID-19 to an extent, the emergence of circulating variants of concern (VOCs) continues to represent a major threat due to the potential for further immune evasion and enhanced pathogenicity. The D614G variant was the earliest variant to emerge and became universally prevalent thereafter. In comparison to wildtype (WT), the D614G variant exhibited increased transmissibility rather than increased pathogenicity and was therefore unlikely to reduce efficacy of vaccines in clinical trials (1). Between the emergence D614G and October 2021, four additional significant VOC evolved worldwide, including Alpha, Beta, Gamma, and Delta. Among these variants, Delta became a serious global threat as a result of its transmissibility, increased disease severity, and partial immune evasion as shown by the reduced ability of polyclonal serum and monoclonal antibodies (mAbs) to neutralize this strain (2-6). Shortly afterwards, in November 2021, the Omicron variant was identified and announced as a novel VOC. This variant possessed the largest number of mutations to date and appeared to spread more rapidly than previous strains (7,8). Currently, there are five major subvariant lineages of Omicron (BA.1, BA.2, BA.3, BA.4 and BA.5) leading to new COVID-19 cases, with BA.5 becoming dominant over BA.2 and accounting for most new cases in the United States at the time of writing. The Omicron variants can escape recognition by COVID-19 vaccine-associated immunity to varying extents, thereby significantly reducing the neutralizing potency of serum antibodies from convalescent and fully mRNA-vaccinated individuals (9). Similarly, Omicron variants were able to escape binding of several Emergency Use-Authorization (EUA) therapeutic mAbs even though these had been previously shown to be effective against earlier VOCs (10,11). Due to the lowered neutralization against Omicron and the continued threat of future VOCs, there is an urgent need to identify broad and potent neutralizing antibodies that can protect against diverse evolving SARS-CoV-2 lineages.


In this study, the inventors identify a potent RBD-reactive monoclonal antibody from the peripheral blood of SARS-CoV-2 convalescent individual that effectively neutralize Alpha, Beta, Kappa, Delta, Mu, and Omicron variants (BA.1, BA.2, BA.2.75, BA.4 and BA.5). This mAb, S728-1157, entirely abrogated BA.1 Omicron replication in vivo and significantly reduced viral loads during wildtype and Delta infection. In terms of specificity, S728-1157 bound the receptor binding site (RBS) that is fully exposed when the RBD on the spike is in the up conformation. S728-1157 binds using motifs found in the CDR-H1 and CDR-H2 domains that are common to IGHV3-53/3-66 class 1 antibodies but also via extensive unique contacts with CDR-H3 to circumvent mutations in the variant virus spikes. This suggests that the rational design of future vaccine boosts covering Omicron variants should be modified to present stabilized spike in the up configuration to optimally induce class 1 mAbs that have similar CDR-H3 features.


B. Results

1. Isolation of RBD-Reactive mAbs that Exhibit Diverse Patterns of Neutralization and Potency


Before the spread of the Omicron variant, the inventors previously characterized 43 mAbs targeting distinct epitopes on the spike protein, including the N-terminal domain (NTD), RBD, and subunit 2 (S2), although none were able to neutralize all existing SARS-CoV-2 variants at that time (12). In the current study, an additional panel of RBD-reactive mAbs were expressed from three high-responder subjects who mounted robust anti-spike IgG responses, as defined previously (Table S1 and Table S2) (13). Although the proportion of spike RBD-binding B cells was similar in high-responders as compared to mid- and low-responders (FIG. 8a-c), heavy chain somatic hypermutation rates were significantly greater in the high-responder group (FIG. 8d), suggesting that these subjects may have the highest potential to generate potent cross-reactive mAbs (13). These antibodies were assayed for binding to key RBD mutants to identify their epitope classifications (Table S3) (14). Among 14 RBD-reactive mAbs, the inventors identified four class 2 mAbs, two class 3 mAbs, and eight unclassified mAbs that showed little to no reduction of binding against any key RBD mutants tested (FIG. 8f). Class 2 and 3 RBD mAbs did not recognize a multivariant RBD mutant containing K417N/E484K/L452R/N501Y substitutions, an artificially designed RBD to include the key mutations for virus escape (14,15), nor cross-reactivity to the RBD of SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS)-CoV (FIG. 8f). Functionally, class 2 and 3 RBD mAbs potently neutralized D614G and Delta but neutralizing activity was limited against Beta, Kappa and Mu (FIG. 8g). No class 2 or 3 antibodies assayed could neutralize any tested Omicron variant.


In contrast, the majority of unclassified mAbs bound to the RBD multivariant and cross-reacted to the SARS-CoV-1 RBD (FIG. 8f). Among these, the inventors went on to identify three bnAbs, S451-1140, S626-161 and S728-1157, that showed high neutralization potency against D614G and could cross-neutralize Beta, Delta, Kappa, Mu and BA.1 with 99% inhibitory concentration (IC99) in the range of 20-2500 ng/ml (FIG. 8g). Given the broad neutralization potency of these three mAbs, in addition of plaque assay platform, the inventors also performed the neutralization activity against authentic BA.4, BA.5 and BA.2.75 viruses using focus reduction neutralization test (FRNT) (FIG. 8g). Of these, S728-1157 displayed high neutralizing activities against the panel of Omicron variants including BA.1, BA.2, BA.4 and BA.5, with IC99 below 100 ng/ml as measured by plaque assay. A similar scenario was observed using FRNT, S728-1157 maintains its extremely high neutralization activity against BA.2.75, BA.4 and BA.5 with 50% inhibitory concentration (IC50) in the range of 8-16 ng/ml (FIG. 8g). S451-1140 neutralized BA.1 and BA.2 potently, but not BA.4 and BA.5 as observed in both neutralization assay platforms. On the other hand, S626-161 did not demonstrate neutralizing activity against Omicron variants beyond the BA.1 variant (FIG. 8g). Although S626-161 had a lower neutralization potency against VOC than the other two, it was the only mAb which showed cross-reactivity to SARS-CoV-1 RBD and was able to neutralize bat coronaviruses WIV-1 and RsSHC014 (FIG. 8f-g). These data suggest that S626-161 recognizes a conserved epitope that is shared between these sarbecovirus lineages, but is absent in BA.2. Additionally, compared to S728-1157 and S451-1140, S626-161 has a longer CDR-H3 which could provide an enhanced capability to recognize a highly conserved patch of residues shared across sarbecoviruses as described in a previous study (16) (FIG. 12). When comparing immunoglobulin heavy (IGHV) and light chain (IGLV or IGKV) variable genes of these three bnAbs with the available SARS-CoV-2 neutralizing mAbs database (12, 17-25), the inventors found that heavy chain variable genes utilized by S728-1157 (IGHV3-66), S451-1140 (IGHV3-23) and S626-161 (IGHV4-39) have been previously reported to encode several potently neutralizing SARS-CoV-2 antibodies targeting the RBD (18, 19, 26, 27). However, our mAbs had unique heavy and light chain variable gene pairings that have not been reported in the database (Table S2), indicating that they are not public clonotypes.


These three bnAbs (S451-1140, S626-161 and S728-1157) were characterized further to determine the binding breadth against SARS-CoV-2 VOCs (FIG. 8h-k). The prefusion-stabilized spike containing two-proline substitutions in the S2 subunit (2P; diproline) has been shown to be a superior immunogen compared to the wildtype spike and is the basis of several current SARS-CoV-2 vaccines, including current mRNA-based vaccines (28,29). More recently, spike protein stabilized with six prolines (6P; hexaproline) was shown to boost expression and be even more stable than the original diproline construct; as a result, it has been proposed for use in improving the next-generation of COVID-19 vaccines (30,31). To determine if there are antigenicity differences between the diproline and hexaproline spike constructs, both immunogens were included in our test panel. As measured by ELISA assay, the inventors found that three bnAbs bound 6P-WT spike antigen to a greater extent compared to WT-2P spike (FIG. 8h-j). All three bnAbs showed comparable binding to the spikes of Alpha, Beta, Gamma and Delta viruses, relative to that of WT-2P (FIG. 8h-j). However, the binding reactivity of these three bnAbs were substantially reduced against a panel of Omicron-family antigens (FIG. 8h-k). S451-1140 binding was sensitive to mutations found in BA.1 and BA.2, resulting in a decrease in binding of more than 3-fold (range of 3- to 11.2-fold) and a 31-fold decrease in neutralization against these variants compared with WT-2P antigen and D614G virus, respectively (FIG. 8g, i, k). The sarbecovirus-cross neutralizing mAb, S626-161 also showed 1.7 to 3.9-fold reduced binding to spike BA.1 antigens and thereby resulted in a 2-fold reduction in neutralization activity against BA.1 (FIG. 8g, j, k). For the most potent bnAb, S728-1157, binding to Omicron antigens was substantially reduced by greater than 1.7-fold (range of 1.7- to 5.5-fold) compared with WT-2P spike but was unaffected in neutralizing activity (FIG. 8g, h, k). Notably, all three bnAbs showed over 3-fold increased binding to spike BA.1-6P compared with the BA.1-2P version, suggesting a better accessibility of bnAbs to the hexaproline spike BA.1 construct. In addition to ELISA, biolayer interferometry (BLI) was used to quantify the binding rate and equilibrium constants (kon, koff, and KD) of these three bnAbs to a panel of spike antigens (FIG. 13b-d). The recognition kon rates of Fabs were 1.5 to 3.3-fold faster to hexaproline spikes, showing that the antibodies bound to the 6P construct more rapidly than to 2P. This is expected if the epitopes are more exposed on the RBD in the open state on the hexaproline spike (FIG. 13c). Except for S626-161, off-rate of the Fabs were also longer such that the overall KD showed that S728-1157 and S451-1140 bound to the hexaproline spike with substantially greater affinity (FIG. 13c-d). The increased off rates further suggest partial occlusion of the binding site on diproline spike. The improved binding to hexaproline spike was even more notable for whole dimeric IgG by the 1:2 interaction model and for all three bnAbs, consistent with exposure of multiple epitopes with 6P stabilization allowing improved avidity (FIG. 13b-d). Taken together, these results suggest that the epitopes targeted may be comparatively more accessible on the 6P-stabilized spike with the RBD in the open state. Structural analyses were next performed to verify this conjecture.


