TRISPECIFIC AND/OR TRIVALENT BINDING PROTEINS FOR PREVENTION OR TREATMENT OF HIV INFECTION

Abstract
Provided herein are compositions comprising trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins or one or more T-cell receptors, where in a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. Also provided herein are methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins for the treatment and/or prevention of HIV/AIDS.
Description
SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 183952027041SEQLIST.txt, date recorded: Oct. 19, 2016, size: 1,064 KB).


FIELD OF THE INVENTION

The disclosure relates to trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. The disclosure also relates to methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins for treating and/or preventing HIV/AIDS.


BACKGROUND

One of the challenges in treating HIV/AIDS with neutralizing antibodies is potential breakthrough infection due to the high mutation rate of HIV-1 viruses. Additionally, virological events in the early weeks following HIV-1 transmission set the stage for lifelong chronic infection that remains incurable with currently available combination antiretroviral therapy (cART). This is due, at least in part, to the early establishment of viral reservoirs, including latently infected cells, which persist despite cART, leading to recrudescent infection when treatment is interrupted. Newly discovered anti-HIV-1 neutralizing antibodies with improved breadth and potency may provide more options for HIV/AIDS treatment and prevention; however, breakthrough infection remains a major issue in the field.


BRIEF SUMMARY

In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II];


a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-hinge-CH2-CH3  [II];


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In some embodiments, the one or more HIV target protein is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160. In some embodiments, the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different. In some embodiments, the binding protein is trispecific and capable of specifically binding three different antigen targets. In some embodiments, the binding protein is capable of inhibiting the function of one or more HIV target proteins. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively, a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively, or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502. In some embodiments, VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502. In some embodiments, VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, VLJ comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, at least one of L1, L2, L3, or L4 is independently 0 amino acids in length. In some embodiments, L1, L2, L3, or L4 are each independently at least one amino acid in length. In some embodiments, L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.


In some embodiments, the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.


In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In some embodiments, at least one of L1, L2, L3, or L4 is independently 0 amino acids in length. In some embodiments, L1, L2, L3, or L4 are each independently at least one amino acid in length. In some embodiments, L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).


In one embodiment, the disclosure provides a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind three different HIV target proteins, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.


In another embodiment, the disclosure provides a binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:


(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;


(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;


(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;


(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;


(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;


(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;


(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;


(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;


(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;


(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;


(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;


(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;


(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;


(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;


(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;


(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;


(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;


(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;


(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;


(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;


(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;


(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;


(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;


(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;


(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;


(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;


(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;


(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;


(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;


(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or


(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II];


a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain:


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II];


a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In some embodiments, the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160. In some embodiments, the one or more T cell target proteins are CD3 or CD28. In some embodiments, the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins. In some embodiments, the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins. In some embodiments, the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively, a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments. VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, at least one of L1, L2, L3, or L4 is independently 0 amino acids in length. In some embodiments, L1, L2, L3, or L4 are each independently at least one amino acid in length. In some embodiments, L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


In some embodiments, the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


In some embodiments, at least one of L1, L2, L3, or L4 is independently 0 amino acids in length. In some embodiments, L1, L2, L3, or L4 are each independently at least one amino acid in length. In some embodiments, L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).


In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


In another embodiment, the disclosure provides a binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:


(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;


(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;


(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;


(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;


(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;


(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;


(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;


(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;


(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;


(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;


(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;


(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;


(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;


(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;


(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;


(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;


(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;


(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;


(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447;


(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;


(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or


(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.


In one embodiment, the disclosure provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein according to any of the above embodiments. In one embodiment, the disclosure provides an expression vector comprising the nucleic acid molecule according to any of the above embodiments. In one embodiment, the disclosure provides an isolated host cell comprising the nucleic acid molecule according to any of the above embodiments. In one embodiment, the disclosure provides an isolated host cell comprising the expression vector according to any of the above embodiments. In some embodiments, the isolated host cell is a mammalian cell or an insect cell. In one embodiment, the disclosure provides a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein according to any of the above embodiments. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein. In some embodiments, the one or more vectors are expression vectors. In one embodiment, the disclosure provides an isolated host cell comprising the vector system according to any of the above embodiments. In some embodiments, the isolated host cell is a mammalian cell or an insect cell. In one embodiment, the disclosure provides a method of producing a binding protein, the method comprising: a) culturing a host cell according to any of the above embodiments under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell.


In one embodiment, the disclosure provides a method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein according to any of the above embodiments. In some embodiments, the binding protein is co-administered with standard anti-retroviral therapy. In some embodiments, administration of the at least one binding protein results in the neutralization of one or more HIV virions. In some embodiments, administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.


In one embodiment, the disclosure provides a binding protein according to any of the above embodiments for the prevention or treatment of an HIV infection in a patient. In some embodiments, the binding protein is co-administered with standard anti-retroviral therapy. In some embodiments, the binding protein causes the neutralization of one or more HIV virions in the patient. In some embodiments, the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.


Specific embodiments of the invention will become evident from the following more detailed description of certain embodiments and the claims.


It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art.





BRIEF DESCRIPTION OF THE DRAWINGS


FIGS. 1A-D show schematic representations of trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind three different epitopes on one or more antigens, wherein a first pair of polypeptides possess dual variable domains having a cross-over orientation forming two antigen binding sites (comprising VH1-VL1 and VH2-VL2) and wherein a second pair of polypeptides possess a single antigen binding site (comprising VH3-VL3), in accordance with some embodiments. FIG. 1A shows a trispecific binding protein comprising a “knobs-into-holes” modification, wherein the knob is on the first pair of polypeptides. FIG. 1B shows a trispecific binding protein comprising a “knobs-into-holes” modification, wherein the knob is on the second pair of polypeptides. FIG. 1C shows the orientation of variable domains on the polypeptide chains, and the knob/hole orientation for binding proteins 1-31 shown in Tables 1 and 2. “Heavy chain A” (e.g., a third polypeptide chain of the present disclosure) indicates the variable domain of heavy chain A. “Light chain A” (e.g., a fourth polypeptide chain of the present disclosure) indicates the variable domain of light chain A. “Heavy chain B” (e.g., a second polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of heavy chain B. “Light chain B” (e.g., a first polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of light chain B. FIG. 1D shows the orientation of variable domains on the polypeptide chains, and the knob/hole orientation for binding proteins 32-53 shown in Tables 1 and 2. “Heavy chain A” (e.g., a third polypeptide chain of the present disclosure) indicates the variable domain of heavy chain A. “Light chain A” (e.g., a fourth polypeptide chain of the present disclosure) indicates the variable domain of light chain A. “Heavy chain B” (e.g., a second polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of heavy chain B. “Light chain B” (e.g., a first polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of light chain B.



FIGS. 2A-B show purification of three trispecific binding proteins first using affinity chromatography, and then using preparative size exclusion chromatography. FIG. 2A shows the elution profile of the trispecific binding proteins during purification using protein A affinity chromatography. FIG. 2B shows purification of monomeric proteins by Superdex200 size exclusion chromatography.



FIGS. 3A-B show purification of the MPER Ab, CD4BS Ab “b”, and V1/V2 directed Ab “a” parental antibodies first using affinity chromatography, and then using preparative size exclusion chromatography. FIG. 3A shows the elution profile of the parental antibodies during purification using protein A affinity chromatography. FIG. 3B shows purification of monomeric proteins by Superdex200 size exclusion chromatography.



FIGS. 4A-B show the size exclusion chromatography profiles of bispecific and trispecific binding proteins. FIG. 4A shows the size exclusion chromatography profiles of the bispecific binding proteins. FIG. 4B shows the size exclusion chromatography profiles of the trispecific binding proteins.



FIG. 5 shows the Biacore sensograms of the binding kinetics of three trispecific binding proteins and the parental MPER Ab antibody for an HIV gp41-derived peptide (the MPER binding site), as assessed by the standard Biacore-based kinetic assay.



FIG. 6 shows the Biacore sensograms of the binding kinetics of three trispecific binding proteins and the parental CD4BS Ab “b” antibody for recombinant HIV gp120, as assessed by the standard Biacore-based kinetic assay.



FIG. 7 shows the results of a pharmacokinetic (PK) study of the indicated proteins after intravenous (IV) injection in rhesus macaques.



FIGS. 8A-8B show schematic representations of trispecific T-cell engagers, in accordance with some embodiments. The binding sites are indicated by the dotted circles.



FIG. 9 shows binding properties of the trispecific binding proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” to CD3 (CD3E represents CD3epsilon protein; CD3D represents CD3delta protein), CD28, and Resurfaced Stabilized Core 3 (RSC3) protein of gp120, as well as a negative control (human IgG).



FIG. 10 shows CD8 T-cell activation using the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).



FIG. 11 shows CD4 T-cell activation using the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).



FIG. 12 shows CD3 downregulation after T cell activation by the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).



FIGS. 13A-C show fluorescence-activated cell sorting (FACS)-based cytotoxicity assay results for trispecific binding proteins against latently infected HIV-1+ T cells. FIG. 13A shows the results for trispecific binding proteins incubated with CEM-BaL cells. FIG. 13B shows the results for trispecific binding proteins incubated with ACH2 cells. FIG. 13C shows the results for trispecific binding proteins incubated with J1.1 cells.





DETAILED DESCRIPTION

The present disclosure provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind to one or more human immunodeficiency virus (HIV) target proteins and/or one or more T-cell receptor target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain.


The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.


Definitions

As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.


The term “polynucleotide” as used herein refers to single-stranded or double-stranded nucleic acid polymers of at least 10 nucleotides in length. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Such modifications include base modifications such as bromuridine, ribose modifications such as arabinoside and 2′,3′-dideoxyribose, and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term “polynucleotide” specifically includes single-stranded and double-stranded forms of DNA.


An “isolated polynucleotide” is a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence.


An “isolated polypeptide” is one that: (1) is free of at least some other polypeptides with which it would normally be found, (2) is essentially free of other polypeptides from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or noncovalent interaction) with portions of a polypeptide with which the “isolated polypeptide” is associated in nature, (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated polypeptide can be encoded by genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free from polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).


Naturally occurring antibodies typically comprise a tetramer. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full-length “light” chain (typically having a molecular weight of about 25 kDa) and one full-length “heavy” chain (typically having a molecular weight of about 50-70 kDa). The terms “heavy chain” and “light chain” as used herein refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CH1, CH2, and CH3), wherein the VH domain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VL domain is at the amino-terminus of the polypeptide and the CL domain is at the carboxyl-terminus.


Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4, IgM has subclasses including, but not limited to, IgM1 and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light/heavy chain pair typically form an antigen binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.


The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-17; Chothia et al., 1989, Nature 342: 877-83) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2, and L3 or H1, H2, and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan, 1995, FASEB J. 9: 133-39; MacCallum, 1996, J. Mol. Biol. 262(5): 732-45; and Lefranc, 2003, Dev. Comp. Immunol. 27: 55-77. Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs. Identification of predicted CDRs using the amino acid sequence is well known in the field, such as in Martin, A. C. “Protein sequence and structure analysis of antibody variable domains,” In Antibody Engineering, Vol. 2. Kontermann R., Dübel S., eds. Springer-Verlag, Berlin, p. 33-51 (2010). The amino acid sequence of the heavy and/or light chain variable domain may be also inspected to identify the sequences of the CDRs by other conventional methods, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. The numbered sequences may be aligned by eye, or by employing an alignment program such as one of the CLUSTAL suite of programs, as described in Thompson, 1994, Nucleic Acids Res. 22: 4673-80. Molecular models are conventionally used to correctly delineate framework and CDR regions and thus correct the sequence-based assignments.


The term “Fc” as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins, although IgG1 and IgG2 are preferred. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, and IgGA2). One example of a Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term “Fc” as used herein is generic to the monomeric, dimeric, and multimeric forms.


A F(ab) fragment typically includes one light chain and the VH and CH1 domains of one heavy chain, wherein the VH-CH1 heavy chain portion of the F(ab) fragment cannot form a disulfide bond with another heavy chain polypeptide. As used herein, a F(ab) fragment can also include one light chain containing two variable domains separated by an amino acid linker and one heavy chain containing two variable domains separated by an amino acid linker and a CH1 domain.


A F(ab′) fragment typically includes one light chain and a portion of one heavy chain that contains more of the constant region (between the CH1 and CH2 domains), such that an interchain disulfide bond can be formed between two heavy chains to form a F(ab′)2 molecule.


The term “binding protein” as used herein refers to a non-naturally occurring (or recombinant or engineered) molecule that specifically binds to at least one target antigen, and which comprises four polypeptide chains that form at least three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


A “recombinant” molecule is one that has been prepared, expressed, created, or isolated by recombinant means.


One embodiment of the disclosure provides binding proteins having biological and immunological specificity to between one and three target antigens. Another embodiment of the disclosure provides nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Another embodiment of the disclosure provides expression vectors comprising nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Yet another embodiment of the disclosure provides host cells that express such binding proteins (i.e., comprising nucleic acid molecules or vectors encoding polypeptide chains that form such binding proteins).


The term “swapability” as used herein refers to the interchangeability of variable domains within the binding protein format and with retention of folding and ultimate binding affinity. “Full swapability” refers to the ability to swap the order of both VH1 and VH2 domains, and therefore the order of VL1 and VL2 domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) while maintaining full functionality of the binding protein as evidenced by the retention of binding affinity. Furthermore, it should be noted that the designations VH and VL refer only to the domain's location on a particular protein chain in the final format. For example, VH1 and VH2 could be derived from VL1 and VL2 domains in parent antibodies and placed into the VH1 and VH2 positions in the binding protein. Likewise, VL1 and VL2 could be derived from VH1 and VH2 domains in parent antibodies and placed in the VH1 and VH2 positions in the binding protein. Thus, the VH and VL designations refer to the present location and not the original location in a parent antibody. VH and VL domains are therefore “swappable.”


The term “antigen” or “target antigen” or “antigen target” as used herein refers to a molecule or a portion of a molecule that is capable of being bound by a binding protein, and additionally is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes. With respect to each target antigen recognized by a binding protein, the binding protein is capable of competing with an intact antibody that recognizes the target antigen.


The term “HIV” as used herein means Human Immunodeficiency Virus. As used herein, the term “HIV infection” generally encompasses infection of a host, particularly a human host, by the human immunodeficiency virus (HIV) family of retroviruses including, but not limited to, HIV I, HIV II, HIV III (also known as HTLV-II, LAV-1, LAV-2). HIV can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV family. Thus, treating HIV infection will encompass the treatment of a person who is a carrier of any of the HIV family of retroviruses or a person who is diagnosed with active AIDS, as well as the treatment or prophylaxis of the AIDS-related conditions in such persons.


The term “AIDS” as used herein means Acquired Immunodeficiency Syndrome. AIDS is caused by HIV.


The terms “CD4bs” or “CD4 binding site” refer to the binding site for CD4 (cluster of differentiation 4), which is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.


The term “CD3” is cluster of differentiation factor 3 polypeptide and is a T-cell surface protein that is typically part of the T cell receptor (TCR) complex.


“CD28” is cluster of differentiation 28 polypeptide and is a T-cell surface protein that provides co-stimulatory signals for T-cell activation and survival.


The term “glycoprotein 160” or “gp160 protein” refers to the envelope glycoprotein complex of HIV and which is a homotrimer that is cleaved into gp120 and gp41 subunits.


The term “MPER” refers to the membrane-proximal external region of glycoprotein 41 (gp41), which is a subunit of the envelope protein complex of retroviruses, including HIV.


The term “glycan” refers to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan. In the disclosed binding proteins, glycan refers to the HIV-1 envelope glycoprotein gp120.


The term “T-cell engager” refers to binding proteins directed to a host's immune system, more specifically the T cells' cytotoxic activity as well as directed to a HIV target protein.


The term “trimer apex” refers to apex of HIV-1 envelope glycoprotein gp120.


The term “monospecific binding protein” refers to a binding protein that specifically binds to one antigen target.


The term “monovalent binding protein” refers to a binding protein that has one antigen binding site.


The term “bispecific binding protein” refers to a binding protein that specifically binds to two different antigen targets.


The term “bivalent binding protein” refers to a binding protein that has two binding sites.


The term “trispecific binding protein” refers to a binding protein that specifically binds to three different antigen targets.


The term “trivalent binding protein” refers to a binding protein that has three binding sites. In particular embodiments the trivalent binding protein can bind to one antigen target. In other embodiments, the trivalent binding protein can bind to two antigen targets. In other embodiments, the trivalent binding protein can bind to three antigen targets.


An “isolated” binding protein is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the binding protein, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the binding protein will be purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated binding proteins include the binding protein in situ, within recombinant cells since at least one component of the binding protein's natural environment will not be present.


The terms “substantially pure” or “substantially purified” as used herein refer to a compound or species that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In some embodiments, a substantially purified fraction is a composition wherein the species comprises at least about 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition. In still other embodiments, the species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.


A “neutralizing” binding protein as used herein refers to a molecule that is able to block or substantially reduce an effector function of a target antigen to which it binds. As used herein, “substantially reduce” means at least about 60%, preferably at least about 70%, more preferably at least about 75%, even more preferably at least about 80%, still more preferably at least about 85%, most preferably at least about 90% reduction of an effector function of the target antigen.


The term “epitope” includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and/or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody or binding protein. In certain embodiments, a binding protein is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In some embodiments, a binding protein is said to specifically bind an antigen when the equilibrium dissociation constant is ≤10−8 M, more preferably when the equilibrium dissociation constant is ≤10−9 M, and most preferably when the dissociation constant is ≤10−10 M.