2. Structural Analysis of Broadly Neutralizing Monoclonal Antibodies

As a first approximation of epitopes bound, an ELISA competition assay was used to determine whether the three broadly-neutralizing mAbs shared any overlap with our current panel of mAbs and a collection of mAbs with known epitope specificities from previous studies (12, 32, 33), plus two other mAbs currently in clinical use (LY-CoV555 (Eli Lilly) (34) and REGN10933 (Regeneron) (35)). The binding sites of S451-1140 and S728-1157 partially overlapped with CC12.3 (33,36), a class 1 neutralizing antibody, and most class 2 antibodies, including LY-CoV555 and REGN10933, but not with class 3 and class 4 antibodies (FIG. 9a). S626-161 shared a notable overlap in binding region with class 1 CC12.3, several class 4 antibodies including CR3022, and other unclassified antibodies, while having some partial overlap with several class 2 and one class 3 antibodies (FIG. 9a). Analogously, competition BLI assay revealed that S451-1140 and S728-1157 strongly competed with one another for binding to spike WT-6P, whereas S626-161 did not (FIG. 14). Overall, these data suggest S451-1140 and S728-1157 recognize similar epitopes that are distinct from S626-161.


S728-1157 was encoded by IGHV3-66 and possessed a short complementarity determining region 3 (CDR-H3). Notably, mAbs that bind the receptor binding site (RBS) in binding mode 1 (i.e. RBS-A or class 1 site), typified by CC12.1, CC12.3, B38, and C105 (15, 25, 27, 36-38), tend to use IGHV3-53/3-66 and are sensitive to VOC mutations (39). However, the CDR-H3 region of S728-1157 is highly distinct from other antibodies of this class, potentially accounting for its broader activity. To understand the structural basis of broad neutralization by S728-1157 at this epitope, the inventors resolved a cryo-electron microscopy (cryo-EM) structure (FIG. 9b) of IgG S728-1157 in complex with spike WT-6P-Mut7, a version of spike WT-6P possessing interprotomer disulfide bond at C705 and C883, at ˜3.3 Å global resolution (FIG. 15e).


Using symmetry expansion, focused classification, and refinement methods, the inventors achieved local resolution at the RBD-Fv interface to ˜4 Å (FIG. 15e and Table S6). A crystal structure of S728-1157 Fab was determined at 3.1 Å resolution and used to build the atomic model at the RBD-Fv interface. Our structures confirm that S728-1157 binds the RBS-A (or class 1) epitope in the RBD-up conformation (FIG. 9b and FIG. 15e), similar to other IGHV3-53/3-66 antibodies (FIG. 9c). Steric blockage of the angiotensin converting enzyme 2 (ACE2) binding site by S728-1157 explains its high neutralization potency against SARS-CoV-2. The 32NY33 motif and 53SGGS56 motif (36) in S728-1157 CDR-H1 and-H2 interact with the RBD in almost the same way as CC12.3 (FIG. 15b-c). However, VH 98DY99 in S728-1157 CDR-H3 forms more extensive interactions including both hydrophobic and polar interactions with the RBD, compared to VH 98DF 99 in CC12.3 (FIG. 9d and Table S5). The diglycine VH 100GG101 in S728-1157 CDR-H3 may also facilitate more extensive binding compared to VH Y100 in CC12.3 likely due to the flexibility in the glycine residues that lead to a different conformation of the tip of the CDR-H3 loop and a relative shift of residues at 98DY 99.


Although the Omicron VOCs have extensive mutations in the RBD (FIG. 9c and FIG. 13a), most of these residues do not make interactions with or are dispensable for binding to S728-1157, as binding is still observed (FIG. 15a). From our spike WT-6P-Mut7+Fab S728-1157 model, Y505 to VL Q31, and E484 to VH Y99 are predicted to make hydrogen bonds (FIG. 15d and Table S5), which have the potential to be disrupted by Omicron mutations Y505H and E484A. However, a Y505H mutation would still allow for a hydrogen bond with VL Q31 and an E484A mutation would add another hydrophobic side chain near hydrophobic residues VL Y99, F456, and Y489. These contacts may explain the mechanism which enabled S728-1157 to retain neutralizing activity (FIG. 8g), albeit reduced binding reactivity against spike BA.1 antigen, which is in turn possibly due to the function of Omicron mutations in altering the conformational landscape of the spike protein (40). Notably, while the variable genes were well-mutated, all but one of the contact residues between the CDR-H3 of S728-1157 and the VOC were predicted to be germline encoded and not introduced by somatic mutations, likely limiting the number of existing memory B cells of this class that could be further adapted by somatic mutation to protect against VOC strains (FIG. 12, Table S5). Overall, our structural studies revealed the basis of broad neutralization of S728-1157 that can accommodate most mutations in the SARS-CoV-2 VOCs.


3. S728-1157 Reduces Replication of SARS-CoV-2 Delta and Omicron Variants in Syrian Hamsters

To evaluate the protective efficacy of our broadly neutralizing mAbs, the inventors utilized a golden Syrian hamster infection model that has been widely used for SARS-CoV-2 infection. Hamsters received 5 mg/kg of individual mAbs or an irrelevant antigen (ebolavirus glycoprotein)-specific isotype control via intraperitoneal injection one day post-infection with SARS-CoV-2 viruses. Lung and nasal tissues were collected at 4 days post-infection (dpi) (FIG. 10a). Therapeutic administration of S728-1157 resulted in reduced titers of wildtype, BA.1 Omicron and Delta variants in both the nasal turbinates and lungs of infected hamsters (FIG. 10b-d). Interestingly, the effect of S728-1157 in the lungs was dramatic, reducing wildtype viral loads by ˜104 PFU, and BA.1 Omicron by ˜105 PFU, with replication of the latter being completely abolished (FIG. 10c). In contrast to in vitro neutralization, S451-1140 did not reduce BA.1 Omicron viral replication in lung and nasal turbinates, indicating the disconnect between in vitro neutralization and in vivo protection for S451-1140 (FIG. 10e). In comparison, S626-161 administration resulted in significant but marginal reductions in lung viral titers following wildtype and BA.1 challenge (FIG. 10f-g). These data underscore that to precisely define broadly protective mAbs, evaluating protection efficacy in parallel with neutralization activity is required. Overall, S728-1157 represents a promising mAb with broad neutralization efficacy against SARS-CoV-2 variants that is capable of dramatically reducing wildtype, Delta and BA.1 replication in vivo.


4. SARS-CoV-2 Infection Rarely Elicits Potent S728-1157-Like Cross-Neutralizing mAbs


Given the cross-neutralization and prophylactic potential of S728-1157, the inventors sought to evaluate whether S728-1157-like antibodies are commonly induced among polyclonal responses in SARS-CoV-2 patients. To assess this, the inventors performed competition ELISAs using convalescent serum to detect anti-RBD antibody titers that could compete for binding with S728-1157 (FIG. 11a). Subjects were divided into three groups based on their magnitude of antibody responses, as defined previously (12,13). Although high- and moderate-responders had higher titers of S728-1157-competitive serum antibodies compared to low-responders (FIG. 11b), the titers were quite low across all groups suggesting that it is uncommon to acquire high levels of S728-1157-like antibodies in polyclonal serum following wildtype SARS-CoV-2 infection. In addition to S728-1157, the inventors tested the competition of convalescent serum with other mAbs, including S451-1140 and S626-161, LY-CoV555, REGN10933, CR3022, and CC12.3. Similar to S728-1157, the inventors observed relatively low titers of antibodies competing with S451-1140, S626-161, LY-CoV555, REGN10933 and CC12.3 in polyclonal serum from most of the convalescent individuals (FIG. 11c-f, h). Nonetheless, high-responders tended to have significantly higher titers against those neutralizing mAbs than low-responders (FIG. 11b-f, h). In contrast, antibodies targeting the CR3022 epitope site were more pronounced in convalescent individuals, suggesting the enrichment of class 4 RBD antibodies in polyclonal serum (FIG. 11g). Notably, there was no difference in titers of CR3022 across the three responder groups, suggesting that CR3022-site antibodies were largely induced during wildtype SARS-CoV-2 infection. Interestingly, as compared to CC12.3, S728-1157 was detected at 4-fold lower levels in the serum of high-responders. Thus, despite class 1 antibodies being frequently induced by natural infection and vaccination (17, 26, 27, 41-44), our data suggest that S728-1157-like antibodies represent a subset of this class that are comparatively rare.


Lastly, the inventors examined the difference in reactivity to 2P-versus 6P-stabilized spike in our convalescent cohort sera (FIG. 11i-k). The inventors found that all three responder groups mounted anti-spike reactive antibodies against 6P-stabilized spike wildtype to a greater extent than 2P-stabilized spike wildtype, by a factor of 6 to 11-fold (FIG. 11j), indicating that the major antigenic epitopes were better exhibited or stabilized on 6P-stabilized antigen. Using the same samples, high and moderate responders also had lower anti-spike antibodies against BA.1-2P than BA.1-6P, by 4 to 5-fold (FIG. 11k). Of note, low responders had a smaller fold change in binding reactivity against spike BA.1 Omicron-2P and 6P (2-fold reduction) compared to wildtype-2P and 6P spike (11-fold reduction) (FIG. 11j-k), suggesting that serum antibody against BA.1 Omicron-reactive epitopes may be limited in low responder subjects. Overall, these data suggest that there is improved polyclonal binding induced by natural infection to 6P-stabilized spike, both for wildtype and Omicron viruses.


C. Materials and Methods
1. Monoclonal Antibody Isolation

The inventors isolated a panel of RBD-reactive mAbs from peripheral blood mononuclear cells (PBMCs) of convalescent donors who previously had experienced symptomatic infection with SARS-CoV-2 (Table S1). The samples were collected during the first wave of the pandemic in May 2020, before other SARS-CoV-2 variants emerged. All studies were performed with the approval of the University of Chicago institutional review board (IRB20-0523). All participants provided prior written informed consent for the use of blood in research applications. This clinical trial was registered at ClinicalTrials.gov under identifier NCT04340050.


PBMCs were isolated from leukoreduction filters and frozen as described previously (21). B cells were enriched from PBMCs via fluorescence-activated cell sorting (FACS). Cells were stained with CD19, CD3, and antigen probes conjugated oligo-fluorophore; cells of interest were identified as CD3−CD19+Antigen+. All mAbs were generated from oligo-tagged antigen bait-sorted cells identified through single-cell RNA sequencing (RNA-seq), as described previously (12,21).


Antigen-specific B cells were selected to generate mAbs based on antigen-probe intensity analyzed by JMP Pro 15. Antibody heavy and light chain genes were synthesized and cloned into human IgG1 and human kappa or lambda light chain expression vectors by Gibson assembly as previously described (56). The heavy and light chains of the corresponding mAb were transiently co-transfected into HEK293T cells. After transfection for 18 h, the transfected cells were supplemented with Protein-Free Hybridoma Medium Supernatant (PFHM-II, Gibco). The supernatant containing secreted mAb was harvested at day 4 and purified using protein A-agarose beads (Thermo Fisher) as detailed previously (56).


2. Recombinant Spike Protein Expression

The recombinant D614G SARS-CoV-2 full-length (FL) spike, WT RBD, single RBD mutants (R346S, K417N, K417T, G446V, L452R, S477N, F486A, F486Y, N487Q, Y489F, Q493A, Q493N, N501Y, Y505A, Y505F), combination RBD mutant (K417N/E484K/L452R/NN501Y), SARS-CoV-1 RBD and MERS-CoV RBD were generated in-house. Briefly, the recombinant antigens were expressed using Expi293F cells. The gene of interest was cloned into mammalian expression vector (in-house modified AbVec) and transfected using ExpiFectamine 293 kit according to the manufacturer's protocol. The supernatant was harvested at day 4 after transfection and incubated with Ni-nitrilotriacetic acid (Ni-NTA) agarose (Qiagen). The purification was carried out using gravity flow column and eluted with imidazole-containing buffer as previously described (57,58). The eluate was buffering-exchanged with PBS using Amicon centrifugal unit (Millipore). The recombinant FL spikes derived from variants B.1.1.7 Alpha, B.1.351 Beta, P.1 Gamma, B.1.617.2 Delta, BA.1, BA.2 and BA.4 Omicron were produced in the Sather Laboratory at Seattle Children's Research Institute. The K417V, N439K, E484K RBDs and recombinant FL spike WT-2P and 6P were produced in Krammer laboratory at the Icahn School of Medicine at Mount Sinai. The SARS-CoV-2-6P-Mut7 and spike BA.1 Omicron-6P were designed and produced as described in a previous study (59). The protein sequences and resources for each antigen are listed in Table S3.


3. Enzyme-Linked Immunosorbent Assay (ELISA)

Recombinant SARS-CoV-2 spike/RBD proteins were coated onto high protein-binding microtiter plates (Costar) at 2 μg/ml in phosphate buffered saline (PBS) at 50 μl/well, and kept overnight at 4° C. Plates were washed with PBS containing 0.05% Tween 20 (PBS-T) and blocked with 150 μl of PBS containing 20% fetal bovine serum (FBS) for 1 h at 37° C. Monoclonal antibodies were serially diluted 3-fold starting from 10 μg/ml in PBS and incubated in the wells for 1 h at 37° C. Plates were then washed and incubated with horseradish peroxidase (HRP)-conjugated goat anti-human IgG antibody (Jackson ImmunoResearch, 1:1000) for 1 h at 37° C. After washing, 100 μl of Super AquaBlue ELISA substrate (eBioscience) was added per well. Absorbance was measured at 405 nm on a microplate spectrophotometer (Bio-Rad). The assays were standardized using control antibodies with known binding characteristics in every plate, and the plates were developed until the absorbance of the control reached an optical density (OD) of 3.0. All mAbs were tested in duplicate, and each experiment was performed twice.


4. Serum ELISA

High protein-binding microtiter plates were coated with recombinant SARS-CoV-2 spike antigens at 2 μg/ml in PBS overnight at 4° C. Plates were washed with PBS 0.05% Tween and blocked with 200 μl PBS 0.1% Tween+3% skim milk powder for 1 hour at room temperature (RT). Plasma samples were heat-inactivated for 1 hour at 56° C. before perform serology experiment. Plasma were serially diluted 2-fold in PBS 0.1% Tween+1% skim milk powder. Plates were incubated with serum dilutions for 2 hours at RT. The HRP-conjugated goat anti-human Ig secondary antibody diluted at 1:3000 with PBS 0.1% Tween+1% skim milk powder was used to detect binding of antibodies. After 1-hour of incubation, plates were developed with 100 μl SigmaFast OPD solution (Sigma-Aldrich) for 10 minutes. Then, 50 μl 3M HCl was used to stop the development reaction. Absorbance was measured at 490 nm on a microplate spectrophotometer (BioRad). End point titers were extrapolated from sigmoidal 4PL (where X is log concentration) standard curve for each sample. Limit of detection (LOD) is defined as the mean plus 3 S.D. of the O.D. signal recorded using plasma from pre-SARS-CoV-2 subjects. All calculations were performed in GraphPad Prism software (version 9.0).