The dissociation constant (KD) of a binding protein can be determined, for example, by surface plasmon resonance. Generally, surface plasmon resonance analysis measures real-time binding interactions between ligand (a target antigen on a biosensor matrix) and analyte (a binding protein in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor; Piscataway, N.J.). Surface plasmon analysis can also be performed by immobilizing the analyte (binding protein on a biosensor matrix) and presenting the ligand (target antigen). The term “KD,” as used herein refers to the dissociation constant of the interaction between a particular binding protein and a target antigen.


The term “specifically binds” as used herein refers to the ability of a binding protein or an antigen-binding fragment thereof to bind to an antigen containing an epitope with an Kd of at least about 1×10−6 M, 1×10−7 M, 1×10−8 M, 1×10−9 M, 1×10−10 M, 1×10−11 M, 1×10−12 M, or more, and/or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen.


The term “linker” as used herein refers to one or more amino acid residues inserted between immunoglobulin domains to provide sufficient mobility for the domains of the light and heavy chains to fold into cross over dual variable region immunoglobulins. A linker is inserted at the transition between variable domains or between variable and constant domains, respectively, at the sequence level. The transition between domains can be identified because the approximate size of the immunoglobulin domains are well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modeling or secondary structure prediction. The linkers described herein are referred to as L1, which is located on the light chain between the C-terminus of the VL2 and the N-terminus of the VL1 domain; and L2, which is located on the light chain between the C-terminus of the VL1 and the N-terminus of the CL domain. The heavy chain linkers are known as L3, which is located between the C-terminus of the VH1 and the N-terminus of the VH2 domain; and L4, which is located between the C-terminus of the VH2 and the N-terminus of the CH1 domain.


The term “vector” as used herein refers to any molecule (e.g., nucleic acid, plasmid, or virus) that is used to transfer coding information to a host cell. The term “vector” includes a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid,” which refers to a circular double-stranded DNA molecule into which additional DNA segments may be inserted. Another type of vector is a viral vector, wherein additional DNA segments may be inserted into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms “plasmid” and “vector” may be used interchangeably herein, as a plasmid is the most commonly used form of vector. However, the disclosure is intended to include other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.


The phrase “recombinant host cell” (or “host cell”) as used herein refers to a cell into which a recombinant expression vector has been introduced. A recombinant host cell or host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term “host cell” as used herein. A wide variety of host cell expression systems can be used to express the binding proteins, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. To express a binding protein recombinantly, a host cell is transformed or transfected with one or more recombinant expression vectors carrying DNA fragments encoding the polypeptide chains of the binding protein such that the polypeptide chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the binding protein can be recovered.


The term “transformation” as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transformation, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. The term “transfection” as used herein refers to the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into suitable host cells.


The term “naturally occurring” as used herein and applied to an object refers to the fact that the object can be found in nature and has not been manipulated by man. For example, a polynucleotide or polypeptide that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man is naturally-occurring. Similarly, “non-naturally occurring” as used herein refers to an object that is not found in nature or that has been structurally modified or synthesized by man.


As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids; unnatural amino acids and analogs such as α-,α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for the polypeptide chains of the binding proteins. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxyl-terminal direction, in accordance with standard usage and convention.


Naturally occurring residues may be divided into classes based on common side chain properties:


(1) hydrophobic: Met, Ala, Val, Leu, Ile, Phe, Trp, Tyr, Pro;


(2) polar hydrophilic: Arg, Asn, Asp, Gln, Glu, His, Lys, Ser, Thr;


(3) aliphatic: Ala, Gly, Ile, Leu, Val, Pro;


(4) aliphatic hydrophobic: Ala, Ile, Leu, Val, Pro;


(5) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;


(6) acidic: Asp, Glu;


(7) basic: His, Lys, Arg;


(8) residues that influence chain orientation: Gly, Pro;


(9) aromatic: His, Trp, Tyr, Phe; and


(10) aromatic hydrophobic: Phe, Trp, Tyr.


Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class.


A skilled artisan will be able to determine suitable variants of the polypeptide chains of the binding proteins using well-known techniques. For example, one skilled in the art may identify suitable areas of a polypeptide chain that may be changed without destroying activity by targeting regions not believed to be important for activity. Alternatively, one skilled in the art can identify residues and portions of the molecules that are conserved among similar polypeptides. In addition, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.


The term “patient” as used herein includes human and animal subjects.


The terms “treatment” or “treat” as used herein refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having the disorder as well as those prone to have a disorder or those in which the disorder is to be prevented. In particular embodiments, binding proteins can be used to treat humans infected with HIV, or humans susceptible to HIV infection, or ameliorate HIV infection in a human subject infected with HIV. The binding proteins can also be used to prevent HIV in a human patient.


It should be understood as that treating humans infected with HIV include those subjects who are at any one of the several stages of HIV infection progression, which, for example, include acute primary infection syndrome (which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache), asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4+T cells), and AIDS (which is defined by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function). In addition, treating or preventing HIV infection will also encompass treating suspected infection by HIV after suspected past exposure to HIV by e.g., contact with HIV-contaminated blood, blood transfusion, exchange of body fluids, “unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.


The terms “pharmaceutical composition” or “therapeutic composition” as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.


The term “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a binding protein.


The terms “effective amount” and “therapeutically effective amount” when used in reference to a pharmaceutical composition comprising one or more binding proteins refer to an amount or dosage sufficient to produce a desired therapeutic result. More specifically, a therapeutically effective amount is an amount of a binding protein sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount may vary depending on the specific binding protein that is being used, and also depends on a variety of factors and conditions related to the patient being treated and the severity of the disorder. For example, if the binding protein is to be administered in vivo, factors such as the age, weight, and health of the patient as well as dose response curves and toxicity data obtained in preclinical animal work would be among those factors considered. The determination of an effective amount or therapeutically effective amount of a given pharmaceutical composition is well within the ability of those skilled in the art.


One embodiment of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a binding protein.


Trispecific and/or Trivalent Binding Proteins


In one embodiment, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three different) HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In one embodiment, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three different) HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the first polypeptide chain and the second polypeptide chain have a cross-over orientation that forms two distinct antigen binding sites. In some embodiments, the VH1 and VL1 form a binding pair and form the first antigen binding site. In some embodiments, the VH2 and VL2 form a binding pair and form the second antigen binding site. In some embodiments, the third polypeptide and the fourth polypeptide form a third antigen binding site. In some embodiments, the VH3 and VL3 form a binding pair and form the third antigen binding site.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; and VH1, VH2 and VH3, are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs:1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242. In other embodiments, VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-283; and VH1, VH2 and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265. In some embodiments, VL1, VL2 and VL3 are each independently a light chain variable domain comprising a light chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, VH1, VH2 and VH3 are each independently a heavy chain variable domain comprising a heavy chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, VL1, VL2 and VL3 are each independently a light chain variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, VH1, VH2 and VH3 are each independently a heavy chain variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; and VH1, VH2 and VH3, are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472. In other embodiments, VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and VH1, VH2 and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


In particular embodiments, the order of the VH1 and VH2 domains, and therefore the order of VL1 and VL2 domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) are swapped.


In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2.


In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98.


In other embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233.


In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463.


In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.


In other embodiments, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three) HIV target antigens, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3(hole)  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3(knob)  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In other embodiments, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three) HIV target antigens, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3(knob)  [II]


and a third polypeptide chain has a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3(hole)  [III]


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


Additional Examples of Trispecific Binding Proteins

In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


In some embodiments, VL1, VL2, and VL3 comprise an amino acid sequence as set forth in SEQ ID NOs: 518, 519, and 512, respectively, and VH1, VH2, and VH3 comprise an amino acid sequence as set forth in SEQ ID NOs: 504, 506, and 502, respectively. In some embodiments, VL1, VL2, and VL3 comprise an amino acid sequence as set forth in SEQ ID NOs: 518, 519, and 513, respectively, and VH1, VH2, and VH3 comprises an amino acid sequence as set forth in SEQ ID NOs: 504, 506, and 503, respectively. In some embodiments, VL1, VL2, and VL3 comprises an amino acid sequence as set forth in SEQ ID NOs: 519, 518, and 513, respectively, and VH1, VH2, and VH3 comprises an amino acid sequence as set forth in SEQ ID NOs: 506, 504, and 503, respectively.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a light chain variable domain sequence shown in Table C. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a heavy chain variable domain sequence shown in Table C.


In some embodiments, VL1 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, VL2 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, VL3 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 512, VH1 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, VH2 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, and VH3 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 502. In some embodiments, VL1 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, VL2 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, VL3 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, VH1 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, VH, is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, and VH3 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503. In some embodiments. VL1 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, VL2 is a variable domain comprising a CDR-L1. CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, VL3 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, and VH1 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, VH2 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, and VH3 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising: (a) a CDR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 266, 269, 275, 278, 281, and 500; (b) a CDR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 267, 270, 276, 279, 282, and 501; and/or (c) a CDR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 268, 271, 274, 277, 280, and 283. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising amino acid sequences as shown in Table B. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.


In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising: (a) a CDR-H1 comprising a sequence selected from the group consisting of SEQ ID NOs: 248, 251, 254, 257, 263, and 499; (b) a CDR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 252, 255, 258, 261, 264, and 497; and/or (c) a CDR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 250, 253, 256, 259, 262, 265, and 498. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences as shown in Table B. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.


In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 266, 267, and 268, respectively; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 248, 497, and 250, respectively. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; V2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively.


Additional Trispecific Binding Proteins Targeting One or More HIV Target Proteins and One or More T Cell Target Proteins


In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., one or two) HIV target proteins and one or more (e.g., one or two) T cell target proteins, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II];


a third polypeptide chain has a structure represented by the formula:





VH3-CH1  [III];


and a fourth polypeptide chain has a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., one or two) HIV target proteins and one or more (e.g., one or two) T cell target proteins, wherein a first polypeptide chain has a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain has a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II];


a third polypeptide chain has a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III];


and a fourth polypeptide chain has a structure represented by the formula





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


In some embodiments, the first polypeptide chain and the second polypeptide chain have a cross-over orientation that forms two distinct antigen binding sites. In some embodiments, the VH1 and VL1 form a binding pair and form the first antigen binding site. In some embodiments, the VH2 and VL2 form a binding pair and form the second antigen binding site. In some embodiments, the third polypeptide and the fourth polypeptide form a third antigen binding site. In some embodiments, the VH3 and VL3 form a binding pair and form the third antigen binding site.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%/0, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 990% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


In some embodiments, VL1, VL2, and VL3 comprise an amino acid sequence as set forth in SEQ ID NOs: 522, 524, and 513, respectively, and VH1, VH2, and VH3 comprise an amino acid sequence as set forth in SEQ ID NOs: 509, 511, and 503, respectively. In some embodiments, VL1, VL2, and VL3 comprise an amino acid sequence as set forth in SEQ ID NOs: 524, 522, and 513, respectively, and VH1, VH2, and VH3 comprise an amino acid sequence as set forth in SEQ ID NOs: 511, 509, and 503, respectively.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


In some embodiments, VL1 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 522, VL2 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 524, VL3 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, VH1 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 509, VH2 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 511, and VH3 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503. In some embodiments, VL1 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 524, VL2 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 522, VL3 is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a light chain variable domain sequence of SEQ ID NO: 513, VH1 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 511, VH2 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 509, and VH3 is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503.


In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising: (a) a CDR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 266, 269, 275, 278, 281, 488, 491, 494 and 500; (b) a CDR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 267, 270, 276, 279, 282, 489, 492, 495, and 501; and (c) a CDR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 268, 271, 274, 277, 280, 283, 490, 493, and 496. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising amino acid sequences as shown in Table B. In some embodiments, VL1, VL2 and VL3 are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.


In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising: (a) a CDR-H1 comprising a sequence selected from the group consisting of SEQ ID NOs: 248, 251, 254, 257, 263, 479, 482, 485, and 499; (b) a CDR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 252, 255, 258, 261, 264, 480, 483, 486, and 497; and (c) a CDR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 250, 253, 256, 259, 262, 265, 481, 484, 487, and 498. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences as shown in Table B. In some embodiments, VH1, VH2 and VH3 are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.


In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 488, 489, and 490, respectively; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 494, 495, and 496, respectively; VL3 comprises a CDR-L1. CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 479, 480, and 481, respectively; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 485, 486, and 487, respectively; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively. In some embodiments, VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 494, 495, and 496, respectively; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 488, 489, and 490, respectively; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 485, 486, and 487, respectively; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 479, 480, and 481, respectively; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein.


In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, VL2 and VH2 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein. In some embodiments, VL1 and VH1 are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, VL2 and VH2 are light and heavy chain variable domains comprising the six CDRs of antibody CD3 or CD28_2 described herein, and VL3 and VH3 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein.


Target Proteins


In one embodiment, the binding proteins specifically bind to one or more HIV target proteins. In some embodiments, the binding proteins are trispecific and specifically bind to MPER of the HIV-1 gp41 protein, a CD4 binding site of the HIV-1 gp120 protein, a glycan in the V3 loop of the HIV-1 gp120 protein, a trimer apex of the HIV-1 gp120 protein or gp160. In other embodiments, the binding proteins specifically bind to one or more HIV target proteins and one or more target proteins on a T-cell including T cell receptor complex. These T-cell engager binding proteins are capable of recruiting T cells transiently to target cells and, at the same time, activating the cytolytic activity of the T cells. The T-cell engager trispecific antibodies can be used to activate HIV-1 reservoirs and redirect/activate T cells to lyse latently infected HIV-1+ T cells. Examples of target proteins on T cells include but are not limited to CD3 and CD28, among others. In some embodiments, the trispecific binding proteins may be generated by combining the antigen binding domains of two or more monospecific antibodies (parent antibodies) into one antibody. See International Publication Nos. WO 2011/038290 A2, WO 2013/086533 A1, WO 2013/070776 A1, WO 2012/154312 A1, and WO 2013/163427 A1, which are hereby incorporated into this disclosure by reference. The binding proteins of the disclosure may be prepared using domains or sequences obtained or derived from any human or non-human antibody, including, for example, human, murine, or humanized antibodies.


In some embodiments of the disclosure, the trivalent binding protein is capable of binding three different antigen targets. In one embodiment, the binding protein is trispecific and one light chain-heavy chain pair is capable of binding two different antigen targets or epitopes and one light chain-heavy chain pair is capable of binding one antigen target or epitope. In another embodiment, the binding protein is capable of binding three different HIV antigen targets that are located on the HIV envelope glycoprotein structure composed of gp120 and gp41 subunits. In other embodiments, the binding protein is capable of inhibiting the function of one or more of the antigen targets.


In some embodiments, a binding protein of the present disclosure binds one or more HIV target proteins. In some embodiments, the binding protein is capable of specifically binding three different epitopes on a single HIV target protein. In some embodiments, the binding protein is capable of binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein. In some embodiments, the first and second HIV target proteins are different. In some embodiments, the binding protein is capable of specifically binding three different HIV target protein. In some embodiments, the one or more HIV target proteins are one or more of glycoprotein 120, glycoprotein 41, and glycoprotein 160.


In some embodiments, a binding protein of the present disclosure binds one or more HIV target proteins and one or more T cell target proteins. In some embodiments, the binding protein is capable of specifically binding one HIV target protein and two different epitopes on a single T cell target protein. In some embodiments, the binding protein is capable of specifically binding one HIV target protein and two different T cell target proteins (e.g., CD28 and CD3). In some embodiments, the binding protein is capable of specifically binding one T cell target protein and two different epitopes on a single HIV target protein. In some embodiments, the binding protein is capable of specifically binding one T cell target protein and two different HIV target proteins. In some embodiments, the first and second polypeptide chains of the binding protein form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains of the binding protein form an antigen binding site that specifically binds an HIV target protein. In some embodiments, the one or more HIV target proteins are one or more of glycoprotein 120, glycoprotein 41, and glycoprotein 160. In some embodiments, the one or more T cell target proteins are one or more of CD3 and CD28.


Linkers


In some embodiments, the linkers L1, L2, L3, and L4 range from no amino acids (length=0) to about 100 amino acids long, or less than 100, 50, 40, 30, 20, or 15 amino acids or less. The linkers can also be 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids long. L1, L2, L3, and L4 in one binding protein may all have the same amino acid sequence or may all have different amino acid sequences.


Examples of suitable linkers include a single glycine (Gly) residue; a diglycine peptide (Gly-Gly); a tripeptide (Gly-Gly-Gly); a peptide with four glycine residues (Gly-Gly-Gly-Gly; SEQ ID NO: 285); a peptide with five glycine residues (Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 286); a peptide with six glycine residues (Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 287); a peptide with seven glycine residues (Gly-Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 288); a peptide with eight glycine residues (Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 289). Other combinations of amino acid residues may be used such as the peptide Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 290), the peptide Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 291) and the peptide Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 292). Other suitable linkers include a single Ser, and Val residue; the dipeptide Arg-Thr, Gln-Pro, Ser-Ser, Thr-Lys, and Ser-Leu; Thr-Lys-Gly-Pro-Ser (SEQ ID NO: 293), Thr-Val-Ala-Ala-Pro (SEQ ID NO: 294), Gln-Pro-Lys-Ala-Ala (SEQ ID NO: 295), Gln-Arg-Ile-Glu-Gly (SEQ ID NO: 296); Ala-Ser-Thr-Lys-Gly-Pro-Ser (SEQ ID NO: 297), Arg-Thr-Val-Ala-Ala-Pro-Ser (SEQ ID NO: 298), Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299), and His-Ile-Asp-Ser-Pro-Asn-Lys (SEQ ID NO: 300). The examples listed above are not intended to limit the scope of the disclosure in any way, and linkers comprising randomly selected amino acids selected from the group consisting of valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline have been shown to be suitable in the binding proteins.


The identity and sequence of amino acid residues in the linker may vary depending on the type of secondary structural element necessary to achieve in the linker. For example, glycine, serine, and alanine are best for linkers having maximum flexibility. Some combination of glycine, proline, threonine, and serine are useful if a more rigid and extended linker is necessary. Any amino acid residue may be considered as a linker in combination with other amino acid residues to construct larger peptide linkers as necessary depending on the desired properties.


In some embodiments, the length of L1 is at least twice the length of L3. In some embodiments, the length of L2 is at least twice the length of L4. In some embodiments, the length of L1 is at least twice the length of L3, and the length of L2 is at least twice the length of L4. In some embodiments, L1 is 3 to 12 amino acid residues in length, L2 is 3 to 14 amino acid residues in length, L3 is 1 to 8 amino acid residues in length, and L4 is 1 to 3 amino acid residues in length. In some embodiments, L1 is 5 to 10 amino acid residues in length, L2 is 5 to 8 amino acid residues in length, L3 is 1 to 5 amino acid residues in length, and L4 is 1 to 2 amino acid residues in length. In some embodiments, L1 is 7 amino acid residues in length, L2 is 5 amino acid residues in length, L3 is 1 amino acid residue in length, and L4 is 2 amino acid residues in length.


In some embodiments, L1, L2, L3, and/or L4 comprise the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525). In some embodiments, L1 comprises the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525). In some embodiments, L3 comprises the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).


In some embodiments, L1, L2, L3, and/or L4 comprise the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L1 comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L1 comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299), L2 comprises the sequence Thr-Lys-Gly-Pro-Ser-Arg (SEQ ID NO: 526), L3 comprises the sequence Ser, and L4 comprises the sequence Arg-Thr. In some embodiments, L3 comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L1 comprises the sequence Ser, L2 comprises the sequence Arg-Thr, L3 comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299) and L4 comprises the sequence Thr-Lys-Gly-Pro-Ser-Arg (SEQ ID NO: 526).


Fc Regions and Constant Domains


In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a third polypeptide chain further comprising an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


To improve the yields of the binding proteins, in some embodiments, the CH3 domains can be altered by the “knob-into-holes” technology which is described in detail with several examples in, for example, International Publication No. WO 96/027011, Ridgway et al., 1996, Protein Eng. 9: 617-21; and Merchant et al., 1998, Nat. Biotechnol. 16: 677-81. Specifically, the interaction surfaces of the two CH3 domains are altered to increase the heterodimerisation of both heavy chains containing these two CH3 domains. Each of the two CH3 domains (of the two heavy chains) can be the “knob,” while the other is the “hole.” The introduction of a disulfide bridge further stabilizes the heterodimers (Merchant et al., 1998; Atwell et al., 1997, J. Mol. Biol. 270: 26-35) and increases the yield. In particular embodiments, the knob is on the second pair of polypeptides with a single variable domain. In other embodiments, the knob is on the first pair of polypeptides having the cross-over orientation. In yet other embodiments, the CH3 domains do not include a knob in hole.


In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the second polypeptide chain and a “hole” mutation on the third polypeptide chain. In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the third polypeptide chain and a “hole” mutation on the second polypeptide chain. In some embodiments, the “knob” mutation comprises substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are S354C and T366W. In some embodiments, the “hole” mutation comprises substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


In some embodiments, a binding protein of the present disclosure comprises one or more mutations to improve serum half-life (See e.g., Hinton, P. R. et al. (2006) J. Immunol. 176(1):346-56). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve serum half-life.


In some embodiments, CH1, CH2, CH3 and CL of the trispecific binding proteins described herein may comprise any of CH1, CH2, CH3 and CL sequences of binding proteins 1-53.


Nucleic Acids


Standard recombinant DNA methodologies are used to construct the polynucleotides that encode the polypeptides which form the binding proteins, incorporate these polynucleotides into recombinant expression vectors, and introduce such vectors into host cells. See e.g., Sambrook et al., 2001, MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratory Press, 3rd ed.). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications, as commonly accomplished in the art, or as described herein. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Similarly, conventional techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients.


Other aspects of the present disclosure relate to isolated nucleic acid molecules comprising a nucleotide sequence encoding any of the binding proteins described herein. In some embodiments, the isolated nucleic acid is operably linked to a heterologous promoter to direct transcription of the binding protein-coding nucleic acid sequence. A promoter may refer to nucleic acid control sequences which direct transcription of a nucleic acid. A first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence of a binding protein if the promoter affects the transcription or expression of the coding sequence. Examples of promoters may include, but are not limited to, promoters obtained from the genomes of viruses (such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, Simian Virus 40 (SV40), and the like), from heterologous eukaryotic promoters (such as the actin promoter, an immunoglobulin promoter, from heat-shock promoters, and the like), the CAG-promoter (Niwa et al., Gene 108(2): 193-9, 1991), the phosphoglycerate kinase (PGK)-promoter, a tetracycline-inducible promoter (Masui et al., Nucleic Acids Res. 33:e43, 2005), the lac system, the trp system, the tac system, the trc system, major operator and promoter regions of phage lambda, the promoter for 3-phosphoglycerate kinase, the promoters of yeast acid phosphatase, and the promoter of the yeast alpha-mating factors. Polynucleotides encoding binding proteins of the present disclosure may be under the control of a constitutive promoter, an inducible promoter, or any other suitable promoter described herein or other suitable promoter that will be readily recognized by one skilled in the art.


In some embodiments, the isolated nucleic acid is incorporated into a vector. In some embodiments, the vector is an expression vector. Expression vectors may include one or more regulatory sequences operatively linked to the polynucleotide to be expressed. The term “regulatory sequence” includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Examples of suitable enhancers may include, but are not limited to, enhancer sequences from mammalian genes (such as globin, elastase, albumin, α-fetoprotein, insulin and the like), and enhancer sequences from a eukaryotic cell virus (such as SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, and the like). Examples of suitable vectors may include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (e.g., adenoviral, vaccinia viral, Sindbis-viral, measles, herpes viral, lentiviral, retroviral, adeno-associated viral vectors, etc.). Expression vectors can be used to transfect host cells, such as, for example, bacterial cells, yeast cells, insect cells, and mammalian cells. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art, and can be used to transfect any cell of interest.


Other aspects of the present disclosure relate to a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of any of the binding proteins described herein. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and third polypeptide chains of the binding protein, and a second vector encoding the second and fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and fourth polypeptide chains of the binding protein, and a second vector encoding the second and third polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first, second, third, and fourth polypeptide chains of the binding protein. The one or more vectors of the vector system may be any of the vectors described herein. In some embodiments, the one or more vectors are expression vectors.


Host Cells


Other aspects of the present disclosure relate to a host cell (e.g., an isolated host cell) comprising one or more isolated polynucleotides, vectors, and/or vector systems described herein. In some embodiments, an isolated host cell of the present disclosure is cultured in vitro. In some embodiments, the host cell is a bacterial cell (e.g., an E. coli cell). In some embodiments, the host cell is a yeast cell (e.g., an S. cerevisiae cell). In some embodiments, the host cell is an insect cell. Examples of insect host cells may include, for example, Drosophila cells (e.g., S2 cells), Trichoplusia ni cells (e.g., High Five™ cells), and Spodoptera frugiperda cells (e.g., Sf21 or Sf9 cells). In some embodiments, the host cell is a mammalian cell. Examples of mammalian host cells may include, for example, human embryonic kidney cells (e.g., 293 or 293 cells subcloned for growth in suspension culture), Expi293™ cells, CHO cells, baby hamster kidney cells (e.g., BHK, ATCC CCL 10), mouse sertoli cells (e.g., TM4 cells), monkey kidney cells (e.g., CV1 ATCC CCL 70), African green monkey kidney cells (e.g., VERO-76, ATCC CRL-1587), human cervical carcinoma cells (e.g., HELA, ATCC CCL 2), canine kidney cells (e.g., MDCK, ATCC CCL 34), buffalo rat liver cells (e.g., BRL 3A, ATCC CRL 1442), human lung cells (e.g., W138, ATCC CCL 75), human liver cells (e.g., Hep G2, HB 8065), mouse mammary tumor cells (e.g., MMT 060562, ATCC CCL51), TRI cells, MRC 5 cells, FS4 cells, a human hepatoma line (e.g., Hep G2), and myeloma cells (e.g., NS0 and Sp2/0 cells).


Other aspects of the present disclosure relate to a method of producing any of the binding proteins described herein. In some embodiments, the method includes a) culturing a host cell (e.g., any of the host cells described herein) comprising an isolated nucleic acid, vector, and/or vector system (e.g., any of the isolated nucleic acids, vectors, and/or vector systems described herein) under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell. Methods of culturing host cells under conditions to express a protein are well known to one of ordinary skill in the art. Methods of isolating proteins from cultured host cells are well known to one of ordinary skill in the art, including, for example, by affinity chromatography (e.g., two step affinity chromatography comprising protein A affinity chromatography followed by size exclusion chromatography).


Use for Binding Proteins

The binding proteins can be employed in any known assay method, such as competitive binding assays, direct and indirect sandwich assays, and immunoprecipitation assays for the detection and quantitation of one or more target antigens. The binding proteins will bind the one or more target antigens with an affinity that is appropriate for the assay method being employed.


For diagnostic applications, in certain embodiments, binding proteins can be labeled with a detectable moiety. The detectable moiety can be any one that is capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety can be a radioisotope, such as 3H, 14C, 32P, 35S, 125I, 99Tc, 111In, or 67Ga; a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme, such as alkaline phosphatase, β-galactosidase, or horseradish peroxidase.


The binding proteins are also useful for in vivo imaging. A binding protein labeled with a detectable moiety can be administered to an animal, e.g., into the bloodstream, and the presence and location of the labeled antibody in the host assayed. The binding protein can be labeled with any moiety that is detectable in an animal, whether by nuclear magnetic resonance, radiology, or other detection means known in the art.


The disclosure also relates to a kit comprising a binding protein and other reagents useful for detecting target antigen levels in biological samples. Such reagents can include a detectable label, blocking serum, positive and negative control samples, and detection reagents. In some embodiments, the kit comprises a composition comprising any binding protein, polynucleotide, vector, vector system, and/or host cell described herein. In some embodiments, the kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing a condition (e.g., HIV infection) and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In some embodiments, the label or package insert indicates that the composition is used for preventing, diagnosing, and/or treating the condition of choice. Alternatively, or additionally, the article of manufacture or kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.


Therapeutic or pharmaceutical compositions comprising binding proteins are within the scope of the disclosure. Such therapeutic or pharmaceutical compositions can comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration.


Acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed.


The pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides—e.g., sodium or potassium chloride—or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A. R. Gennaro, ed., Mack Publishing Company 1990), and subsequent editions of the same, incorporated herein by reference for any purpose).


The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the binding protein.


The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the disclosure, binding protein compositions can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, the binding protein can be formulated as a lyophilizate using appropriate excipients such as sucrose.


The pharmaceutical compositions of the disclosure can be selected for parenteral delivery or subcutaneous. Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.


The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.


When parenteral administration is contemplated, the therapeutic compositions for use can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising the desired binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a binding protein is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustained release of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.


In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a binding protein can be formulated as a dry powder for inhalation. Binding protein inhalation solutions can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized.


It is also contemplated that certain formulations can be administered orally. In one embodiment of the disclosure, binding proteins that are administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract where bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the binding protein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.


Another pharmaceutical composition can involve an effective quantity of binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.


Additional pharmaceutical compositions of the disclosure will be evident to those skilled in the art, including formulations involving binding proteins in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(−)-3-hydroxybutyric acid. Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art.


Pharmaceutical compositions to be used for in vivo administration typically must be sterile. This can be accomplished by filtration through sterile filtration membranes. Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.


Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.


The disclosure also encompasses kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this disclosure are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).


The effective amount of a binding protein pharmaceutical composition to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the binding protein is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.


Dosing frequency will depend upon the pharmacokinetic parameters of the binding protein in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data.


The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems; or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.


The composition can also be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.


The pharmaceutical compositions can be used to prevent and/or treat HIV infection. The pharmaceutical compositions can be used as a standalone therapy or in combination with standard anti-retroviral therapy.


In some embodiments, the present disclosure relates to a method of preventing and/or treating HIV infection in a patient. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of at least one of the binding proteins described herein. In some embodiments, the at least one binding protein is administered in combination with an anti-retroviral therapy (e.g., an anti-HIV therapy). In some embodiments, the at least one binding protein is administered before the anti-retroviral therapy. In some embodiments, the at least one binding protein is administered concurrently with the anti-retroviral therapy. In some embodiments, the at least one binding protein is administered after the anti-retroviral therapy. In some embodiments, the at least one binding protein is co-administered with any standard anti-retroviral therapy known in the art. In some embodiments, administration of the at least one binding protein results in neutralization of one or more HIV virions. In some embodiments, administration of the at least one binding protein results in elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, administration of the at least one binding protein results in neutralization of one or more HIV virions and results in elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.


Without limiting the present disclosure, a number of embodiments of the present disclosure are described below for purpose of illustration.


Item 1: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


Item 2: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is an immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3 and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


Item 3: The binding protein of item 1 or item 2, wherein the one or more HIV target proteins is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 60.


Item 4: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein.


Item 5: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different.


Item 6: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding three different antigen targets.


Item 7: The binding protein of item 1 or item 2, wherein the binding protein is capable of inhibiting the function of one or more HIV target proteins.


Item 8: The binding protein of any one of items 1-7, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.


Item 9: The binding protein of any one of items 1-7, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 10: The binding protein of any one of items 1-9, wherein VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 11: The binding protein of any one of items 1-10, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.


Item 12: The binding protein of any one of items 1-10, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 13: The binding protein of any one of items 1-12, wherein VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 14: The binding protein of any one of items 1-13, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.


Item 15: The binding protein of any one of items 1-13, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 16: The binding protein of any one of items 1-15, wherein VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.


Item 17: The binding protein of any one of items 1-16, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.


Item 18: The binding protein of any one of items 1-16, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 19: The binding protein of any one of items 1-18, wherein VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 20: The binding protein of any one of items 1-19, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively, a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.


Item 21: The binding protein of any one of items 1-19, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 22: The binding protein of any one of items 1-21, wherein VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 23: The binding protein of any one of items 1-22, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.


Item 24: The binding protein of any one of items 1-22, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 25: The binding protein of any one of items 1-24, wherein VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.


Item 26: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250.


Item 27: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504, VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502.


Item 28: The binding protein of any one of items 1-27, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502.


Item 29: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.


Item 30: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.


Item 31: The binding protein of any one of items 1-25 and 29-30, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.


Item 32: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.


Item 33: The binding protein of any one of items 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.


Item 34: The binding protein of any one of items 1-25 and 32-33, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.


Item 35: The binding protein of item 1, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 36: The binding protein of item 1, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 37: The binding protein of item 1, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 38: The binding protein of item 1, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 39: The binding protein of any one of items 1, 37, and 38, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 40: The binding protein of item 2, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 41: The binding protein of item 2, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 42: The binding protein of any one of items 2, 40, and 41, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 43: The binding protein of item 1 or item 2, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.


Item 44: The binding protein of item 1 or item 2, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.


Item 45: The binding protein of any one of items 1-44, wherein L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).


Item 46: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.


Item 47: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.


Item 48: The binding protein of item 46, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 49: The binding protein of item 46, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 50: The binding protein of item 46, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 51: The binding protein of item 46, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 52: The binding protein of any one of items 46, 50, and 51, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 53: The binding protein of item 47, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 54: The binding protein of item 47, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 55: The binding protein of any one of items 47, 53, and 54, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 56: The binding protein of item 46 or item 47, wherein at least one of L1, L2, L3 or L4 is independently 0 amino acids in length.


Item 57: The binding protein of item 46 or item 47, wherein L1, L2, L3 or L4 are each independently at least one amino acid in length.


Item 58: The binding protein of any one of items 46-57, wherein L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).


Item 59: A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:


(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;


(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;


(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;


(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;


(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;


(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;


(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;


(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;


(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;


(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;


(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;


(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;


(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;


(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;


(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;


(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;


(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;


(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;


(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;


(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;


(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;


(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;


(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;


(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;


(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;


(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;


(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;


(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;


(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;


(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or


(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.


Item 60: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II];


a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


Item 61: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I];


a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II];


a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III];


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV];


wherein


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.


Item 62: The binding protein of item 60 or item 61, wherein the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.


Item 63: The binding protein of item 60 or item 61, wherein the one or more T cell target proteins are CD3 or CD28.


Item 64: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein.


Item 65: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins.


Item 66: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein.


Item 67: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins.


Item 68: The binding protein of item 60 or item 61, wherein the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein.


Item 69: The binding protein of any one of items 60-68, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.


Item 70: The binding protein of any one of items 60-68, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 71: The binding protein of any one of items 60-70, wherein VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 72: The binding protein of any one of items 60-71, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.


Item 73: The binding protein of any one of items 60-71, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 74: The binding protein of any one of items 60-73, wherein VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 75: The binding protein of any one of items 60-74, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.


Item 76: The binding protein of any one of items 60-74, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 77: The binding protein of any one of items 60-76, wherein VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.