5. Competition ELISA

To determine the target epitope classification of RBD-reactive mAbs, competition ELISAs were performed using other mAbs with known epitope binding characteristics as competitor mAbs. Competitor mAbs were biotinylated using EZ-Link sulfo-NHS-biotin (Thermo Scientific) for 2 h at room temperature (RT). The excess biotin of biotinylated mAbs was removed with 7k molecular weight-cutoff (MWCO) Zeba spin desalting columns (Thermo Scientific). Plates were coated with 2 μg/ml RBD antigen overnight at 4° C. Plates were blocked with PBS-20% FBS for 2 h at RT, and the 2-fold dilution of the mAbs of an undetermined class, or serum, was added, starting at 20 μg/ml of mAbs and a 1:10 dilution of serum. After antibody incubation for 2 h at RT, the biotinylated competitor mAb was added at a concentration twice that of its dissociation constant (KD) and incubated for another 2 h at RT together with the mAb or serum that was previously added. Plates were washed and incubated with 100 μl HRP-conjugated streptavidin (Southern Biotech) at a dilution of 1:1000 for 1 h at 37° C. The plates were developed with the Super AquaBlue ELISA substrate (eBioscience). To normalize the assays, the competitor biotinylated mAb was added in a well without any competing mAbs or serum as a control. Data were recorded when the absorbance of the control well reached and OD of 1.0-1.5. The percent competition between mAbs was then calculated by dividing a sample's observed OD by the OD reached by the positive control, subtracting this value from 1, and multiplying by 100. For serum, ODs were log10-transformed and analyzed by nonlinear regression to determine the 50% inhibition concentration (IC50) values using GraphPad Prism software (version 9.0). The data were transformed to Log 1P and plotted into graph representative of reciprocal serum dilution of the IC50 of serum dilution that can achieve 50% competition with the competitor mAb of interest. All mAbs were tested in duplicate, each experiment was performed two times independently, and values from two independent experiments were averaged.


6. Plaque Assays

Plaque assays were performed with SARS-CoV-2 variant viruses on Vero E6/TMPRSS2 cells (Table S4). Cells were cultured to achieve 90% confluency prior to being trypsinized and seeded at a density of 3×104 cells/well in 96-well plates. On the following day, 102 plaque-forming unit (PFU) of SARS-CoV-2 variant was incubated with 2-fold-diluted mAbs for 1 h. The antibody-virus mixture was incubated with Vero E6/TMPRSS2 cells for 3 days at 37° C. Plates were fixed with 20% methanol and then stained with crystal violet solution. The complete inhibitory concentrations (IC99) were calculated using the log (inhibitor) versus normalized response (variable slope), performed in GraphPad Prism (version 9.0). All mAbs were tested in duplicate, and each experiment was performed twice.


7. Focus Reduction Neutralization Test (FRNT)

Focus reduction neutralization test (FRNT) were used to determine neutralization activities as an additional platform beside plaque assay. Serial dilutions of serum starting at a final concentration of 1:20 will be mixed with 103 focus-forming units of virus per well and incubated for 1 h at 37° C. A pooled pre-pandemic serum sample is served as a control. The antibody-virus mixture will be inoculated onto Vero E6/TMPRSS2 cells in 96-well plates and incubated for 1 h at 37° C. An equal volume of methylcellulose solution was added to each well. The cells were incubated for 16 h at 37° C. and then fixed with formalin. After the formalin was removed, the cells were immunostained with a mouse monoclonal antibody against SARS-CoV-1/2 nucleoprotein [clone 1C7C7 (Sigma-Aldrich)], followed by a HRP-labeled goat anti-mouse immunoglobulin (SeraCare Life Sciences). The infected cells were stained with TrueBlue Substrate (SeraCare Life Sciences) and then washed with distilled water. After cell drying, the focus numbers were quantified by using an ImmunoSpot S6 Analyzer, ImmunoCapture software, and BioSpot software (Cellular Technology). The IC50 was calculated from the interpolated value from the log (inhibitor) versus normalized response, using variable slope (four parameters) nonlinear regression performed in GraphPad Prism (version 9.0).


8. Negative Stain Electron Microscopy

Spike BA.1 Omicron-6P was complexed with a 0.5-fold molar excess of IgG S728-1157 and incubated for 30 mins at room temperature. The complex was diluted to 0.03 mg/ml and deposited on a glow-discharged carbon-coated copper mesh grid. 2% uranyl formate (w/v) was used to stain the sample for 90 seconds. The negative stain dataset was collected on a Thermo Fisher Tecnai T12 Spirit (120 keV, 56,000× magnification, 2.06 apix) paired with a FEI Eagle 4k×4k CCD camera. Leginon (60) was used to automate the data collection and raw micrographs were store in the Appion database (61). Dogpicker (62) picked particles and the dataset was processed in RELION 3.0 (62). UCSF Chimera (63) was used for map segmentation and figure making.


9. Cryo-Electron Microscopy and Model Building

SARS-CoV-2-6P-Mut7 was complexed with a 0.5-fold molar excess of IgG S728-1157 and incubated for 30 mins at room temperature. Grids were prepared using a Thermo Fisher Vitrobot Mark IV set to 4° C. and 100% humidity. The complex, at 0.7 mg/ml, was briefly incubated with lauryl maltose neopentyl glycol (final concentration of 0.005 mM; Anatrace), deposited on a glow-discharged Quantifoil 1.2/1.3-400 mesh grid, and blotted for 3 seconds. The grid was loaded into a Thermo Fisher Titan Krios (130,000× magnification, 300 kEV, 1.045-Å pixel size) paired with a Gatan 4k×4k K2 Summit direct electron detector. The Leginon software was used for data collection automation and resulting images were stored in the Appion database. Initial data processing was performed with cryoSPARC v3.2 (64), which included CTF correction using GCTF (65), template picking, and 2D and 3D classification and refinement methods leading to a ˜3.3 Å Cl global reconstruction. The particles from this reconstruction were imported into Relion 3.1 (66), subjected to C3 symmetry expansion, followed by focused 3D classifications without alignments using a mask around the antibody Fab and S-protein RBD regions of a single protomer. Classes with well-resolved density in this region were selected and subjected to additional rounds of focused classification. Refinements were performed with limited angular searches and a mask around the trimeric S-protein and a single Fab. The final set of particles reconstructed to ˜3.7 Å global resolution.


Model building was initiated by rigid body docking of the x-ray structure of the Fab and a published cryo-EM model of the SARS-CoV-2 spike open state (PDB ID: 6VYB) into the cryo-EM map using UCSF Chimera (63). Manual building, mutagenesis and refinement were performed in Coot 0.9.6 (67), followed by relaxed refinement using Rosetta Relax (68). Model manipulation and validation was also done using Phenix 1.20 (69). More complete data collection, processing and model building statistics are summarized in Table S6. Figures were generated using UCSF ChimeraX (70).


10. Crystallization and X-Ray Structure Determination

384 conditions of the JCSG Core Suite (Qiagen) were used for crystal screening of S728-1157 Fab crystals on the robotic CrystalMation system (Rigaku) at Scripps Research. Crystallization trials were set-up by the vapor diffusion method in sitting drops containing 0.1 μl of protein complex and 0.1 μl of reservoir solution. Crystals appeared on day 14, were harvested on day 21, pre-equilibrated in cryoprotectant containing 15% ethylene glycol, and then flash cooled and stored in liquid nitrogen until data collection. Diffraction quality crystals were obtained in solution containing 0.2 M di-Ammonium tartrate, 20% (w/v) polyethylene glycol (PEG) 3350. Diffraction data were collected at cryogenic temperature (100 K) on Scripps/Stanford beamline 12-1 at the Stanford Synchrotron Radiation Lightsource (SSRL). The X-ray data were processed with HKL2000 (71). The X-ray structures were solved by molecular replacement (MR) using PHASER (72) with MR models for the Fabs from PDB ID: 7KN4 (73). Iterative model building and refinement were carried out in COOT (74) and PHENIX (75), respectively. (76)


11. Animals and Challenge Viruses

To determine whether mAbs in the panel could reduce viral load in vivo, Syrian hamsters (females, 6-8 weeks old) were intraperitoneally administered 5 mg/kg of candidate mAb 1 day after intranasal infection with 103 PFU of SARS-CoV-2 viruses (an early SARS-CoV-2 isolate, Delta or BA.1 Omicron). Control animals were treated with an Ebola-specific mAb (KZ52) of matched isotype. At day 4 post-infection, lung tissues and nasal turbinate were collected to evaluate viral titers by standard plaque assay on Vero E6/TMPRRSS2 cells. The animal study was conducted in accordance with the recommendations for care and use of animals by the Institutional Animal Care and Use Committee at the University of Wisconsin under BSL-3 containment using approved protocols.


12. Biolayer Interferometry (BLI)

To determine precise binding affinity, the dissociation constant (KD) of each mAb was performed by biolayer interferometry (BLI) with an Octet K2 instrument (Forte Bio/Sartorious). The trimeric spike SARS-CoV-2 and its variants were biotinylated (EZ-Link Sulfo-NHS-Biotin, ThermoFisher), desalted (Zeba Spike Desalting, ThermoFisher), and loaded at a concentration of 500 nM onto streptavidin (SA) biosensor (Forte Bio/Sartorious) for 300 s, followed by kinetic buffer (1× PBS containing 0.02% Tween-20 and 0.1% bovine serum albumin) for 60 s. The biosensor was then moved to associate with mAbs of interest (142 nM) for 300 s, followed by disassociation with the kinetic buffer for 300 s. On rate, off-rate, and KD were evaluated with a global fit, the average of those values with high R-squared from two independent experiments were presented. Analysis was performed by Octet Data Analysis HT software (Forte Bio/Sartorious) with 1:1 fitting model for Fabs and 1:2 interacting model for IgG.


For competitive assay by BLI, streptavidin (SA) biosensor was pre-equilibrated in 1×PBS for at least 600 s to bind with the biotinylated trimeric spike WT-6P and spike BA.1 Omicron-6P for 300 s. The first mAb was associated on the loaded sensor for 300 s, followed by the second mAb for another 300 s. The final volume for all the solutions was 200 μl/well. All of the assays were performed with kinetic buffer at 30° C. Data were analyzed by Octet Data Analysis HT software (Forte Bio/Sartorious) and plotted using GraphPad Prism.


13. Statistics

All statistical analyses were performed using GraphPad Prism software (version 9.0). The numbers of biological repeats for experiments and specific tests for statistical significance used are described in the corresponding figure legends. P values of ≤0.05 were considered significant [*, P≤0.05; **, P≤0.01; ***, P≤0.001; ****, P<0.0001), while P values of >0.05 were considered as non-significant (ns)].


D. Tables

Table S1: COVID-19 convalescent subjects. Related to FIG. 8 and FIG. 11. The mAbs from high responder subjects, S451, S626, S728 were characterized in this study. Responder group and severity were categorized in a previous study13. Serum antibody from each responder group were tested for competition ELISA with broad neutralizing mAbs, other therapeutic mAbs and non-neutralizing mAb.
























Symptom








Duration of
start to


Subject


SARS-CoV-
symptoms
donation
Responder
Severity


ID
Age
Sex
2 PCR Test
(days)
(days)
Category26
Category26






















3
20
M
Mar. 16, 2020
4
33
Low
Moderate


11
66
M
Mar. 30, 2020
16
49
High
Severe









(hospitalized)


17
42
M
Mar. 21, 2020
17
55
High
Severe


19
55
F
Mar. 15, 2020
14
44
Low
Moderate


20
31
M
Mar. 31, 2020
19
48
High
Critical









(hospitalized)


22
31
F
Mar. 23, 2020
3
31
Mid
Moderate


24
34
M
Mar. 23, 2020
12
41
High
Severe


42
30
M
Mar. 18, 2020
11
39
Mid
Moderate


63
44
M
Mar. 30, 2020
2
33
Low
Moderate


80
33
M
Mar. 26, 2020
12
40
Mid
Moderate


89
64
M
Mar. 19, 2020
13
43
High
Mild


108
58
M
Mar. 15, 2020
11
39
High
Moderate


109
34
M
Mar. 15, 2020
9
41
Low
Moderate


112
43
M
Mar. 20, 2020
9
40
Low
Moderate


116
65
F
Mar. 25, 2020
18
49
Low
Moderate


130
52
M
Mar. 26, 2020
7
35
Mid
Mild


135
28
F
Mar. 24, 2020
7
36
Low
Moderate


141
66
M
Mar. 20, 2020
19
48
High
Moderate


144
56
M
Mar. 16, 2020
23
54
Low
Moderate


156
50
F
Mar. 23, 2020
11
41
High
Moderate


166
42
F
Mar. 25, 2020
17
55
Low
Moderate


176
26
M
Mar. 22, 2020
6
35
Low
Moderate


210
47
M
Apr. 4, 2020
7
41
Low
Moderate


218
51
F
Mar. 16, 2020
19
48
Mid
Severe


229
55
M
Mar. 11, 2020
2
42
Low
Mild


251
53
M
Mar. 18, 2020
22
51
Low
Severe


266
20
F
Mar. 25, 2020
4
32
Low
Mild


270
50
M
Mar. 18, 2020
9
39
Mid
Moderate


272
42
M
Mar. 18, 2020
14
43
Mid
Moderate


277
65
M
Mar. 18, 2020
13
45
High
Moderate


278
52
F
Mar. 12, 2020
12
47
Mid
Moderate


293
72
M
Mar. 8, 2020
17
63
High
Severe









(hospitalized)


305
43
F
Apr. 17, 2020
4
47
Low
Moderate


319
76
M
Mar. 27, 2020
4
36
High
Mild


332
32
M
Mar. 21, 2020
6
35
Mid
Moderate


346
30
M
Mar. 16, 2020
11
39
Mid
Moderate


355
45
F
Mar. 14, 2020
14
44
Low
Moderate


373
48
M
Mar. 16, 2020
7
39
High
Moderate


377
44
M
Mar. 14, 2020
9
41
High
Moderate


385
33
M
Mar. 11, 2020
7
47
Mid
Moderate


407
34
M
Apr. 1, 2020
11
43
Mid
Moderate


433
33
M
Mar. 20, 2020
6
35
Low
Moderate


447
42
M
Apr. 1, 2020
21
61
High
Severe



451


46


M


Apr. 4, 2020


11


49


High


Severe










(hospitalized)


537
36
M
Mar. 23, 2020
14
59
Mid
Moderate


564
24
F
Mar. 19, 2020
32
60
Low
Severe


573
25
M
Mar. 20, 2020
17
56
High
Severe









(hospitalized)



626


44


M


Mar. 31, 2020


19


56


High


Moderate




728


62


F


Mar. 15, 2020


53


130


High


Severe











Table S2: Characteristics of SARS-CoV-2 RBD-reactive mAbs. Related to FIG. 8. Cross-neutralizing mAbs against D614G and B.1.351 Beta, B.1., 617.2 Delta, B.1.617.1 Kappa, B. 1.621 Mu, BA.1 Omicron are bolded.




















Epitope


# VH
#VL
CDR-H3
CDR-L3


mAb ID
specificity
VH gene
VL gene
SHM
SHM
length
length






















S451-5
RBD
IGHV2-70*01
IGLV1-44*01
4
1
12
11



Class 2


S451-506
RBD
IGHV3-53*02
IGKV1-9*01
9
4
12
10



Class 3



S451-1140

RBD


IGHV3-23*04

IGKV4-1*01

8


7


12


9





Unclassified



S451-1190
RBD
IGHV2-5*02
IGLV2-14*01
8
8
9
11



Class 3


S626-84
RBD
IGHV1-2*02
IGLV2-23*02
7
9
16
10



Class 2



S626-161

RBD


IGHV4-39*01

IGKV3-20*01

8


2


18


10





Unclassified



S626-664
RBD
IGHV4-39*01
IGLV1-51*02
8
5
19
10



Unclassified


S728-209
RBD
IGHV2-5*04
IGKV1-12*01
14
12
12
9



Unclassified


S728-369
RBD
IGHV4-31*03
IGKV1-5*03
18
13
23
8



Unclassified


S728-430
RBD
IGHV3-53*01
IGKV1-33*01
1
1
12
10



Class 2


S728-537
RBD
IGHV1-2*02
IGKV1-12*01
15
9
17
9



Class 2



S728-1157

RBD


IGHV3-66*02

IGLV3-9*01

20


9


10


9





Unclassified



S728-1261
RBD
IGHV4-4*02
IGKV3-20*01
8
12
13
10



Unclassified


S728-1690
RBD
IGHV1-69*04
IGKV3-20*01
19
8
15
9



Class 2










Table S3: Antigen information and resource. Proline substitutions are indicated as italic. Related to FIG. 8 and FIG. 13.

