Item 78: The binding protein of any one of items 60-77, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.


Item 79: The binding protein of any one of items 60-77, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 80: The binding protein of any one of items 60-79, wherein VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 81: The binding protein of any one of items 60-80, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.


Item 82: The binding protein of any one of items 60-80, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 83: The binding protein of any one of items 60-82, wherein VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 84: The binding protein of any one of items 60-83, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively, a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.


Item 85: The binding protein of any one of items 60-83, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 86: The binding protein of any one of items 60-85, wherein VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.


Item 87: The binding protein of any one of items 60-86, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.


Item 88: The binding protein of any one of items 60-86, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.


Item 89: The binding protein of any one of items 60-88, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.


Item 90: The binding protein of any one of items 60-86, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.


Item 91: The binding protein of any one of items 60-86, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.


Item 92: The binding protein of any one of items 60-86 and 90-91, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.


Item 93: The binding protein of item 60, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 94: The binding protein of item 60, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 95: The binding protein of item 60, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 96: The binding protein of item 60, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 97: The binding protein of any one of items 60, 95, and 96, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 98: The binding protein of item 61, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 99: The binding protein of item 61, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 100: The binding protein of any one of items 61, 98, and 99, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 101: The binding protein of item 60 or item 61, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.


Item 102: The binding protein of item 60 or item 61, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.


1 Item 103: The binding protein of any one of items 60-102, wherein L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).


Item 104: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


Item 105: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:





VL2-L1-VL1-L2-CL  [I]


and a second polypeptide chain comprises a structure represented by the formula:





VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]


and a third polypeptide chain comprises a structure represented by the formula:





VH3-CH1-hinge-CH2-CH3  [III]


and a fourth polypeptide chain comprises a structure represented by the formula:





VL3-CL  [IV]


wherein:


VL1 is a first immunoglobulin light chain variable domain;


VL2 is a second immunoglobulin light chain variable domain;


VL3 is a third immunoglobulin light chain variable domain;


VH1 is a first immunoglobulin heavy chain variable domain;


VH2 is a second immunoglobulin heavy chain variable domain;


VH3 is a third immunoglobulin heavy chain variable domain;


CL is an immunoglobulin light chain constant domain;


CH1 is the immunoglobulin CH1 heavy chain constant domain;


CH2 is an immunoglobulin CH2 heavy chain constant domain;


CH3 is an immunoglobulin CH3 heavy chain constant domain;


hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and


L1, L2, L3, and L4 are amino acid linkers;


wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;


wherein:


(a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or


(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and


wherein:


(a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or


(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.


Item 106: The binding protein of item 104, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 107: The binding protein of item 104, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.


Item 108: The binding protein of item 104, wherein the second polypeptide chain further comprises a first Fc region linked to CHt, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 109: The binding protein of item 104, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 110: The binding protein of any one of items 104, 108, and 109, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 111: The binding protein of item 105, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.


Item 112: The binding protein of item 105, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.


Item 113: The binding protein of any one of items 105, 111, and 112, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.


Item 114: The binding protein of item 104 or item 105, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.


Item 115: The binding protein of item 104 or item 105, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.


Item 116: The binding protein of any one of items 104-115, wherein L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).


Item 117: A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:


(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;


(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;


(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;


(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;


(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;


(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;


(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;


(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;


(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;


(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;


(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;


(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;


(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;


(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;


(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;


(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;


(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;


(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;


(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447;


(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;


(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or


(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.


Item 118: An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of items 1-117.


Item 119: An expression vector comprising the nucleic acid molecule of item 118.


Item 120: An isolated host cell comprising the nucleic acid molecule of item 118.


Item 121: An isolated host cell comprising the expression vector of item 119.


Item 122: The isolated host cell of item 120 or item 121, wherein the host cell is a mammalian cell or an insect cell.


Item 123: A vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein of any one of items 1-117.


Item 124: The vector system of item 123, wherein the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.


Item 125: The vector system of item 123, wherein the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein.


Item 126: The vector system of any one of items 123-125, wherein the one or more vectors are expression vectors.


Item 127: An isolated host cell comprising the vector system of any one of items 123-126.


Item 128: The isolated host cell of item 127, wherein the host cell is a mammalian cell or an insect cell.


Item 129: A method of producing a binding protein, the method comprising:


a) culturing a host cell of any one of items 120-122 and items 127-128 under conditions such that the host cell expresses the binding protein; and


b) isolating the binding protein from the host cell.


Item 130: A method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of items 1-117.


Item 131: The method of item 130, wherein the binding protein is co-administered with standard anti-retroviral therapy.


Item 132: The method of item 130 or item 131, wherein administration of the at least one binding protein results in the neutralization of one or more HIV virions.


Item 133: The method of any one of items 130-132, wherein administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient.


Item 134: The method of any one of items 130-133, wherein the patient is a human.


Item 135: The binding protein of any one of items 1-117 for the prevention or treatment of an HIV infection in a patient.


Item 136: The binding protein of item 135, wherein the binding protein is co-administered with standard anti-retroviral therapy.


Item 137: The binding protein of item 135 or item 136, wherein the binding protein causes the neutralization of one or more HIV virions in the patient.


Item 138: The binding protein of any one of items 135-137, wherein the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient.


Item 139: The binding protein of any one of items 135-138, wherein the patient is a human.


EXAMPLES

The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only, and should not be construed as limiting the scope of the invention in any way.


Example 1: Production of Trispecific Binding Proteins Targeting the HIV-1 Env Glycoprotein

The HIV-1 envelope glycoprotein (Env/gp160) is located on the surface of the virus particle, and is composed of a homo-trimer comprising three non-covalently-linked transmembrane gp41 and gp120 complexes. Env enables viral entry into target cells by the binding of gp120 to HIV's main receptor (CD4) and co-receptor (CCR5 or CXCR4), followed by the induction of viral/cellular membrane fusion facilitated by conformational changes in gp41, resulting in entry of the viral capsid and delivery of the viral genome into the host cell. Additionally, Env is expressed on the surface of infected cells.


Env acts as the only target for neutralizing antibodies on the HIV-1 virion. Binding of neutralizing antibodies to viral Env inhibits viral attachment/entry. Moreover, binding of neutralizing antibodies to HIV-1 infected, Env expressing cells leads to their destruction by Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC), resulting in reduction of the latent viral reservoir. Thus, neutralizing antibodies targeting Env are an attractive area for anti-viral therapy development. However, because of the high sequence diversity and mutation rate of the HIV-1 virus, developing neutralizing antibodies targeting Env has proven challenging due to the high likelihood that a given HIV-1 strain either lacks the epitope of any given neutralizing antibody, or the strain has evolved a mutation to become resistant to the antibody. Strategies must be developed to mitigate the breakthrough of viral strains when developing novel neutralizing antibodies targeting HIV-1. The studies described herein explore the development of novel trispecific binding proteins comprising four polypeptides forming three antigen binding sites that specifically bind three different epitopes on the HIV Env glycoprotein, and use of these novel trispecific binding proteins in neutralizing HIV-1.


Methods


Binding Protein Production and Purification

The vectors expressing the trispecific binding proteins were constructed by inserting the designed heavy and light chain genes into a mammalian expression vector. Corresponding heavy and light chain pairing occurred spontaneously, and heterodimer formation was promoted by Knob-in-Hole mutations engineered in the Fc region.


Binding proteins were produced in Expi293 cells by cotransfection of four expression plasmids (Life Technologies, Expi293™ Expression System Kit, Cat. No. A14635). Binding proteins were purified using a two-step purification scheme. First, binding proteins were captured on protein A affinity chromatography resin, washed, and then eluted in glycine at pH 3.0. The eluted proteins were then dialyzed in PBS, concentrated, and filtered. The filtered antibodies were further purified using a Superdex 200 SEC column to obtain monomeric binding proteins.


Affinity Measurements of the Binding Proteins

Binding affinities of anti-HIV trispecific binding proteins were measured by surface plasmon resonance (SPR) using a Biacore3000 instrument (GE Healthcare). The assay buffer used was HBS-EP (GE Healthcare).


The affinity of the indicated proteins for the MPER binding site on the HIV-1 protein gp41 was measured by surface plasmon resonance (SPR) analysis using a Biacore Instrument as follows: binding proteins were first captured on a CM5 chip coupled with anti-human Fc antibody, followed by flow through of varying concentrations (100 nM-6.25 nM) of the MPER binding peptide (Acetyl-RRRNEQELLELDKWASLWNWFDITNWLWYIRRR-Ttds-Lys-(Biotin)-NH2) (SEQ ID NO: 284) at 30 μL per minute, and binding was detected by measurement of association for 240 seconds, and dissociation for 300 seconds on a Biacore 3000 at 25° C. HBS-EP buffer was used for sample dilution, as well as running buffer. Regeneration of the chip was done with 3 M MgCl2 at 30 μL per minute. For data analysis the BIAevaluation software v.4.1 (GE Healthcare) was used. Data were fit globally using a 1:1 Langmuir model with mass transfer. After software-based curve fitting, the ON and OFF reates at each concentration of MPER binding peptide was calculated and used to obtain a binding affinity for each binding protein.


The affinity of the indicated proteins for the CD4BS binding site on the HIV-1 protein gp120 was measured by SPR as follows: recombinant HIV-1 gp120 (Thr27-Arg498) protein (HIV-1/Clade B/C (CN54), ARCO Biosystems (Cat. # GP4-V15227)) was captured on a CM5 chip, followed by flow through of varying concentrations (100 nM-6.25 nM) of the binding proteins, and binding was detected by measurement of association for 240 seconds, and dissociation for 300 seconds on a Biacore 3000 at 25° C. HBS-EP buffer was used for sample dilution, as well as running buffer. Regeneration of the chip was done with 3 M MgCl2 at 30 μL per minute. For data analysis the BIAevaluation software v.4.1 (GE Healthcare) was used. Data were fit globally using a 1:1 Langmuir model with mass transfer. After software-based curve fitting, the ON and OFF reates at each concentration of Binding Protein was calculated and used to obtain a binding affinity for each binding protein.


Conformational Stability and Aggregation Assays

Conformational stability of the trispecific binding proteins was assessed by determining the melting point Tm and aggregation onset temperature (Tagg).


Melting point Tm measurements were performed by differential scanning fluorimetry (DSF). Samples were diluted in D-PBS buffer (Invitrogen) to a final concentration of 0.2 μg/μL including a 4× concentration solution of SYPRO-Orange dye (Invitrogen, 5000× stock in DMSO) in D-PBS in white sem-skirt 96-well plates (BIORAD). All measurements were done in duplicate using a MyiQ2 real time PCR instrument (BIORAD). Negative first derivative curves (−d(RFU)/dT) of the melting curves were generated in the iQ5 software v2.1 (BIORAD). Data were then exported into Excel for Tm determination and graphical display.


Melting Point Tm and aggregation onset temperature (Tagg) were also measured by static light scattering (SLS) using a Unit instrument (Unchained Labs). 9 μL of each sample was loaded undiluted into a multicuvette array. The samples were then heated from 20° C. to 95° C. at a heating rate of 0.3° C./minute. The barycentric mean (BCM) of the tryptophan fluorescence spectra was used to measure the protein melting curve, and determine the Tm values. The 266 nm static light scattering (SLS) signal was used to measure the aggregation curve and determine the Tagg. Data analysis was performed using the Unit analysis software v2.1.


Results


A novel strategy was developed for improving neutralizing antibody efficacy against HIV-1, while concomitantly limiting the likelihood of viral breakthrough due to high sequence diversity and/or viral mutation. This strategy involved the generation of trispecific binding proteins comprising four polypeptides that formed three antigen binding sites that specifically bind three different epitopes on the HIV Env glycoprotein (FIG. 1). Each antigen binding site comprised the VH and VL domain from a different HIV-1 neutralizing antibody that targeted a distinct epitope on the Env glycoprotein. The trispecific binding proteins contained a first pair of polypeptides that possessed dual variable domains having a cross-over orientation forming two distinct antigen binding sites (called the CODV Ig format), and a second pair of polypeptides, each with a single variable domain that formed a third antigen binding site (FIGS. 1A and 1B).


The first pair of polypeptides (that possessed the dual variable domains) comprised a first polypeptide having the structure VL2-Linker-VL1-Linker-Immunoglobulin light chain constant domain, and a second polypeptide having the structure VH1-Linker-VH2-Linker-Immunoglobulin CH1, hinge, CH2, and CH3 heavy chain constant domains, resulting in a pair of polypeptides which had a cross over orientation that formed two distinct antigen binding sites: VH1-VL1 and VH2-VL2 (FIGS. 1C and 1D, see light and heavy chains B). The second pair of polypeptides (that each possessed a single variable domain) comprised a first polypeptide having the structure VH3-Immunoglobulin CH1, hinge, CH2, and CH3 heavy chain constant domains, and a second polypeptide having the structure VL3-Immunoglobulin light chain constant domain, resulting in a pair of polypeptides that formed a third antigen binding site: VH3-VL3 (FIGS. 1C and 1D, see light and heavy chains A). In addition, the trispecific binding proteins were constructed to include an LS mutation. Furthermore, the trispecific binding proteins were constructed such that within one binding protein, one CH3 domain included a knob mutation and the other CH3 domain included a hole mutation to facilitate heterodimerization of the heavy chains (FIG. 1).


Using the above described approach for trivalent binding protein design, three trispecific binding proteins (Binding Proteins 2, 3, and 24) were generated. These trispecific binding proteins were created by grafting onto a trispecific binding protein framework the VH and VL domains isolated from antibodies targeting three distinct epitopes on the HIV-1 Env glycoprotein: MPER Ab (targeting the MPER epitope on gp41), CD4BS Ab “b” (targeting the CD4 Binding Site on gp120), and V1/V2 directed Ab “a” (targeting the V1/V2 domain on gp120). Binding Protein 2 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes MPER and V1/V2, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope CD4BS (Binding Protein 2=MPER×V1/V2/CD4BS). Binding Protein 3 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes V1/V2 and MPER, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope CD4BS (Binding Protein 3=V1/V2×MPER/CD4BS). Binding Protein 24 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes V1/V2 and CD4BS, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope MPER (Binding Protein 24=V1/V2×CD4BS/MPER). The three trispecific binding proteins, as well as their parental antibodies, were purified over protein A affinity resin (FIGS. 2A and 3A) followed by size exclusion chromatography (FIGS. 2B and 3B) to obtain monomeric proteins suitable for further characterization. All three trispecific binding proteins were stable and formed monomers at high frequency.


To test the potential for developing binding proteins targeting two different HIV-1 Env protein epitopes (instead of three), bispecific binding proteins were designed based upon the above described CODV Ig format (See WO 2012/135345), using two different VH and VL domains from the same parental antibodies used to create the trispecific binding proteins. However, the bispecific binding proteins with these specific variable domains did not purify well as monomers, showing significantly increased aggregate formation when compared to the corresponding trispecific binding proteins (FIGS. 4A and 4B).


Next, the binding affinity of the purified trispecific binding proteins (and their parental antibodies) was measured for the HIV-1 Env glycoprotein epitopes on gp41 and gp120. First, the binding affinity for gp41 was measured for the three trispecific binding proteins, as well as the parental MPER antibody, by Biacore assay using the MPER binding peptide (FIG. 5). The binding affinity for the MPER antibody was calculated to be 18.7 nM. Surprisingly, the three trispecific binding proteins all had a higher affinity for the MPER binding peptide than did the parental antibody (Table 3), with Binding Protein 2 having an approximately 3.1 fold higher affinity than the MPER antibody (6.05 nM vs. 18.7 nM, respectively).









TABLE 3







Affinity measurements for the MPER binding peptide























MW




ka
kd
Rmax
KA
KD

MPER


Antibody
Analyte
(1/Ms)
(1/s)
(RU)
(1/M)
(M)
Chi2
(kDa)





MPER Ab
Gp41-
5.85E+04
1.09E−03
47.5
5.35E+07
1.87E−08
0.55
5.25



MPER JPT









Binding
Gp41-
1.15E+05
6.97E−04
29.0
1.65E+08
6.05E−09
0.27
2.29


Protein 2
MPER JPT









Binding
Gp41-
4.67E+04
7.79E−04
38.5
6.00E+07
1.67E−08
0.41
5.14


Protein 3
MPER JPT









Binding
Gp41-
6.28E+04
8.06E−04
35.5
7.80E+07
1.28E−08
0.48
5.24


Protein 24
MPER JPT









Similarly, the binding affinity for the CD4 Binding Site on gp120 was measured for the three trispecific binding proteins, as well as the parental CD4BS antibody, by Biacore assay (FIG. 6). The three trispecific binding proteins all had a similar affinity for the CD4 Binding Site when compared to the parental antibody (Table 4).









TABLE 4







Affinity measurements for the CD4BS binding site












Antibody
ka (1/Ms)
kd (1/s)
Rmax (RU)
KD (M)
Chi2





CD4BS
2.79E+05
2.32E−04
31.4
8.30E−10
1.17


Ab “b”







Binding
2.31E+05
2.41E−04
34.0
1.04E−09
0.74


Protein 2







Binding
7.58E+04
2.75E−04
38.2
3.63E−09
0.19


Protein 3







Binding
1.46E+05
2.52E−04
41.6
1.73E−09
0.38


Protein 24









Thus, the trispecific binding proteins were able to bind both of the tested target epitopes on the HIV-1 Env glycoprotein (Table 5). Moreover, all three trispecific binding proteins bound the target epitopes with affinities approximately equal to or exceeding those of their parental antibodies. Binding affinity of the V1/V2 directed Ab “a”, as well as of the V1/V2 directed Ab “a” binding sites within the three trispecific binding proteins 2, 3, and 24 could not be determined by Biacore analysis because this required a specific gp120 protein antigen which was unavailable.









TABLE 5







Summary of binding capabilities of tested binding proteins










Binding on
Binding on


Sample
gp120?
gp41?





MPER Ab
No
Yes


CD4BS Ab “b”
Yes
No


V1/V2 directed
No
No


Ab “a”




Binding
Yes
Yes


Protein 2




Binding
Yes
Yes


Protein 3




Binding
Yes
Yes


Protein 24









The biophysical properties were tested for the trispecific binding proteins and parental antibodies (Table 6). All of the tested proteins had similar stabilities and limited propensities to form aggregates.









TABLE 6







Conformational stability/aggregation of the binding proteins













SLS at




Intrinsic AA
266 nm



DSF Tm
Fluo Tm
Tagg


Sample
(° C.)
(° C.)
(° C.)





MPER Ab
69/75
68
71


CD4BS Ab “b”
69
66
68


V1/V2 directed
69
64
67


Ab “a”





Binding
60/70
54
58


Protein 2





Binding
57/70
55
56


Protein 3





Binding
56/71
53
54


Protein 24









These experiments indicated that stable, monomeric, trispecific binding proteins targeting three distinct epitopes on the HIV-1 Env glycoprotein could be constructed and efficiently purified. Furthermore, the trispecific binding proteins retained their ability to bind their target epitopes, having similar or improved affinity relative to their parental antibodies. Finally, the trispecific binding proteins had suitable biophysical properties, and showed significantly less aggregation than the corresponding bispecific binding proteins.


Example 2: Characterization of the Binding Proteins

Due to the success of developing three trispecific binding proteins with appropriate biophysical properties and binding abilities (as described in Example 1), 21 additional trispecific binding proteins were developed and tested. The experiments described herein explored the ability of the 24 trispecific binding proteins to neutralize HIV-1 in vitro, and the pharmacokinetic properties of a number of these trispecific binding proteins in vivo.


Neutralization assays were performed using the TZM-b1 assay which measures neutralization as a function of reductions in HIV-1 Tat-regulated firefly luciferase (Luc) reporter gene expression after a single round of infection with Env-pseudotyped viruses. The assays were performed as described in Marcella Sarzotti-Kelsoe et al., J. Immunological Methods, 409:131-146 (2014). The neutralization results of various antibodies are shown in Tables 8-10.


Methods


Production of Env-Pseudotyped Viruses

Assay stocks of Env-pseudotyped viruses were produced in 293T/17 cells by co-transfection with two plasmids: an Env expression plasmid and a plasmid expressing the entire HIV-1 genome except for Env. Co-transfection of these plasmids produced infectious pseudovirus particles which were capable of delivering the Tat gene into target cells, but infections with these pseudovirions could not themselves produce infectious viral progeny.


Viral Neutralization Assay

Neutralization of HIV infection using TZM-b1 cells (also known as JC53BL-13 cells) was performed as described previously (Marcella Sarzotti-Kelsoe et al., J. Immunological Methods, 409:131-146 (2014)). Briefly, a single round of infection using the Env-pseudotyped HIV-1 virions was carried out in TZM-b1 cells (a CXCR-4-positive HeLa cell clone). TZM-b1 cells were engineered to express CD4 and CCR5, and to contain integrated reporter genes for firefly luciferase and E. coli β-galactosidase under the control of an HIV long-terminal repeat. Reporter gene expression was induced in trans by viral Tat protein (delivered by the pseudotyped viruses) soon after single cycle infection. Luciferase activity was quantified as relative luminescence units (RLU), and was directly proportional to the number of infectious virus particles present in the initial inoculum over a wide range of values. Neutralization was measured as a function of decreased Tat-regulated Firefly luciferase (Luc) reporter gene expression after administration of varying concentrations of the indicated binding proteins. Neutralization titers were identified as the protein dilution at which RLUs were reduced by 80% compared to virus control wells after subtraction of background RLUs. The assay was performed in 96-well plates for high throughput capacity, and well-characterized reference strains were utilized for uniformity across studies.


Pharmacokinetic (PK) Measurements

Female Indian rhesus macaques weighing between 3 and 6 kg were randomly assigned to groups according to body weight (two macaques per group) and were intravenously injected with the indicated concentration of binding proteins. Blood was collected from the animals before the injection on day 0, and 30 minutes, 6 hours, 1 day, 2 days, 4 days, 7 days, 14 days, 21 days and 28 days after injection. The serum concentration of each binding protein was quantified in the plasma from the collected blood using an RSC3-based ELISA assay.


Results


21 additional trispecific binding proteins targeting three distinct HIV-1 Env glycoprotein epitopes were generated and purified as described in Example 1. These 21 additional trispecific binding proteins (Binding Proteins 1 and 4-23) were created by grafting onto a trispecific binding protein framework the VH and VL domains isolated from antibodies targeting distinct HIV-1 epitopes on the HIV-1 Env glycoprotein: the anti-MPER antibodies MPER Ab “a” and MPER Ab “b” (targeting the MPER epitope on gp41), the anti-CD4BS antibodies CD4BS Ab “a” and CD4BS Ab “b” (targeting the CD4 Binding Site on gp120), the anti-V1/V2 antibodies V1/V2 directed Ab “a” and V1/V2 directed Ab “b” (targeting the V1/V2 domain on gp120), and the anti-V3 antibody V3 directed Ab (targeting the V3 loop on gp120) (Table 7).









TABLE 7







Epitope binding site composition of the


trispecific binding proteins










Binding




Protein:
Epitope Binding Site:







 1
MPER × V1/V2 directed/CD4BS



 2
MPER × V1/V2 directed/CD4BS



 3
V1/V2 directed × MPER/CD4BS



 4
MPER × V1/V2 directed/CD4BS



 5
MPER × V3 directed/CD4BS



 6
V1/V2 directed × MPER/CD4BS



 7
V3 directed × V1/V2 directed/CD4BS



 8
MPER × V1/V2 directed/CD4BS



 9
MPER × V1/V2 directed/CD4BS



10
V1/V2 directed × MPER/CD4BS



11
MPER × V1/V2 directed/CD4BS



12
MPER × V3 directed/CD4BS



13
MPER × V3 directed/V1/V2 directed



14
V1/V2 directed × MPER/CD4BS



15
MPER × V3 directed/V1/V2 directed



16
MPER × V3 directed/CD4BS



17
V1/V2 directed × V3 directed/CD4BS



18
V3 directed × MPER/CD4BS



19
V3 directed × V1/V2 directed/MPER



20
V3 directed × V1/V2 directed/CD4BS



21
MPER × CD4BS/V1/V2 directed



22
CD4BS × MPER/V1/V2 directed



23
CD4BS × V1/V2 directed/MPER



24
V1/V2 directed × CD4BS/MPER










The viral neutralization capabilities of five of the trispecific binding proteins (and their parental antibodies) at varying concentrations were tested against a panel of 208 different HIV-1 Env-pseudotyped viruses (Table 8). Binding protein-mediated neutralization of the pseudotyped HIV-1 isolates was measured using the TZM-b1 luciferase reporter gene assay. The inhibitory dose for each binding protein was calculated for each pseudotyped virus as the dilution that caused an 80% reduction in luminescence (IC80) after infection. Surprisingly, the IC80 geometric means calculated for each of the tested trispecific binding proteins was lower than the parental antibodies, suggesting that these trispecific binding proteins were more potent at neutralizing pseudotyped HIV-1 than their parental neutralizing antibodies.









TABLE 8







IC80 measurements from viral neutralization assay





















Parental Antibody:


























V1/V2
V3
















Binding Protein:
MPER
directed
directed
CD4BS
CD4BS



















15
1
2
19
20
3
Ab
Ab “a”
Ab
Ab “b”
Ab “a”





















# Viruses
208
208
208
208
208
208
208
208
208
208
208


Total VS













Neutralized:













IC80 <50 μg/mL
190
202
206
198
206
206
203
151
113
202
183


IC80 <10 μg/mL
180
199
206
180
206
206
193
149
109
200
175


IC80 <1.0 μg/mL
166
169
191
145
188
186
61
133
98
184
108


IC80 <0.1 μg/mL
122
109
136
80
144
123
10
99
72
79
10


IC80 <0.01 μg/mL
74
7
70
22
54
47
5
24
26
6
0


% VS













Neutralized:













IC80 <50 μg/mL
91
97
99
95
99
99
98
73
54
97
88


IC80 <10 μg/mL
87
96
99
87
99
99
93
72
52
96
84


IC80 <1.0 μg/mL
80
81
92
70
90
89
29
64
47
88
52


IC80 <0.1 μg/mL
59
52
65
38
69
59
5
48
35
38
5


IC80 <0.01 μg/mL
36
3
34
11
26
23
2
12
13
3
0


Median IC80
0.033
0.088
0.026
0.164
0.029
0.045
1.69
0.037
0.054
0.149
0.780


Geometric Mean
0.033
0.135
0.028
0.199
0.034
0.051
1.34
0.063
0.057
0.144
0.814









Next, the viral neutralization capabilities of a larger panel of trispecific binding proteins (and their parental antibodies) at varying concentrations were tested against 20 pseudotyped viruses representing 10 different HIV-1 clades (Table 9). The trispecific binding proteins provided robust protection against infection with these 20 viruses (Table 10).









TABLE 9







20 representative viruses used for


viral neutralization assay










Virus
Clade







KER2008.12.SG3
A



620345.c1.SG3
AE



DJ263.8.SG3
AG



T266-60.SG3
AG



T278-50.SG3
AG



BL01.DG.SG3
B



BR07.DG.SG3
B



CNE57.SG3
B



H086.8.SG3
B



QH0692.42.SG3
B



SS1196.01.SG3
B



CNE21.SG3
BC



6471.V1.C16.SG3
C



CAP210.E8.SG3
C



DU156.12.SG3
C



DU422.01.SG3
C



TV1.29.SG3
C



ZM106.9.SG3
C



3817.v2.c59.SG3
CD



X2088.c9.SG3
G

















TABLE 10







IC80 measurements from viral neutralization assay of 20 representative viruses












Total VS















Neutralized
% VS Neutralized


















IC80
IC80
IC80
IC80
Median
Geometric



# Viruses
<50 μg/mL
<1 μg/mL
<50 μg/mL
<1 μg/mL
IC80
Mean

















Binding Protein 4
20
17
11
85
55
0.474
0.398


Binding Protein 5
20
14
11
70
55
0.199
0.324


Binding Protein 6
20
16
9
80
45
0.453
0.449


Binding Protein 7
20
16
9
80
45
0.523
0.312


Binding Protein 8
20
17
12
85
60
0.578
0.488


Binding Protein 9
20
14
9
70
45
0.836
0.531


Binding Protein 10
20
16
12
80
60
0.222
0.173


Binding Protein 11
20
18
15
90
75
0.310
0.181


Binding Protein 12
20
17
12
85
60
0.526
0.566


Binding Protein 13
20
19
12
95
60
0.202
0.189


Binding Protein 14
20
17
15
85
75
0.208
0.088


Binding Protein 15
20
17
10
85
50
0.345
0.378


Binding Protein 16
20
18
11
90
55
0.228
0.314


Binding Protein 17
20
17
12
85
60
0.086
0.180


Binding Protein 18
20
15
10
75
50
0.536
0.501


Binding Protein 19
20
18
11
90
55
0.563
0.538


Binding Protein 20
20
18
14
90
70
0.224
0.229


Binding Protein 21
20
15
9
75
45
0.627
0.501


Binding Protein 2
20
18
13
90
65
0.375
0.222


Binding Protein 22
20
13
8
65
40
0.856
0.634


Binding Protein 23
20
17
6
85
30
1.930
1.129


Binding Protein 3
20
18
12
90
60
0.469
0.287


Binding Protein 24
20
16
7
80
35
2.130
1.054


MPER Ab “a”
20
16
8
80
40
1.007
0.981


MPER Ab “b”
20
16
16
80
80
0.071
0.024


CD4BS A “b”
20
15
9
75
45
0.181
0.399


V1/V2 directed Ab “a”
20
11
9
55
45
0.060
0.094


V3 directed Ab
20
12
10
60
50
0.183
0.136


CD4BS Ab “a”
20
10
1
50
5
1.530
1.811


V1/V2 directed Ab “b”
20
9
9
45
45
0.051
0.039









Finally, the pharmacokinetics (PK) of a subset of the trispecific binding proteins and parental antibodies were tested in rhesus macaques. Briefly, 10 or 20 mg/kg of the proteins were intravenously injected into female rhesus macaques, and ELISA assays were performed on the plasma from blood samples taken prior to injection, and on the plasma from blood samples taken at many time points after the injection (up to 42 days) (FIG. 7). All of the trispecific binding proteins could be detected at least 14 days after IV administration, with Binding Protein 1 remaining detectable at least 35 days after injection, showing that the binding proteins were stable in vivo.


Taken together, this data suggested that broadly neutralizing trispecific binding proteins could be constructed which targeted three distinct epitopes on the HIV-1 Env glycoprotein. These binding proteins showed similar or increased potency/much improved neutralizing capabilities (breadth) relative to the parental neutralizing antibodies. Furthermore, these trispecific binding proteins appeared to be well tolerated in vivo. Without wishing to be bound by theory, the development of broadly neutralizing trispecific binding proteins targeting multiple epitopes on HIV may allow for improved anti-viral therapy relative to monospecific or bispecific antibodies, as HIV viral particles are less likely to be resistant to all three antigen binding sites on the neutralizing trispecific binding proteins than the single or dual antigen binding sites on monospecific or bispecific neutralizing antibodies, respectively.


Example 3: Characterization of T-Cell Engagers

As noted above, Env is expressed on the surface of HIV-infected cells. Because of this, Env can act as an antibody target to identify infected cells, and induce Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC), resulting in reduction of the latent viral reservoir. The studies described herein explore the development of novel trispecific binding proteins (termed “T cell engagers”) that contain three antigen binding sites targeting three different antigens (HIV-1 Env glycoprotein, CD3, and CD28). These novel proteins not only include antigen binding sites from neutralizing antibodies, but also the ability to bind effector T cells, bringing them into close proximity to infected target cells, thus inducing HIV-infected cell lysis.


Methods


Binding Properties of T-Cell Engagers

The binding properties of the T-cell engagers was measured by ELISA assay using a horse radish peroxidase-conjugated anti-Fab probe to detect T-cell engager binding to the surface of ELISA plates coated with CD3, CD28, or Resurfaced Stabilized Core 3 (RSC3) protein of gp120. Human CD3ge-hIgG4 (KIH) (Cat. No: 03-01-0051) from Cambridge Biologics, MA, USA; Human CD28-hIgG4 (Cat. No: 03-01-0303) from Cambridge Biologics, MA, USA.


T-Cell Activation Assay

CD4 and CD8 T cell activation were measured as follows: peripheral blood mononuclear cells (PBMCs) were enriched from buffy coats obtained from naïve donors (NIH blood bank) using magnetic beads (Miltenyi Biotec). These cells were co-cultured for 14-16 hours with either uninfected or HIV-1 infected CEM cells in the presence of increasing concentrations of the binding proteins (0.01-1.0 μg/mL) with brefeldin A. The cells were then stained for surface expression of T-cell markers (CD3, CD4, and CD8) and activation markers (CD25 and CD69), followed by intracellular staining for cytokines (IFN-γ, TNF-α, and IL-2) using fluorescently conjugated antibodies (BD Biosciences, eBiosciences, Biolegend). The number of CD4 and CD8 T cells expressing each cytokine or activation marker was determined by running the samples on an LSRII flow cytometer and analyzing the data with Flowjo software (Treeestar).


CD3 Downregulation

CD3 downregulation after T cell activation by the T-cell engagers was measured by staining activated PBMCs with non-competing mouse anti-human CD3 antibody and quantitated using flow cytometry.


Cytotoxicity Assay

Cytotoxicity of the T-cell engagers to CEM-BaL, ACH2, and J1.1 cells was monitored by flow cytometry as follows: latent cell lines (ACH2, J1.1, OM10) were obtained from the NIH AIDS Reagent Program. The activation of these cells was performed by culturing the cells in the presence or absence of TNF-α (10 ng/mL) for 14-16 hours. Activation was measured by determining the expression of cell surface HIV envelope glycoprotein by flow cytometry using an allophycocyanin-conjugated anti-HIV Env antibody (2G12). The CEM-IIIb, ACH2, J1.1 and OM10 cells were labeled with the membrane dye PKH-26 (Sigma) and used as target cells in a cytotoxicity assay. These labeled target cells were co-cultured for 14-16 hours at an E:T ratio of 10:1 with enriched human T cells as effector cells in the presence of increasing amounts of the binding proteins. The extent of cell lysis in the target cells was determined by staining with a live/dead cell marker (Life technologies) and measuring the number of dead cells in the labeled target cell population by running the samples on an LSRII flow cytometer followed by analysis using Flowjo software (Treestar).


Results


The capacity to develop T cell engagers with antigen binding sites targeting both T cell surface proteins and neutralizing epitopes on HIV-1 was explored. T cell engagers were constructed which contained two antigen binding sites targeting two different T cell surface receptors (CD3 and CD28), and a third antigen binding site targeting the HIV-1 Env glycoprotein (FIGS. 8A and 8B). In addition, the T cell engagers were constructed to include an LS mutation. Furthermore, the T cell engagers were constructed such that within one binding protein, one CH3 domain included a knob mutation and the other CH3 domain included a hole mutation to facilitate heterodimerization of the heavy chains (FIGS. 8A and 8B).