Antigen
S1 NTD
RBD
S1 CTD
S2
Source















Spike FL, trimer












Wildtype(WT)-2P
—
—
—

K986P,

Krammer lab







V987P



Wildtype(WT)-6P
—
—
—

F817P,

Krammer lab







A829P,








A899P,








A942P,








K986P,








V987P



B.1.1.7 Alpha-2P
del69-70,
N501Y
A570D,
T716I,
Sather lab



del144

D614G,
S982A,





P681H

K986P,








V987P,







D1118H


B.1.351 Beta-2P
L18F,
K417N,
D614G
A701V,
Sather lab



D80A, D215G,
E484K,


K986P,




del241-243,
N501Y


V987P




R246I


P.1 Gamma-2P
L18F,
K417T,
D614G,

K986P,

Sather lab



T20N,
E484K,
H655Y

V987P,




P26S, D138Y,
N501Y

T1027I,



R190S


V1176F


B.1.617.2 Delta-2P
T19R, G142D,
L452R,
D614G,
D950N,
Sather lab



del156-157,
T478K,
P681R

K986P,




R158G



V987P



BA.1 Omicron-2P
A67V,
G339D,
T547K,
N764K,
Sather lab



H69del,
S371L,
D614G,
D796Y,



V70del,
S373P,
H655Y,
N856K,



T95I,
S375F,
N679K,
Q954H,



G142D,
K417N,
P681H
N969K,



V143del,
N440K,

L981F,



Y144del,
G446S,


K986P,




Y145del,
S477N,


V987P




N211del, L212I,
T478K,



insert214EPE
E484A,




Q493R,




G496S,




Q498R,




N501Y,




Y505H


BA.1 Omicron-6P
A67V,
G339D,
T547K,

V705C,

Ward lab



H69del,
S371L,
D614G,
N764K,



V70del,
S373P,
H655Y,
D796Y,



T95I,
S375F,
N679K,

F817P,




G142D,
K417N,
P681H

A829P,




V143del,
N440K,

N856K,



Y144del,
G446S,


T883C,




Y145del,
S477N,


A899P,




N211del,
T478K,


A942P,




insert214EPE
E484A,

Q954H,




Q493R,

N969K,




G496S,

L981F,




Q498R,


K986P,





N501Y,


V987P





Y505H


BA.2
T19I,
G339D,
D614G,
N764K,
Sather lab


Omicron-2P
L24del,
S371F,
H655Y,
D796Y,



P25del,
S373P,
N679K,
Q954H,



P26del,
S375F,
P681H,
N969K,



A27S,
T376A,


K986P,




G142D,
D405N,


V987P




V213G,
R408S,




K417N,




N440K,




S477N,




T478K,




E484A,




Q493R,




Q498R,




N501Y,




Y505H


BA.4
T19I,
G339D,
D614G,
N764K,
Sather lab


Omicron-2P
L24del,
S371F,
H655Y,
D796Y,



P25del,
S373P,
N679K,
Q954H,



P26del,
S375F,
P681H,
N969K,



A27S,
T376A,


K986P,




H69del,
D405N,


V987P




V70del,
R408S,



G142D,
K417N,



V213G,
N440K,




L452R,




S477N,




T478K,




E484A,




F486V,




Q498R,




N501Y,




Y505H,







RBD












WT
—
—
—
—
In-house


R346S
—
R346S
—
—
In-house


K417N
—
K417N
—
—
In-house


K417V
—
K417V
—
—
Krammer lab


K417T
—
K417T
—
—
In-house


G446V
—
G446V
—
—
In-house


N439K
—
N439K
—
—
Krammer lab


L452R
—
L452R
—
—
In house


S477N
—
S477N
—
—
In-house


E484K
—
E484K
—
—
Krammer lab


F486A
—
F486A
—
—
In-house


F486Y
—
F486Y
—
—
In-house


N487Q
—
N487Q
—
—
In-house


Y489F
—
Y489F
—
—
In-house


Q493A
—
Q493A
—
—
In-house


Q493N
—
Q493N
—
—
In-house


N501Y
—
N501Y
—
—
In-house


Y505A
—
Y505A
—
—
In-house


Y505F
—
Y505F
—
—
In-house


K417N/E484K/
—
K417N/
—
—
In-house


L452R/N501Y

E484K/




L452R/




N501Y








SARS-CoV-1 RBD WT
In-house


MERS-CoV RBD WT
In-house










Table S4: SARS-CoV-2 virus information and resource. Related to FIGS. 8 and 10.

















Virus
S1 NTD
RBD
S1 CTD
S2
Source







D614G
—
—
D614G
—
2019-nCoV/USA-







WA1/2020 D614G


B.1.351
L18F,
K417N,
D614G
A701V
hCoV-19/USA/MD-


Beta
D80A,
E484K,


HP01542/2021



D215G,
N501Y



L241del,



L242del,



A243del


P.1
L18F,
K417T,
D614G,
T1027I,
hCoV-19/Japan/TY7-


Gamma
T20N,
E484K,
H655Y
V1176F
501/2021 from BEI



P26S,
N501Y



D138Y,



G181V,



R190S


B.1.621
in3T,
R346K,
D614G,
D950N
hCoV-19/USA/WI-UW-


Mu
T95I,
E484K,
P681H

4340/2021



Y144S,
N501Y



Y145N,


B.1.617.1
G142D,
L452R,
D614G,
Q1071H,
hCoV-19/USA/CA-


Kappa
E154K
E484Q
P681R
H1101D
Stanford-15_S02/2021 from







BEI


B.1.617.2
T19R,
L452R,
D614G,
D950N
hCoV-19/USA/WI-UW-


Delta
T95I,
T478K
P681R

5250/2021



G142D,



E156G,



F157del,



R158del


BA.1
A67V,
G339D,
T547K,
N764K,
hCoV-19/USA/WI-WSLH-


Omicron
H69del,
S371L,
D614G,
D796Y,
221686/2021



V70del,
S373P,
H655Y,
N856K,



T95I,
S375F,
N679K,
Q954H,



G142D,
K417N,
P681H
N969K,



V143del,
N440K.

L981F



Y144del,
G446S,



Y145del,
S477N,



N211del,
T478K,



L212I,
E484A,



ins214EPE
Q493R,




G496S,




Q498R,




N501Y,




Y505H


BA.2
T19I,
G339D,
D614G,
N764K,
hCoV-19/Japan/UT-


Omicron
delL24,
S371F,
H655Y,
D796Y,
NCD1288-2N/2022



delP25,
S373P,
N679K,
Q954H,



delP26,
S375F,
P681H
N969K



A27S,
T376A,



G142D,
D405N,



V213G
R408S,




K417N,




N440K,




S477N,




T478K,




E484A,




Q493R,




Q498R,




N501Y,




Y505H


BA.2.75
T19I,
G339H,
D614G,
N764K,
hCoV-19/Japan/TY41-


Omicron
delL24,
S371F,
H655Y,
D796Y,
716/2022



delP25,
S373P,
N679K,
Q954H,



delP26,
S375F,
P681H
N969K



A27S,
T376A,



G142D,
D405N,



K147E,
R408S,



W152R,
K417N,



F157L,
N440K,



I210V,
G446S,



V213G,
N460K,



G257S
S477N,




T478K,




E484A,




Q498R,




N501Y,




Y505H


BA.4
T19I,
G339D,
D614G,
N764K,
hCoV-19/USA/MD-


Omicron
delL24,
S371F,
H655Y,
D796Y,
HP30386-



delP25,
S373P,
N679K,
Q954H,
PIDNBNVCCQ/2022



delP26,
S375F,
P681H,
N969K



A27S,
T376A,



delH69,
D405N,



delV70,
R408S,



G142D,
K417N,



V213G
N440K,




L452R,




S477N,




T478K,




F486V,




E484A,




Q498R,




N501Y,




Y505H,


BA.5
T19I,
G339D,
D614G,
N764K,
SARS-CoV-2/


Omicron
delL24,
S371F,
H655Y,
D796Y,
human/USA/COR-22-



delP25,
S373P,
N679K,
Q954H,
063113/2022



delP26,
S375F,
P681H,
N969K



A27S,
T376A,



delH69,
D405N,



delV70,
R408S,



G142D,
K417N,



V213G
N440K,




L452R,




S477N,




T478K,




F486V,




E484A,




Q498R,




N501Y,




Y505H,









Table S5: Pairs of S728-1157 and spike-WT-6P-Mut7 residues within predicted hydrogen bonding distances. Calculated using EpitopeAnalyzer63 using a cutoff distance of 3.4 Å. Related to FIG. 9 and FIG. 15.
























RBD residue



RBD



RBD residue
conserved



Residue
Ab Residue
Antibody
Distance
mutated in
across all


#
[Atom]
[atom]
Region
(Å)
Omicron VOC
VOC's





















1
T415 [OG]
S56 [OG1]
CDRH2
2.78
No
Yes


2
Y421 [OH]
S53 [O]
CDRH2
2.73
No
Yes


3
Y453 [OH]
D98 [OD1]
CDRH3
3.5
No
Yes


4
L455 [O]
Y33 [OH]
CDRH1
3.29
No
Yes


5
R457 [O]
S53 [OG]
CDRH2
3.25
No
Yes


6
Y473 [OH]
R31 [O]
CDRH1
2.76
No
Yes


7
Y473 [OH]
S53 [OG]
CDRH2
3.26
No
Yes


8
Q474 [O]
R31 [NH1]
CDRH1
3.08
No
Yes


9
A475 [O]
L28 [N]
CDRH1
3.05
No
Yes


10
A475 [O]
N32 [ND2]
CDRH1
2.98
No
Yes


11
E484 [OE2]
Y99 [OH]
CDRH3
2.61
Yes
No


12
N487 [ND2]
G26 [O]
FR1
3.01
No
Yes


13
C488 [O]
Y99 [OH]
CDRH3
3.25
No
Yes


14
Y489 [OH]
R94 [NH1]
FR3
2.64
No
Yes


15
Y505 [OH]
Q31 [NE2]
CDRL1
2.62
Yes
No









Table S6. Cryo-EM data collection, refinement and model building statistics. Related to FIG. 9 and FIG. 15.