Using this approach, two T cell engagers were constructed which targeted both T cell surface proteins and the HIV-1 Env glycoprotein (Binding Protein 32 and CD3×CD28/CD4BS “b” Ab). These two T cell engagers were created by grafting onto a trispecific binding protein framework the VH and VL domains isolated from parental antibodies targeting the T cell surface proteins CD3 and CD28, and the anti-HIV-1 antibody CD4BS Ab “b” (targeting the CD4 Binding Site on gp120). Binding Protein 32 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the T cell surface receptors CD28 and CD3, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 antigen CD4BS (Binding Protein 32=CD28×CD3/CD4BS). The CD3×CD28/CD4BS “b” Ab trispecific binding protein was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the T cell surface receptors CD3 and CD28, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 antigen CD4BS (Table 11).









TABLE 11







Format of T-cell engagers













Arm 1
Arm 2
Arm 3


Format
Name of Construct
Antigen
Antigen
Antigen





T cell engagers,
CD3 × CD28/CD4BS
CD4BS
CD3
CD28


trispecific
Ab “b”





T cell engagers,
Binding Protein 32
CD4BS
CD28
CD3


trispecific






Monospecific
CD4BS IgG4
CD4BS
CD4BS










The ability of the two T cell engagers to bind to each of their three target antigens was tested by ELISA assay. The T cell engagers were capable of binding both the CD3 and CD28 T cell surface proteins with the CD3 and CD28 antigen binding sites in either orientation in the bispecific arms of the T cell engagers (i.e., CD3×CD28 for CD3×CD28/CD4BS Ab “b” or CD28×CD3 for Binding Protein 32). Both T cell engagers were also capable of binding to gp120 (as measured using the HIV-1 RSC3 protein, a gp120 variant lacking the V1, V2, and V3 variable regions) (FIG. 9).


The effect on T cell activity was next tested for both of the T cell engagers. Incubation of the T cell engagers with monocytes revealed that the T cell engagers induced robust CD8+ T cell activation (FIG. 10). Similarly, the T cell engagers were capable of inducing significant CD4+ T cell activation on PBMCs alone, or PBMCs incubated with either of the HIV-1 infected T cell lines CEM-NKr cells or CEM-BaL cells (FIG. 11). Additionally, both of the T cell engagers reduced cell surface expression of CD3 on activated T cells (FIG. 12).


Finally, the ability of the T cell engagers to induce lysis of HIV-infected cells was tested. The T cell engagers (and positive and negative control bispecific binding proteins targeting CD3 and an HIV antigen) were incubated with the HIV-1 infected T cell line CEM-BaL cells. Incubation of the T cell engagers with the infected cells induced robust cell lysis over a wide range of concentrations (FIG. 13A). Likewise, incubation of these T cell engagers induced lysis of the latently infected T cell line ACH2 cells (FIG. 13B), as well as J1.1 cells (FIG. 13C). Surprisingly, the T cell engagers showed comparable or better cytotoxic activity against chronic and latent HIV-infected cell lines when compared to the bispecific binding proteins.


Taken together, the novel T cell engagers described herein retained the ability from their parental antibodies to bind their target antigens on the HIV-1 Env glycoprotein gp120 on HIV-infected cells, as well as the cell-surface exposed T cell proteins CD3 and CD28. The T cell engagers induced robust CD4+ and CD8+ T cell activation, and diminished CD3 surface expression. Finally, these T cell engagers induced significant lysis of HIV-1 infected T cells. Without wishing to be bound by theory, these T cell engagers may provide a novel strategy for anti-viral therapeutics by reducing/eliminating the latent viral reservoir through T cell engagement in HIV/AIDS patients.


While the present disclosure includes various embodiments, it is understood that variations and modifications will occur to those skilled in the art. Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the disclosure. In addition, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.


Each embodiment herein described may be combined with any other embodiment or embodiments unless clearly indicated to the contrary. In particular, any feature or embodiment indicated as being preferred or advantageous may be combined with any other feature or features or embodiment or embodiments indicated as being preferred or advantageous, unless clearly indicated to the contrary.


All references cited in this application are expressly incorporated by reference herein.


SEQUENCES









TABLE 1







Heavy and light chain SEQ ID NOs for binding proteins 1-53


and the target antigens to which the binding proteins are directed.









Binding




Protein
SEQ ID NOs
Target





 1
4, 3, 1, 2
MPER × V1/V2 directed/CD4BS


 2
12, 11, 9, 10
MPER × V1/V2 directed/CD4BS


 3
20, 9, 17, 18
V1/V2 directed × MPER/CD4BS


 4
28, 27, 25, 26
MPER × V1/V2 directed/CD4BS


 5
36, 35, 33, 34
MPER × V3 directed/CD4BS


 6
44, 43, 41, 42
V1/V2 directed × MPER/CD4BS


 7
52, 51, 49, 50
V3 directed × V1/V2 directed/CD4BS


 8
60, 59, 57, 58
MPER × V1/V2 directed/CD4BS


 9
68, 67, 65, 66
MPER × V1/V2 directed/CD4BS


10
76, 75, 73, 74
V1/V2 directed × MPER/CD4BS


11
84, 83, 81, 82
MPER × V1/V2 directed/CD4BS


12
92, 91, 89, 90
MPER × V3 directed/CD4BS


13
100, 99, 97, 98
MPER × V3 directed/V1/V2 directed


14
108, 107, 105, 106
V1/V2 directed × MPER/CD4BS


15
116, 115, 113, 114
MPER × V3 directed/V1/V2 directed


16
124, 123, 121, 122
MPER × V3 directed/CD4BS


17
132, 131, 129, 130
V1/V2 directed × V3 directed/CD4BS


18
140, 139, 137, 138
V3 directed × MPER/CD4BS


19
148, 147, 145, 146
V3 directed × V1/V2 directed/MPER


20
156, 155, 153, 154
V3 directed × V1/V2 directed/CD4BS


21
164, 163, 161, 162
MPER × CD4BS/V1/V2 directed


22
172, 171, 169, 170
CD4BS × MPER/V1/V2 directed


23
180, 179, 177, 178
CD4BS × V1/V2 directed/MPER


24
188, 187, 185, 186
V1/V2 directed × CD4BS/MPER


25
196, 195, 193, 194
MPER × V1/V2 directed/CD4BS


26
204, 203, 201, 202
MPER × V1/V2 directed/CD4BS


27
212, 211, 209, 210
MPER × V1/V2 directed/CD4BS


28
220, 219, 217, 218
MPER × V1/V2 directed/CD4BS


29
228, 227, 225, 226
MPER × V1/V2 directed/CD4BS


30
235, 234, 232, 233
MPER × V1/V2 directed/CD4BS


31
243, 242, 240, 241
MPER × V1/V2 directed/CD4BS


32
305, 304, 302, 303
CD28 × CD3/CD4BS


33
313, 312, 310, 311
CD28 × CD3/CD4BS


34
321, 320, 318, 319
CD28 × CD3/V1/V2 directed


35
329, 328, 326, 327
CD28 × CD3/V1/V2 directed


36
337, 336, 334, 335
CD28 × CD3/CD4BS


37
345, 344, 342, 343
CD28 × CD3/CD4BS


38
353, 352, 350, 351
CD4BS × CD3/CD28


39
361, 360, 358, 359
CD4BS × CD3/CD28


40
369, 368, 366, 367
CD3 × CD4BS/CD28


41
377, 376, 374, 375
CD3 × CD4BS/CD28


42
385, 384, 382, 383
CD4BS × CD3/CD28


43
393, 392, 390, 391
CD4BS × CD3/CD28


44
401, 400, 398, 399
CD3 × CD4BS/CD28


45
409, 408, 406, 407
CD3 × CD4BS/CD28


46
417, 416, 414, 415
V1/V2 directed × CD3/CD28


47
425, 424, 422, 423
V1/V2 directed × CD3/CD28


48
433, 432, 430, 431
CD3 × V1/V2 directed/CD28


49
441, 440, 438, 439
CD3 × V1/V2 directed/CD28


50
449, 448, 446, 447
V1/V2 directed × CD3/CD28


51
457, 456, 454, 455
V1/V2 directed × CD3/CD28


52
465, 464, 462, 463
CD3 × V1/V2 directed/CD28


53
473, 472, 470, 471
CD3 × V1/V2 directed/CD28
















TABLE 2





Heavy and light chain sequences of binding proteins. CDR sequences are


bolded and italicized.







Binding Protein 1 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefcustom-character wirlapgkrpewmgcustom-character
SEQ ID 




custom-character rvtmtrdvysdtaflelrsltvddtavyfctrcustom-character

NO: 1



wgrgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalt





sgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd






kthtcppcpapellggpsvflfppkpkdtimisrtpevtcvvvdvshedpevkfnw






yvdgvevhnaktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapi






ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe






nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg







Light chain A
Eivltqspgtlslspgetaiisccustom-character wqqrpgqaprlviycustom-character gipdrf
SEQ ID 



sgsrwgpdynltisnlesgdfgvyyccustom-character fgqgtkvqvdiktrtvaapsvfifpps
NO: 2




deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst






ltlskadyekhkvyacevthqglsspvtksfnrgec







Heavy chain B
Evrtvesggglvkpggslrlscsascustom-character mtwvrqppgkglewvgrcustom-character
SEQ ID 




custom-character dyaesvkgrftisrdntkntlylemnnvrtedtgyyfcarcustom-character

NO: 3




custom-character wgqgtlvivssdkthtqvhltqsgpevrkpgtsvkvsckapgntlktyd





lhwvrsvpgqglqwmgwishegdkkviverfkakvtidwdrstntaylqlsgltsg




dtavyycustom-charactercustom-character gqgtavtvssdkt




htastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglysissvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcp




apellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevh




naktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakg




qprepqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttpp




vldsdgsfflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
Dfvltqsphslsvtpgesasiscksscustom-character lawyvqkpgrspqlliycustom-character s
SEQ ID 



rasgvpdrfsgsgsdkdftlkisrvetedvgtyyccustom-character gqgtkvdikdkt
NO: 4



ht




aseltqdpavsvalkqtvtitccustom-character wyqkkpgqapvllfycustom-character gi




pdrfsgsasgnrasltitgaqaedeadyyccustom-character fgggtkltvldkthtrtv




aapsvfifppsdeqlksgtusvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 1 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga
NO: 5



ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct




gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcgcgtcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagageacatctggcggaacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca




gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca




gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt




ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg




caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg




tggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacaac
SEQ ID 



catcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcc
NO: 6



tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc




ccgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacct




ggaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggc




accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc




cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa




cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg




gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg




cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctgaataacctgggtcaggcag
NO: 7



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgaggactg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagaigaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg




tcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc




gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga




aagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacca




acaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactg




cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg




ccctgaactgggccgtggatgtggactacctgagcaacctagaattctggggccaggg




cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatcg




gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct




gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct




gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca




gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt




gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga




caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt




cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 8



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcatgcccgatagattttctggcageggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg




gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt




ccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt




gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 2 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgyfftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 9



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtvicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvscsvlhealhshytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 10



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadvekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 11



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv




kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak




vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav




dvdylsnlefwgygtavtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt




lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty




rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp




pcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgs




fflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 12



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 2 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 13



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac




acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt




gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga
SEQ ID 



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 14



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc




tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcacggcagaggc




agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag




cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag




ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca




ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga




cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 15



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacatgagaactaaaaacaccggatattacttct




gtgccagaacaggcaaatactacgacttgtggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg




tcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc




gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga




aagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacca




acaccgcctacctgcagctgagcggcctaacctctggcgataccgccgtgtactactg




cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg




ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg




cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatcg




gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct




gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct




gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca




gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt




gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga




caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt




cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtatggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 16



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg




gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt




ccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt




gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 3 Amino Acid Sequences









Heavy chain A
rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyg
SEQ ID 



avnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldaw
NO: 17



gqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 18



glksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg
SEQ ID 



wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk
NO: 19



hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves




ggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpgeg




wsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfws




gyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt




yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk




dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns




tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvyt




lppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd




gsfflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
aseltqdpavsvalkqtvtitcrgdsltshyaswyqkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfvlt
NO: 20



qsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgv




pdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtva




apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds




kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 3 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtatcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 21



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac




acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt




gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga
SEQ ID 



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 22



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc




tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc




agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag




cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag




ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca




ccctgacactgagcaaggccgactacgagaaacacaaggtgtacgcctacgaagtga




cccaccagggcctatctagccccgtgaccaagagatcaaccagggcgagtgt






Heavy chain B
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctct
SEQ ID 



gtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgca
NO: 23



ctgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcag




ccacgagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgac




catcgactgggacagaagcaccaacaccgcctacctgcagctgagcggcctg




acctctggcgataccgccgtgtactactgcgccaagggcagcaagcaccggc




tgagagactacgccctgtacgacgatgacggcgccctgaactgggccgtgga




tgtggactacctgagcaacctggaattaggggccagggcacagccgtgacc




gtgtcatctgacaaaacccataccgaggttagactggtggagtcaggaggggg




gcttgtgaagcccggtgggtctctccgcctgagagttctgcctccggctttgatt




tcgataacgcctggatgacctgggtcaggcagcaccaggtaagggactgga




gtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgc




ggaatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttg




tatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgcca




gaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatattt




tcaagactggggtcagggaacccttgttatcgtgtcctccgataagacccacac




cgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagagcac




ctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaac




cggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacctt




cccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgt




gccctccagcagcttgggcacccagacctacatagcaacgtgaatcacaagc




ccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaact




cacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtctt




cctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt




cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaact




ggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagga




gcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccagg




actggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctccca




gcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaacca




caggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggga




gagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctgga




ctccgacggctccttcttcactactcaaaactcaccgtggacaagagcaggtg




gcagcaggggaacgtatctcatgctccgtgctgcatgaggctctscacagcc




actacacgcagaagagcctctccctgtctccgggt






Light chain B
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtgactat
SEQ ID 



tacttgccgaggcgactcactgcggagccactacgcttcctggtatcagaagaaaccc
NO: 24



ggccaggcacctgtgctgctgttctacggaaagaacaataggccatctggcatccccg




accgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccggcgccca




ggctgaggacgaagccgattactattgcagctcccaggataaaagcggctccagact




gagcgtgttcggaagaggaactaaactgaccgtcctcgacaaaacccataccgacttc




gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatc




agctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggt




acgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag




ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa




gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagag




agagcccctggacctttgaccagggcaccaaggtggacatcaagaataagacccata




cccgtacaatggccgctcccagcgtgacatcttcccacctagcgacgagcagctgaa




gtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa




gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtga




ccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagc




aaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct




gtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 4 Amino Acid Sequences









Heavy chain A
qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 25



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevhnaktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrf
SEQ ID 



sgsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifpps
NO: 26



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst




ltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri
SEQ ID 



tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 27



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvhltqgpevrkpgts




vkvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfka




kvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwa




vdvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt




yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk




dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns




tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvyt




lppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd




gsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 28



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 4 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga
NO: 29



ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct




gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcatcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagagcacatctgacggaacagccgccagggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca




gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca




gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcatggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacatggacgacgtggaa




gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt




ggtgtccgtgctgaccgtgagcaccaggactggctgaacggcaaagagtacaagtg




caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccagatgtccctgagagtaccatgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg




tggcagcagggcaacgtgttcagagaccgtgatgcacgaggccctgcacaaccact




acacccagaagtccagagcctgagccccggc






Light chain A
Gagatcgtgctgacacagagccaggcaccctgagcctgtctccaggcgagacagc
SEQ ID 



catcatcagtgccggacaagccagtacggcagcctggcctggtatcagcagaggcc
NO: 30



tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc




ccgatagattcagcggctccagatggggccagactacaacctgaccatcagcaacct




ggaaagcgacgacttcgacgtgtactactgccagcaatacgagttcttcggccagggc




accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc




cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa




cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg




gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg




cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggagaggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 31



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




ggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt




gtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcag




cgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaag




aaaggatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacc




aacaccgcctacctacaactgagcggcctaacctctggcgataccgccgtgtactact




gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggc




gccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg




gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatc




ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg




ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgcc




ctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct




cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac




gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg




acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag




tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtagaggtgcataataccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatagcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaattggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccgaaacaactacctg
NO: 32



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctagtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg




gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt




ccggcacagcctctatcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt




gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 5 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 33



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyggrpgqaprlviysgstraagipdrfs
SEQ ID 



gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd
NO: 34



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 35



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse




tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl




sldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw




gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv




swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk




vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv




vvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqd




wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv




slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks




rwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
Sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp
NO: 36



avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas




gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp




psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls




stltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 5 Nucleotide Sequences









Heavy chain A
Caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgc
SEQ ID 



ggatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcag
NO: 37



actggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggag




ccgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtaca




gcgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttc




tgcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagagg




cacccctgtgatcgtgtcaagc




gcgtcgaccaagggccccagcgtgttccctctggcccctagcagcaagagcacatct




ggcggaacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc




gtgtcctagaattctgacgccctgaccagcggcgtgcacacctttccagctgtgctgca




gtccagcggcctgtacagcctgagcagcgtcgtgacagtgcccagcagctctctggg




cacccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaa




gaaggtggaacccaagagctgcgacaagacccacacctgtcccccttgtcctgcccc




cgaactgctgggaggcccttccgtgttcctgttccccccaaagcccaaggacaccctg




atgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacgaggac




cctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaagacca




agccaagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgaccgtgc




tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaaggccc




tgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaaccc




caggtgtgcacactgcccccaagcagggacgagctgaccaagaaccaggtgtccctg




agctgtgccgtgaaaggcttctacccctccgatatcgccgtggaatgggagagcaacg




gccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctcat




tcttcctggtgtccaaactgacagtggacaagtcccggtggcagcagggcaacgtgttc




agctctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgagc




ctgagccccggc






Light chain A
Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagc
SEQ ID 



catcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcc
NO: 38



tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc




ccgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacct




ggaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggc




accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc




cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa




cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg




gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg




cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccagtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 39



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcaaggaacccttgttatcgtgtcctccgacaaaacccataccca




gatacagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgaacc




tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga




ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc




aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc




aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc




caggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttcacc




tacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgataaga




cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag




cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc




ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc




tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca




gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt




ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca




gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggaca




ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga




agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga




caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc




gtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaa




gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga




accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc




aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg




ctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggggaac




gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcct




ctccctgtctccaggt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgagaagag
SEQ ID 



cctgggaagcagggctgtgcagtagtaccaacacagggccggacaggctcccagcc
NO: 40



tgatcatctacaacaaccaggacaggcccagcggcatccctgagaggttcagcggaa




gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtggaagcc




ggcgacgaggccgactactactgccacatctgggacagcagggtgcccaccaagtg




ggtgtttggcggcggcaccaccctgaccgtgctggacaaaacccataccgcatccga




actgactcaggaccctgccgtctctgtggcactgaagcagactgtgactattacttgccg




aggcgactcactgcggagccactacgcttcctggtatcagaagaaacccggccaggc




acctgtgctgctgttctacggaaagaacaataggccatctggcatccccgaccgcttttc




tggcagtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgagga




cgaagccgattactattgcagctcccgggataagagcggctccagactgagcgtgttc




ggaggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgct




cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgt




cgtgtgcctgagaacaacttctacccccgcgaggccaaagtgcagtggaaggtggac




aacgccctgcagagcggcaacaaccaggaaagcgtgaccgagcaggacagcaag




gactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaag




agcttcaaccggggcgagtgt











Binding Protein 6 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 41



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs
SEQ ID 



gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd
NO: 42



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg
SEQ ID 



wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk
NO: 43



hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves




ggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpgeg




wsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfw




wgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaa




lgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgt




qtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppk




pkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqy




nstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepq




vytlppcrdeltknqvstwclvkgfypsdiavewesngqpennykttppvl




dsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
Aseltqdpavsvalkqvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
SEQ ID 



pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfv
NO: 44



ltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasg




vpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqatkvdikdkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 6 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga
NO: 45



ctggcccctggcaaacggcctgagtggatgggatggctgaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct




gcacccggggcaagaactgegactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca




gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca




gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcgtggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacatggacgacgtggaa




gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt




ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg




caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccaggtgtccctgagctgtgccatgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg




tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccggc






Light chain A
gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc
SEQ ID 



atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct
NO: 46



ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc




cgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacctg




gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca




ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcatgttcatcttccc




acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac




ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga




gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc




gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
caggtgcacctgacacaaagcggacccgaagtgcggaagcctagcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 47



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc




agggcacagccgtgaccgtgtcatctgacaaaacccataccgaggttagactggtgga




gtcaggaggggggcttgtgaagcccggtgggtctctccgcctgagctgttctgcctcc




ggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggact




ggagtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcgg




aatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttgga




gatgaacaacgtgagaactgaagacaccagatattacttctgtgccagaacaggcaaa




tactacgacttctggtggggctatccccctggcgaggaatattttcaagactggggtcag




ggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatc




ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg




ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgcc




ctgaccagcggcgtgcaccttcccggctcgtcctacagtcctcaggactctactccct




cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac




gtgaatcacaagcccagcaacaccaaggtgaacaagaaagttgagcccaaatcttgtg




acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag




tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct




gcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
Gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt
SEQ ID 



gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca
NO: 48



gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg




ccatctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagt




ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc




ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg




accgtcctcgacaaaacccataccgacttcgtgctgacccagagccctcacag




cctgagcgtgacacctggcgagagcgccagcatcagctgcaagagcagcca




ctccctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagc




ccggcagatccccccagctgctgatctacctggccagcagcagagccagcgg




cgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaagat




cagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcaga




gagagcccctggacctttggccagggcaccaaggtggacatcaaggataaga




cccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacg




agcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc




aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagc




ctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgt




acgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttc




aaccggggcgagtgt











Binding Protein 7 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 49



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs
SEQ ID 



gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsyfifppsd
NO: 50



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh
SEQ ID 



ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi
NO: 51



vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv




sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti




dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv




dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk




dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn




vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm




isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv




vsvltvlhqdwlngkeykekvsnkalpapiektiskakgqprepqvytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf




flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 52



tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs




pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnqesvteqdskd




styslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 7 Nucleotide Sequences









Heavy chain A
caggtgcagaggtgcagtctggcggccagatgaagaaacccggcgagagcatacg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga
NO: 53



ctggcccctggcaagcggcctgagtggatgggatggagaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccgcctcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct




gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagagtgagcagtccagcggcctgtacagcctgagcagcgtcgtgaca




gtacccagcagctactgagcacccagacctacatctgcaacgtgaaccacaagccca




acaacaccaaggtagacaagaaggtgaaacccaagagctacgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt




ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg




caagatgtccaacaaggccctgcctacccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg




tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccggc






Light chain A
gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc
SEQ ID 



atcatcagagccggacaagccagtacggcagcctagcctggtatcaacagaggcct
NO: 54



ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc




cgatagattcagcggaccagatggggccctgactacaacctgaccatcagcaacctg




gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca




ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc




acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac




ttctacccccgcgaggccaaagtgcagtggaaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga




gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc




gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
cagatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgag
SEQ ID 



cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag
NO: 55



gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcgacgac




accaactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaaga




accaggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactg




tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc




acctacttctacatggacgtggggcaacggcacccaggtgaccgtgagctccgaca




aaacccatacccaggtgcacctgacacagagcggacccgaagtgcggaagcctggc




acctagtgaagatgtcctgcaagacccaggcaacaccctgaaaacctacgacctgc




actgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccac




gagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgg




gacagaagcaccaacaccgcctacctgcagctgagcggcctgacctctggcgatacc




gccgtgtactactgcgccaagggcagcaagcaccggctgagagactacgccctgtac




gacgatgacggcgccctgaactgggccgtggatgtggactacctgagcaacctggaa




ttctgaggccaggacacaaccatgaccatgtcatctgataagacccacaccgcttcca




ccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcac




agcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtgg




aactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcag




gactctactccctcagcagcgtggtgaccgtgccctccagcttgcttgggcacccagac




ctacatagcaacgtgaatcacaagcccagcaacaccaaggtgaacaagaaagttga




gcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcagg




ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgg




acccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag




ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagg




agcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactg




gctgaatggcaaggaatacaagtgcaaggtctccaacaaagccctcccagcccccat




cgagaaaaccataccaaagccaaagggcagccccgagaaccacaggtgtacaccc




tgcccccatgccgaaataagctgaccaaaaatcaagtcagcctgtggtacctggtaaa




aggctctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggaga




acaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctactcaa




aactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat




gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga
SEQ ID 



gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa
NO: 56



caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga




tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc




ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac




gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca




gggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgtg




gcccccggagagacagccaggatctcctgcggcgagaagagcctgggaag




cagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgatc




atctacaacaaccaggacaggcccageggcatccctgagaggttcagcggaa




gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgga




agccggcgacgaggccgactactactgccacatctgggacagcagggtgcc




caccaagtgggtgtttggcggcggcaccaccctgaccgtgctggataagaccc




atacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc




agctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac




agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac




gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa




ccggggcgagtgt











Binding Protein 8 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 57



wgqgttvvvsaastkapsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




cktiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsffvskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain A
Yihvtqspsslsvsigdrvtincqtsqvgsdlhwyqhkpgrapkllihhtssvedg
SEQ ID 



vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsd
NO: 58



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksthrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqpgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 59



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgt




slrlscaasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwg




rftisrdnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkq




lpcaksrgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsg




gtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlssglyslssvvtvpss




slgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflf




ppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpr




eeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpr




epqvytlppcrdeltknqvslwelvkgfypsdiavewesngqpennykttp




pvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
Qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrps
SEQ ID 



gipdrfsasksgtsgtlaitglqtgdeadyycatwaaslssarvftgtkvivldkthtas
NO: 60



eltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr




fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaap




svfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdsk




dstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 8 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca
NO: 61



ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg




tgaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcg




agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg




cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg




gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc




ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg




actactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtg




cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga




cagtacccaacaactctctgggcacccagacctacatagcaacgtgaaccacaagc




ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca




cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt




ggtggatgtgtcccacgaggaccctgaagtgaattcaattggtacgtggacggcgtg




gaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctacc




gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca




agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg




ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga




gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgat




atcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc




cccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaag




tcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcac




aaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
Tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgaca
SEQ ID 



gagtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactg
NO: 62



gtatcagcacaagcctggcagagcccccaagctgctgatccaccacacaagc




agcgtggaagatggcgtgcccagcagattttccggcagcggcttccacacca




gcttcaacctgaccatcagcgatctgcaggccgacgacattgccacctactatt




gtcaggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc




ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaa




agtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaa




gcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccc




tgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt




gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 63



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




ggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgagact




ctcctgtgcagcctctcaattcaggtttgatggttatgacatgcactgggtccgccaggc




cccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagtat




cacgcagaaaaagtgtggggccgcttcaccatctccagagacaattccaagaacaca




ctgtatctacaaatgaacagcctgcgacctgaggacacggctctctactactgtgcgaa




agatttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaac




aactcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggcca




agggacaatggtcaccgtctcttcagataagacccacaccgcttccaccaagggccca




tcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgg




gctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc




cctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccc




tcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa




cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt




gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca




gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgaacccctgaggt




cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat




gttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa




cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc




aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc




atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc




cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc




cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag




accacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtg




gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatacatgaggct




ctgcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
Cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaagg
SEQ ID 



tcaccatctcctgactggaaacacctccaacattggcaataattttgtgtcctggt
NO: 64



atcaacagcgccccggcagagccccecaactcctcatttatgaaactgacaag




cgaccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggca




ccctggccatcaccgggctgcagactggggacgaggccgattattactgcgc




cacatgggctgccagcctgagttccgcgcgtgtatcggaactgggaccaagg




tcatcgtcaggacaaaacccataccgcatccgaactgactcaggaccctgcc




gtctctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgc




ggagccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctg




ctgttctacggaaagaacaataggccatctggcatccccgaccgcttttctggca




gtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgagga




cgaagccgattactattgcagctcccgggataagagcggctccagactgagcg




tgttcggaggaggaactaaactgaccgtcctcgataagacccatacccgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc




ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaa




agtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaa




gcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccc




tgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt




gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt











Binding Protein 9 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 65



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppcpapellggpsvflfppkpkdtlmisrtpevrcvvvdvshedpevkfnwyv




dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakaqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs
SEQ ID 



gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd
NO: 66



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqpgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 67



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgt




slrlscaasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwg




rftisrdnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkq




lpcaksrgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsg




gtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpss




slgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflf




ppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpr




eeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpr




epqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttp




pvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrps
SEQ ID 



gipdtgsasksgtsgtlaitglqtgdeadyycatwaaslssarvfgtgtkvivldkthtas
NO: 68



eltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr




fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaap




svfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdsk




dstyslsstlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 9 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgadgcaccctgaactggatcaga
NO: 69



ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccaccttcctagaactacgaagcctgaccgtagatgataccgccgtgtacttct




gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagageacatctggcggaacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagctgtactacagtccagcggcctgtacaacctgagcagcgtcgtgaca




gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca




gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa




gtacacaacaccaagaccaagccaagagaggaacagtacaacageacctaccggat




ggtgtccgtgctgaccgtgctgcaccaggactgactgaacggcaaagagtacaagtg




caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgaggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg




tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccggc






Light chain A
gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc
SEQ ID 



atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct
NO: 70



ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc




cgatagattcagcggaccagatggggccctgactacaacctgaccatcagcaacctg




gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca




ccaagatgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc




acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac




ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga




gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc




gaagtgacccaccagggcctgtctagccccatgaccaagagatcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctaccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 71



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacatgagaactgaagacaccggatattacttct




gtaccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




ggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgagact




ctcctgtgcagcctctcaattcaggtttgatggttatggcatgcactgggtccgccaggc




cccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagtatc




acgcagaaaaagtgtagggccgcttcaccatctccagagacaattccaagaacacact




gtatctacaaataaacaacctgcgacctgaggacacggctctctactactgtgcgaaag




atttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaacaac




tcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggccaagg




gacaatggtcaccgtacttcagataagacccacaccgcttccaccaagggcccatcg




gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct




gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct




gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca




gcagcgtggtgaccgtaccctccagcagcttgggcacccagacctacatctgcaacgt




gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga




caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt




cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctgaactccgacggctccttatcctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct




gcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
cagtctgtgctgacgcagccgccctcagtatctgcgaccccaggacagaaggtcacc
SEQ ID 



atctcctgactggaaacacctccaacattggcaataattttgtgtcctggtatcaacagc
NO: 72



gccccggcagagccccccaactcctcatttatgaaactgacaagcgaccctcagggat




tcctgaccgattctctgcttccaagtctggtacgtcaggcaccetggccatcaccgggct




gcagactggggacgaggccgattattactgcgccacatgggctgccagcctgagttcc




gcgcgtgtcttcggaactgggaccaaggtcatcgtcctg




gacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactga




agcagactgtgactattacttgccgaggcgactcactgcggagccactacgcttcagg




tatcagaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggc




catctggcatccccgaccgcttttaggcagtacatcagggaaccgagccagtctgacc




attaccggcacccaaactgaggacgaagccaattactattgcaactcccgggataaga




gcggctccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagac




ccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcag




ctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggc




caaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagc




gtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacact




gagcaaggccgactacgagaagcacaagatgtacacctgcgaagtgacccaccagg




gcctatctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 10 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr
SEQ ID 



ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw
NO: 73



grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt




htcppepapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv




dgvevnnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt




iskakaqprepqvctlppsrdeltknqvslscavkgypsdiavewesngqpenny




kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs
SEQ ID 



gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd
NO: 74



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qvqlvesgggvvqpgtslrlscaasqfrfdgygmhwvrqapgkglewvas
SEQ ID 



ishdgikkyhaekvwgrftisrdnskntlylqmnslrpedtalyycakdlred
NO: 75



eceewwsdyydfgkqlpcaksrgglvgiadnwgqgtmvtvssdkthtevr




lvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgp




gegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyyd




fwwgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsgg




taalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpsss




lgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfp




pkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpree




qynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpre




pqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttpp




vldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtqsvlt
NO: 76



qppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgipdr




fsasksgtsgtlaitglqtgdeadyycatwaaslssarvfgtgtkvivldkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd




styslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 10 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg
SEQ ID 



gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga
NO: 77



ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc




cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag




cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct




gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc




acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc




ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca




cacctttccagctgtgctgcagtccagcggcctgtacaacctgagcagcgtcgtgaca




gtacccagcagctctctgagcacccagacctacatctgcaacgtgaaccacaagccc




agcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccaca




cctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccc




caaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg




gtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtgg




aagtacacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccg




ggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaa




gtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggc




caagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgag




ctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatat




cgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc




cctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtc




ccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaa




ccactacacccagaagtccctgagcctgagccccggc






Light chain A
gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc
SEQ ID 



atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct
NO: 78



ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc




cgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacctg




gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca




ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc




acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac




ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg




cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcg




agtgt






Heavy chain B
caggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgaga
SEQ ID 



ctctcctgtgcagcctctcaattcaggtttgatggttatggcatgcactgggtccgccag
NO: 79



gccccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagt




atcacgcagaaaaagtgtggggccgcttcaccatctccagagacaattccaagaacac




actgtatctacaaatgaacagcctgcgacctgaggacacggctctctactactgtgcga




aagatttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaa




caactcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggcc




aagggacaatggtcaccgtctcttcagacaaaacccataccgaggttagactggtgga




gtcaggaggggggcttgtgaagcccggtgggtctctccgcctgagctgttctgcctcc




ggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggact




ggagtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcgg




aatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttgga




gatgaacaacgtgagaactgaagacaccggatattacttctgtgccagaacaggcaaa




tactacgacttctggtccggctatccccctggcgaggaatattttcaagactggggtcag




ggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatc




ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg




ctacctggtcaaggactacttccccgaaccggtgacggtatcatggaactcaggcgcc




ctgaccagcagcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct




cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa




cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt




gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca




gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt




cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat




gttgacggcgtggaggtgcataataccaagacaaagccgcgggaggagcagtacaa




cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc




aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc




atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc




cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc




cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag




accacgcctcccgtgctgaactccgaeggctcatatcctctactcaaaactcaccatg




gacaagaacaggtgacaacaagggaacatcttctcataaccatgatgcataaggct




ctacacaaccactacacgcagaagaacctaccagtaccgggt






Light chain B
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt
SEQ ID 



gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca
NO: 80



gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg




ccatctggcatccccgaccgctatctggcagtgcatcagggaaccgagccagt




ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc




ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg




accgtcctcgacaaaacccatacc




cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaagg




tcaccatctcctgctctggaaacacctccaacattggcaataattttgtgtcctggt




atcaacagcgccccggcagagccccccaactcctcatttatgaaactgacaag




cgaccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggca




ccctggccatcaccgggctgcagactggggacgaggccgattattactgcgc




cacatgggctgccagcctgagttccgcgcgtgtcttcggaactgggaccaagg




tcatcgtcctg




gataagacccatacccgtacggtggccgctcccagcgtgacatcttcccacct




agcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa




cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcag




agcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac




ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagca




caaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc




aagagcttcaaccggggcgagtgt











Binding Protein 11 Amino Acid Sequences









Heavy chain A
Rahlvgsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 81



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpeakfnw




yvdgvevhnaktkpreegynstvvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 82



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri
SEQ ID 



tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 83



yydfwwgyppgeeyfqdwgqgtlvivssdkthtgvhltqsgpevrkpgts




vkvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfka




kvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwa




vdvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt




yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk




dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns




tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgrqprepqvyt




lppcerdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd




gsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrsplliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 84