S728-1157 + SARS-CoV-2-
S728-1157 + SARS-CoV-2-



6P-Mut7 (global
6P-Mut7 (focused


Map
refinement)
refinement)







EMDB
EMD-27112
EMD-27113







Data collection








Microscope
Thermo Fisher Titan Krios


Voltage (kV)
300


Detector
Gatan K2 Summit


Recording mode
Counting


Nominal magnification
130kx


Movie micrograph pixelsize (Å)
1.045


Dose rate (e−/[(camera pixel)*s])
6.017


Number of frames per movie micrograph
36


Frame exposure time (ms)
250


Movie micrograph exposure time (s)
9


Total dose (e−/Å2)
50.0


Defocus range (μm)
−0.8 to −1.5







EM data processing









Number of movie micrographs
1,718
1,718


Number of molecular projection images
151,948
29,595


in map


Symmetry
C1
C1


Map resolution (FSC 0.143; Å)
3.3
3.7


Map sharpening B-factor (Å2)
−85.3
−71.1







Structure Building and Validation


Number of atoms in deposited model









SARS-CoV-2-6P-Mut7
n/a
20,759


Fab Fv
n/a
1,653


Glycans
n/a
182


MolProbity score
n/a
1.07


Clashscore
n/a
1.66


Map correlation coefficient
n/a
0.75


EMRinger score
n/a
2.57


d FSC model (0.5; Å)
n/a
3.8







RMSD from ideal









Bond length (Å)
n/a
0.021


Bond angles (°)
n/a
1.81







Ramachandran plot









Favored (%)
n/a
97.13


Allowed (%)
n/a
2.87


Outliers (%)
n/a
0.00


Side chain rotamer outliers (%)
n/a
0.08


Cβ outliers (%)
n/a
0.00


PDB
n/a
8d0z









E. References

The following references and the references cited throughout the specification, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

Claims
  • 1. An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region: (i) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1565, 1566, and 1567 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1572, 1573, and 1574;(ii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1457, 1458, and 1459 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1464, 1465, and 1466; or(iii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 of SEQ ID NOs: 1492, 243, and 1493 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1497, 1498, and 1499.
  • 2. The antibody or antigen binding fragment of claim 1: (i) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1565, 1566, and 1567 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having the amino acid sequence of SEQ ID NOs: 1572, 1573, and 1574;(ii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1457, 1458, and 1459 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having the amino acid sequence of SEQ ID NOs: 1464, 1465, and 1466; or(iii) wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NOs: 1492, 243, and 1493 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having the amino acid sequence of SEQ ID NOs: 1497, 1498, and 1499.
  • 3. The antibody or antigen binding fragment of claim 1 or 2: (i) wherein the heavy chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1563 or 1564 and/or the light chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO:1570 or 1571;(ii) wherein the heavy chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1455 or 1456 and/or the light chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO:1462 or 1463; or(iii) wherein the heavy chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1490 or 1491 and/or the light chain comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NO: 1495 or 1496.
  • 4. The antibody or antigen binding fragment of claim 3: (i) wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 1563 or 1564 and/or the light chain comprises the amino acid sequence of SEQ ID NO: 1570 or 1571;(ii) wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 1455 or 1456 and/or the light chain comprises the amino acid sequence of SEQ ID NO: 1462 or 1463; or(iii) wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 1490 or 1491 and/or the light chain comprises the amino acid sequence of SEQ ID NO: 1495 or 1496.
  • 5. The antibody or antigen binding fragment of any one of claims 1-4, wherein the antibody or antigen binding fragment comprises: (i) a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1568, 130, 1569, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1575, 950, 1576, and 69;(ii) a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1460, 1461, 146, and 60, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1467, 1468, 1469, and 53; or(iii) a heavy chain framework region HFR1, HFR2, HFR3, and HFR4 and light chain framework region LFR1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 245, 7, 1494, and 44, respectively, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to SEQ ID NOs: 1500, 1501, 1502, and 18.
  • 6. The antibody or antigen binding fragment of any one of claims 1-5: (i) wherein the HFR1, HFR2, HFR3, and HFR4 comprises the amino acid sequence of SEQ ID NOs: 1568, 130, 1569, and 60, and the LFR1, LFR2, LFR3, and LFR4 comprises the amino acid sequence of SEQ ID NOs: 1575, 950, 1576, and 69;(ii) wherein the HFR1, HFR2, HFR3, and HFR4 comprises the amino acid sequence of SEQ ID NOs: 1460, 1461, 146, and 60, and the LFR1, LFR2, LFR3, and LFR4 comprises the amino acid sequence of SEQ ID NOs: 1467, 1468, 1469, and 53; or(iii) wherein the HFR1, HFR2, HFR3, and HFR4 comprises the amino acid sequence of SEQ ID NOs: 245, 7, 1494, and 44, and the LFR1, LFR2, LFR3, and LFR4 comprises the amino acid sequence of SEQ ID NOs: 1500, 1501, 1502, and 18.
  • 7. An antibody or antigen binding fragment comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity to the HCDR1, HCR2, HCR3 from a heavy chain variable region of a antibody clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity to the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same antibody clone of Table 1.
  • 8. The antibody or antigen binding fragment of claim 7, wherein the heavy chain variable region comprises a HCDR1, HCDR2, and HCDR3 having the amino acid sequence of an of a HCDR1, HCDR2, and HCDR3 of a clone of Table 1 and wherein the light chain variable region comprises a LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of the LCDR1, LCDR2, and LCDR3 from the light chain variable region of the same clone of Table 1.
  • 9. The antibody or antigen binding fragment of claim 7 or 8, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 each comprise an amino acid sequence that has at least 80% sequence identity to an HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 of Table 1, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 are from the same antibody clone.
  • 10. The antibody or antigen binding fragment of claim 7 or 8, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 each comprise the amino acid sequence of an HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 of Table 1, wherein the HCDR1, HCDR2, HCDR2, LCDR1, LCDR2, and LCDR3 are from the same antibody clone.
  • 11. The antibody or antigen binding fragment of any one of claims 7-10, wherein the heavy chain variable region comprises an amino acid sequence with at least 80% sequence identity to a heavy chain variable region of an antibody clone of Table 1 and/or the light chain variable region comprises an amino acid sequence with at least 80% sequence identity to the light chain variable region of the same antibody clone of Table 1.
  • 12. The antibody or antigen binding fragment of claim 11, wherein the heavy chain variable region comprises the amino acid sequence of a heavy chain variable region of an antibody clone of Table 1 and/or the light chain variable region comprises the amino acid sequence of the same antibody clone of Table 1.
  • 13. The antibody or antigen binding fragment of any one of claims 7-12, wherein the antibody or antigen binding fragment comprises a heavy chain framework region (HFR) 1, HFR2, HFR3, and HFR4 and light chain framework region (LFR) 1, LFR2, LFR3, and LFR4, and wherein the HFR1, HFR2, HFR3, and HFR4 comprises an amino acid sequence with at least 80% sequence identity to an HFR1, HFR2, HFR3, and HFR4, respectively, of an antibody clone of Table 1, and the LFR1, LFR2, LFR3, and LFR4 comprises an amino acid sequence with at least 80% sequence identity to the LFR1, LFR2, LFR3, and LFR4, respectively, of the same antibody clone of Table 1.
  • 14. The antibody or antigen binding fragment of any one of claims 7-12, wherein the HFR1, HFR2, HFR3, and HFR4 comprises the amino acid sequence of an HFR1, HFR2, HFR3, and HFR4, respectively, of an antibody clone of Table 1, and the LFR1, LFR2, LFR3, and LFR4 comprises the amino acid sequence of the LFR1, LFR2, LFR3, and LFR4, respectively, of the same antibody clone of Table 1.
  • 15. The antibody or antigen binding fragment of any one of claims 7-14, wherein the antibody comprises a heavy chain and a light chain and wherein the heavy chain comprises an amino acid sequence with at least 70% sequence identity to a heavy chain of an antibody clone of Table 1 and the light chain comprises an amino acid sequence with at least 70% sequence identity to the light chain of the same antibody clone of Table 1.
  • 16. The antibody or antigen binding fragment of claim 15, wherein the antibody comprises a heavy chain and a light chain and wherein the heavy chain comprises the amino acid sequence of an antibody clone of Table 1 and the light chain comprises the amino acid sequence of the same antibody clone of Table 1.
  • 17. The antibody of any one of claims 1-16, wherein the antibody is human, chimeric, or humanized.
  • 18. The antibody or antigen-binding fragment of any one of claims 1-17, wherein the antibody, or antigen binding fragment binds a SARS-CoV-2 protein with a KD of about 10−6 nM to about 10−12 pM.
  • 19. The antibody or antigen binding fragment of any one of claims 1-18, wherein the antibody is a neutralizing antibody.
  • 20. The antibody or antigen binding fragment of any one of claims 1-19, wherein the antibody is a human antibody, humanized antibody, recombinant antibody, chimeric antibody, an antibody derivative, a veneered antibody, a diabody, a monoclonal antibody, a single domain antibody, or a single chain antibody.
  • 21. The antigen binding fragment of any one of claims 1-19, wherein the antigen binding fragment is a single chain variable fragment (scFv), F(ab′)2, Fab′, Fab, Fv, or rIgG.
  • 22. A polypeptide comprising the antigen binding fragment of any one of claims 1-21.
  • 23. The polypeptide of claim 22, wherein the polypeptide comprises at least two antigen binding fragments, wherein each antigen binding fragment is independently selected from an antigen binding fragment of any one of claims 1-21.
  • 24. The polypeptide of claim 22 or 23, wherein the polypeptide is multivalent.
  • 25. The polypeptide of any one of claims 22-24, wherein the polypeptide is bispecific.
  • 26. A composition comprising the antibody or antigen binding fragment of any one of claims 1-25.
  • 27. The composition of claim 26, wherein the composition comprises a pharmaceutical excipient.
  • 28. The composition of claim 26 or 27, wherein the composition further comprises an adjuvant.
  • 29. The composition of any one of claims 26-28, wherein the composition is formulated for parenteral, intravenous, subcutaneous, intramuscular, or intranasal administration.
  • 30. The composition of any one of claims 26-29, wherein the composition comprises at least two antibodies or antigen binding fragments.
  • 31. One or more nucleic acids encoding the antibody or antigen binding fragment of any one of claims 1-21 or the polypeptide of claim 25.
  • 32. A nucleic acid encoding an antibody heavy chain, wherein the nucleic acid has at least 70% sequence identity to one of the nucleic acid sequences of a heavy chain of Table 2.
  • 33. A nucleic acid encoding an antibody light chain, wherein the nucleic acid has at least 70% sequence identity to one of the nucleic acid sequences of a light chain of Table 2.
  • 34. A vector comprising the nucleic acid(s) of any one of claims 31-33.
  • 35. A host cell comprising the nucleic acid of any one of claims 31-33 or the vector of claim 34.
  • 36. The host cell of claim 35, wherein the host cell is a human cell, B cell, T cell, Chinese hamster ovary, NS0 murine myeloma cell, or PER.C6 cell.
  • 37. A method of a making a cell comprising transferring the nucleic acid(s) of any one of claims 31-33 or the vector of claim 34 into a cell.
  • 38. The method of claim 37, wherein the method further comprises culturing the cell under conditions that allow for expression of a polypeptide from the nucleic acid.
  • 39. The method of claim 38, wherein the method further comprising isolating the expressed polypeptide.
  • 40. The method of any one of claims 37-39, wherein the cell is a human cell, B cell, T cell, Chinese hamster ovary, NS0 murine myeloma cell, or PER.C6 cell.
  • 41. A method for producing a polypeptide comprising culturing cells comprising the nucleic acid(s) of any one of claims 31-33 or the vector of claim 34 and isolating polypeptides expressed from the nucleic acid.
  • 42. The method of claim 41, wherein the cell is a human cell, B cell, T cell, Chinese hamster ovary, NS0 murine myeloma cell, or PER.C6 cell.
  • 43. A method for treating or preventing a coronavirus infection in a subject, the method comprising administering to the subject, the antibody or antigen binding fragment of any one of claims 1-21, the polypeptide of claim 25, or the host cell of claim 35.
  • 44. The method of claim 43, wherein the subject is a human subject.
  • 45. The method of claim 43 or 44, wherein the coronavirus infection is SARS-CoV-2.
  • 46. The method of claim 43 or 44, wherein the subject has one or more symptoms of a coronavirus infection.
  • 47. The method of claim 43 or 44, wherein the subject does not have any symptoms of a coronavirus infection.
  • 48. The method of any one of claims 43-47, wherein the subject has been diagnosed with a coronavirus infection.
  • 49. The method of any one of claims 43-47, wherein the subject has not been diagnosed with a coronavirus infection.
  • 50. The method of any one of claims 43-49, wherein the subject has been previously vaccinated for coronavirus.
  • 51. The method of any one of claims 43-49, wherein the subject has not been previously vaccinated for coronavirus.
  • 52. The method of any one of claims 43-51, wherein the antibody, antigen binding fragment, polypeptide, or cell is administered by parenteral, intravenous, subcutaneous, intramuscular, or intranasal administration.
  • 53. The method of any one of claims 43-49, wherein the subject has been previously treated for a coronavirus infection.
  • 54. The method of any one of claims 43-53, wherein the subject is administered an additional therapeutic.
  • 55. The method of claim 54, wherein the additional therapeutic comprises a steroid or an anti-viral therapeutic.
  • 56. The method of claim 55, wherein the additional therapeutic comprises dexamethasone or remdesivir.
  • 57. A method for evaluating a sample from a subject, the method comprising contacting a biological sample from the subject, or extract thereof, with at least one antibody, antigen binding fragment, or polypeptide of any one of claims 1-25.
  • 58. The method of claim 57, wherein the at least one antibody, antigen binding fragment, or polypeptide is operatively linked to a detectable label.
  • 59. The method of claim 57 or 58, wherein the method further comprises incubating the antibody, antigen binding fragment, or polypeptide under conditions that allow for the binding of the antibody, antigen binding fragment, or polypeptide to antigens in the biological sample or extract thereof.
  • 60. The method of any one of claims 57-59, wherein the method further comprises detecting the binding of an antigen to the antibody, antigen binding fragment, or polypeptide.
  • 61. The method of any one of claims 57-60, wherein the method further comprises contacting the biological sample with at least one capture antibody, antigen, or polypeptide.
  • 62. The method of claim 61, wherein the at least one capture antibody, antigen binding fragment, or polypeptide comprises at least one antibody of claims 7-25.
  • 63. The method of claim 61 or 62, wherein the capture antibody is linked to a solid support.
  • 64. The method of any one of claims 57-63, wherein the biological sample comprises a blood sample, urine sample, fecal sample, or nasopharyngeal sample.
  • 65. A method for diagnosing a SARS-CoV-2 infection in a subject, the method comprising contacting a biological sample from the subject, or extract thereof, with at least one antibody, antigen binding fragment, or polypeptide of any one of claims 7-25.
  • 66. The method of claim 65, wherein the at least one antibody, antigen binding fragment, or polypeptide is operatively linked to a detectable label.
  • 67. The method of claim 65 or 66, wherein the method further comprises incubating the antibody, antigen binding fragment, or polypeptide under conditions that allow for the binding of the antibody, antigen binding fragment, or polypeptide to antigens in the biological sample or extract thereof.
  • 68. The method of any one of claims 65-67, wherein the method further comprises detecting the binding of an antigen to the antibody, antigen binding fragment, or polypeptide.
  • 69. The method of any one of claims 65-68, wherein the method further comprises contacting the biological sample with at least one capture antibody, antigen, or polypeptide.
  • 70. The method of claim 69, wherein the at least one capture antibody, antigen, or polypeptide comprises at least one antibody, antigen, or polypeptide of claims 7-25.
  • 71. The method of claim 69 or 70, wherein the capture antibody is linked to a solid support.
  • 72. The method of any one of claims 65-71, wherein the biological sample comprises a blood sample, urine sample, fecal sample, or nasopharyngeal sample.
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. Provisional Patent Application No. 63/264,173 filed Nov. 16, 2021, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant Numbers 75N93019C00062 and 75N93019C00051, awarded by the National Institutes of Health. The government has certain rights in the invention.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2022/079916 11/16/2022 WO
Provisional Applications (1)
Number Date Country
63264173 Nov 2021 US