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 11 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 85



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggagcctgaagcccgatgacaccgccgtatactactgca




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaatttgggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac




acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt




gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaagaccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcaggtgtccaagetgacagtggacaagtcccggt




ggcagcagagcaacatgttcagctgaccgtgatacacgaggccctacacaaccact




acacccagaagtccctgagcctgagccccggcaag






Light chain A
tacatccacgtgacccagagccecagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt
NO: 86



atcagcacaagcctggcagagcccccaagagctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 87



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtagactacgcggaatctgttaaagagcggtttacaatacaagagacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




ggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt




gtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcag




cgtgccaggacagggactgcagtggatgggaggatcagccacgagggcgacaag




aaagtgatcgtagaacggttcaaggccaaagtgaccatcgactgggacagaagcacc




aacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactact




gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggc




gccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg




gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatc




ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg




ctgcctggtcaaggactacttccccgaaccggtgacgatgtcgtggaactcaggcgcc




ctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct




cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac




gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg




acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag




tcttcctcttccccccaaaacccaaggacaccacatgatacccggacccctgaggtca




catgcatggtggtagacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt




gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca




gcacgtaccgtgtggtcagectcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagcccegagaaccacaggtgtacaccctgcccccatgcc




gggatgaactgaccaagaatcaagtcagcctgtggtgcctgataaaaggcttctatccc




agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga




ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtag




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct




gcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga
SEQ ID 



gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa
NO: 88



caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga




tctacctggccagcagcagagccagcgcgtgcccgatagattttctggcagc




ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac




gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca




gggcaccaaggtggacatcaaggacaaaacccataccgcatccgaactgact




caggaccctgccgtctctgtggcactgaagcagactgtgactattacttgccga




ggcgactcactgcggagccactacgcttcctggtatcagaagaaacccggcca




ggcacctgtgctgctgttctacggaaagaacaataggccatctggcatccccga




ccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccggcgc




ccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacc




catacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgag




cagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccc




cgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaa




cagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct




gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta




cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttca




accggggcgagtgt











Binding Protein 12 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 89



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 90



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri
SEQ ID 



tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 91



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse




tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl




sldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw




gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv




swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk




vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv




vvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqd




wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv




slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks




rwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp
NO: 92



avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas




gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthrttvaapsvfifp




psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls




stltlskadyekhkvyacevthqglsspytksfnrgec











Binding Protein 12 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 93



gcccctggcagaggactggaatgggttgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtaaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac




acctttccaactatgctgcagtccagcggcctgtacagcctaagcagcgtcgtgacagt




gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaaaaccctgaagtaaaattcaattagtacgtggacggcgtgaaaat




gcacaacgccaagaccaagccaagagaagaacaatacaacagcacctaccgggta




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacgactcattatcaggtatccaagagacaatggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccggcaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctacagggcgtgggcagcgacctgcactggt
NO: 94



atcagcacaagectggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtgaagtcaagagaggggatgtgaagcccaatggatactccac
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 95



cctccaggtaaggggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggatacaatctcaagggacaatacca




agaataccctgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




gatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgagcc




tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga




ggagccctggcaagggcctggagtggatcggctacgtgcacaagageggegacacc




aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc




aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc




caggaccctacacggcaggaggatctacggcatcgtagccttcaacgagtagttcacc




tacttctacatgaacatgtggggcaacggcacccaggtgaccgtgagctccgataaga




cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag




cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc




ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc




tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca




gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt




ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca




gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggaca




ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga




agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga




caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc




gtcctgcaccaggactggctgaatagcaaggagtacaagtgcaagataccaacaaa




gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga




accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc




aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg




ctccttcttcctctactcaaaactcaccatggacaagagcaggtagcagcaggggaac




gtcttctcatactccatgatgcatgaggctctgcacaaccactacacacagaagagcct




ctccctgtctccgggt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag
SEQ ID 



aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag
NO: 96



gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga




gaggttcagcggaagccccgacagccccttcggaaccacagccaccctgacc




atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg




acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt




gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt




ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc




actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta




cggaaagaacaataggccatctggcatccccgaccgatttctggcagtgcatc




agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc




cgattactattgcagctcccgggataagagcggctccagactgagcgtgacgg




aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg




ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca




gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag




tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga




gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc




agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 13 Amino Acid Sequences









Heavy chain A
qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe
SEQ ID 



gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd
NO: 97



dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl





vkdvfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn






hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt






cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltylhqdwl






ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg






fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv






mhealhnhytqkslslspg







Light chain A
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva
NO: 98



apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd




skdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 99



yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse




tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl




sldtskngyslslvaataadsgkyycartlhgrriygivafnewftyfymdv




wgngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepv




tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsn




tkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdttmisrtpevt




evvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlh




qdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltkn




qvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltv




dksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
sdisvapgetariscgekslgsravgwyqhragqapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqd
NO: 100



pavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgs




asgnrasltitgaqacdeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif




ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys




lsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 13 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgagtgcg
NO: 101



cagcgtgccaggacagggactacagtggatgaactagatcaaccacgaggacgac




aagaaagtgatcatggaacggttcaaggccaaagtgaccatcgactaggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggc




cagggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctc




tggcccctagcagcaagagcacataggcggaacagccgccagggctgcctcgtga




aggactactacccgagcccgtgaccgtgtcaggaattaggcgccctgaccagcgg




cgtgcacacctttccaactatgctgcagtccagcggcctgtacagcctgagcagcgtc




gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca




agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac




ccacacctgtcccccagtcctgcccccgaactgctgggaggcccttccgtgttcctgtt




ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcg




tggtggtggatgtatcccacgaggaccagaaatgaagttcaattggtacgtagacgg




cgtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacct




accgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagt




acaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagca




aggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcaggga




cgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggatctacccacc




gatatcgccgtagaatgggagagcaacagccagcccgagaacaactacaagaccac




cccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggaca




agtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgc




acaaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gacacgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 102



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtaggcacctactactgtatgcagg




gcagagagaacccaggacattggccagagcaccaaagtggacatcaaacgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtg




gaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagca




ggacagcaaggactccacctacagcctgagcagcaccagacactgagcaaggccg




actacgagaagcacaaggtgtacgcctacgaagtgacccaccaaggcctgtctagcc




ccgtgaccaagagatcaaccgaggcgagtat






Heavy chain B
gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 103



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata




ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca




gatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgagcc




tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagg




aggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgaca




ccaactacagcccctccctgaagtccagagtgaacctatccaggacaccagcaaga




accaggtgagcctgtccaggtggctgccacagctgctgacagcggcaagtactactg




tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc




acctacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgata




agacccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaa




gagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga




accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttccc




ggctgtcctacaatcctcaggactctactccctcagcagcgtggtgaccgtgccacca




gcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacacca




aggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtg




cccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaag




gacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc




acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgc




caagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcc




tcaccgtcctgcaccaggactggctgaatggcaaggagtacaaatgcaaggtctccaa




caaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagcccc




gagaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaag




tcagcctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggga




gagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccg




acggctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggg




gaacgtcttctcatgctccgtgatacatgaggctctacacaaccactacacgcagaaga




gcctctccctgtctccgggt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag
SEQ ID 



aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag
NO: 104



gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctg




agaggttcagcggaagccccgacagccccttcggaaccacagccaccctga




ccatcacaagcgtggaagccggegacgaggccgactactactgccacatctg




ggacagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgac




cgtgctggacaaaacccataccgcatccgaactgactcaggaccctgccgtct




ctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgcgga




gccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgt




tctacggaaagaacaataggccatctggcatccccgaccgcttttctggcagtg




catcagggaaccgagccagtctgaccattaccggcgcccaggctgaggacg




aagccgattactattgcagctcccgggataagagcggctccagactgagcgtg




ttcggaggaggaactaaactgaccgtcctcgataagacccatacccgtacggt




ggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccg




gcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa




gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag




cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccct




gacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt




gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt











Binding Protein 14 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 105



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedg
SEQ ID 



vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsd
NO: 106



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg
SEQ ID 



wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk
NO: 107



hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves




ggglvkpggslrlscsasgfdfdnawmtwvalppgkgtewvgritgpgeg




wsvdyaesvkgrftisrdnktntlylemnnvrtedtgyyfcartgkyydfw




wgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaa




lgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgt




qtyicnvnhkpsnkvdkkvepkscdkthtcppcpapellggpsvflfppk




pkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeq




ynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprep




qvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppv




ldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
SEQ ID 



pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfv
NO: 108



ltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqliiylassrasg




vpdrfsgsgsdkdftlkisrvetedvatyycmqgrespwtfgqtkvdikdkthtrt




vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvte




qdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 14 Nucleotide Sequences









Heavy chain A
aaagcccacctaatgcagtctagcaccgccataaaaaaaccagacgcctctatgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca
NO: 109



ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg




tgaacttcgacggaggcttccggaatagaatgaccctaacccaggacgtgtaccgcg




agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg




cgccagagacagaagctacggcgacagcaactgggctctagatgcttggggccagg




gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc




ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg




actactttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcggcgtg




cacacctttccagagtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga




cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc




ccagcaacaccaaggtggacaagaaggtggaacccaagagagcgacaagaccca




cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccatgttcctgttccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt




ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtg




gaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctacc




gggtggtgtccgtgagaccgtgagcaccaggactggctgaacggcaaagagtaca




agtgcaaggtgtccaacaaggccagcctgcccccatcgagaaaaccatcagcaagg




ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaaacagggacga




gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgat




atcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc




cccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaag




tcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcac




aaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt
NO: 110



atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtc




aggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtg




gccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccgg




cacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt




gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg




tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctga




cactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga




cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtg




t






Heavy chain B
caggtgcacctgacacagagcggacccgaagtgcggaagcctagcacctagtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 111



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacaccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggc




cagggcacagccgtgaccgtgtcatctgacaaaacccataccgaggttagactggtg




gagtcaggaggggggcagtgaagcccggtgggtctctccgcctgagctgttctgcct




ccggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaaggg




actggagtgggtgggaagaatcacaggtccaggcgagggaggtccgtggactacg




cggaatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtattt




ggagatgaacaacgtgagaactgaagacaccggatattacttctgtgccagaacaggc




aaatactacgacttctggtggggctatccccctggcgaggaatattttcaagactggggt




cagggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcc




catcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccct




gggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcagg




cgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctact




ccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctg




caacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatc




ttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggacc




gtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctg




aggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaact




ggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcag




tacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctga




atggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgaga




aaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc




ccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggct




tctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac




tacaagaccacgcctcccatgaggactccgacggaccttcttcactactcaaaactc




accgtagacaagagcaggtggcagcaggagaacgtatacatgctccgtgatacat




gaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt
SEQ ID 



gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca
NO: 112



gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg




ccatctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagt




ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc




ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg




accgtcctcgacaaaacccataccgacttcgtgctgacccagagccctcacag




cctgagcgtgacacctggcgagagcgccagcatcagctgcaagagcagcca




ctccctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagc




ccggcagatccccccagctgctgatctacctggccagcagcagagccagcgg




cgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaaga




tcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcag




agagagcccctsgacctttggccagggcaccaaggtggacatcaaggataag




acccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgac




gagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctac




ccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacag




cctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggt




gtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagc




ttcaaccggggcgagtgt











Binding Protein 15 Amino Acid Sequences









Heavy chain A
qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe
SEQ ID 



gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd
NO: 113



dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn




hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt




cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl




ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg




fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv




mhealhnhytqkslslspg






Light chain A
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva
NO: 114



apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds




kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 115



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpset




lsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnls




ldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw




gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv




swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk




vdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlmisrtpevtcv




vvdvshedpevkfnwyydgvevhnaktkpreeqynstyrvvsvltvlhqd




wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv




slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks




rwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
sdisvapgetariscgekslgsravqwyqhraaqapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltgdp
NO: 116



avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas




gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp




psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls




stltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 15 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 117



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc




agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct




ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga




aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg




cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc




gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca




agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac




ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt




ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt




ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc




gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta




ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta




caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa




ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac




gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg




atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc




ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa




gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca




caaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 118



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg




aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg




acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact




acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg




tgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccagtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 119



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgaaaagggcggatacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacact




gtgccagaacaggcaaatactacgacactagtccggctatccccctggcgaggaatat




tttcaagactagggtcaaggaacccttgttatcgtgtcctccaacaaaacccatacccag




atgcagctgcaggagageggccaggactcgtaaaacccagcgagaccctgagcct




gacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga




ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc




aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc




aggtgagcctgtccctggtggctgccacagctgctgacagcagcaagtactactgtgc




caggaccctacacggcaggaggatctacggcatcgtaaccttcaacgagtaattcacc




tacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgataaga




cccacaccgcttccaccaagggcccatcggtcaccccctggcaccctcctccaagag




cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc




ggtgacggtgtcgtggaactcaagcgccctgaccagcggcatgcacaccttcccggc




tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca




gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt




ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca




gcacctgaactcctggggggaccgtcagtcttcctcttcccccccaaaaccaaggaca




ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga




agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga




caaagccacgggaggagcagtacaacagcacataccatgtagtcagcgtcctcacc




gtcctgcaccaggactggctgaatagcaaggagtacaagtgcaagataccaacaaa




gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga




accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc




aatgggcagceggagaacaactacaagaccacgcctcccgtgctggactccgacgg




ctccttcttcctctactcaaaactcaccgtagacaaaagcaggtggcagcaggagaac




gtcttctcatgctccgtaatacatgaagctctacacaaccactacacgcagaagagcct




ctccctgtctccaggt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag
SEQ ID 



aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag
NO: 120



gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga




gaggttcagcggaagccccgacagccccttcggaaccacagccaccctgacc




atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg




acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt




gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt




ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc




actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta




cggaaagaacaataggccatctggcatccccgaccgcttactggcagtgcatc




agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc




cgattactattgcagctcccgggataagagcggctccagactgagcgtgttcgg




aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg




ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca




gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag




tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga




gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc




agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 16 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 121



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 122



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 123



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpset




lsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnls




ldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw




gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv




swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk




vdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlmisrtpevtcv




vvdvshedpevkfnwyydgvevhnaktkpreeqynstyrvvsvltvlhqd




wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv




slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks




rwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp
NO: 124



avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas




gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp




psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls




stltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 16 Nucleotide Sequences









Heavy chain A
agaacccacctggtacagtctggcaccgccatgaagaaaccaggcgcctctgtacgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 125



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccggaatagaatgaccctaacccgagacgtgtaccgcgag




atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgaactctagatacttgggaccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac




acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt




gcccagcagctctctgggcacccagacctacatagcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgaccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacaccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactacccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccgacaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctacagggcgtgggcagcgacctgcactggt
NO: 126



atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctaccgc
SEQ ID 



ctaagctgactgcctccggattgatttcaataacgcctgaataacctgaatcaggcag
NO: 127



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcoogggacaatacca




agaataccttgtataggagatgaacaacgtgagaactgaagacaccggatattacact




gtgccagaacaggcaaatactacgacactggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag




atgcagctgcaggagagcggccaggactcgtgaaacccagcgagaccctgagcct




gacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga




ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc




aactacagcccctccctgaagtccagggtgaacctgtccaggacaccagcaagaacc




aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc




caggaccctacacggcaggaggatctacggcatcgtaaccttcaacgagtaattcacc




tacttctacatgaacatgtggggcaacggcacccaggtgaccgtgagctccgataaga




cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag




cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc




ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc




tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca




gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt




ggacaagaaaattaagcccaaatcagtgacaaaactcacacatgcccaccgtaccca




gcacctgaactcctggaaggaccatcagtcttcctcttccccccaaaacccaaggaca




ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga




agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga




caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc




gtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaa




gccctcccagcccccatcgagaaaaccatctccaaaaccaaagggcagccccgaga




accacaggtatacaccctgcccccataccaggatgaactaaccaagaatcaaatcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc




aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg




ctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggggaac




gtcttctcatgctccdgatgcatgaggctctgcacaaccactacacgcagaagagcct




ctccctgtctccgggt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag
SEQ ID 



aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag
NO: 128



gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga




gaggttcagcggaagccccgacagcccatcggaaccacagccaccctgacc




atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg




acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt




gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt




ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc




actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta




cggaaagaacaataggccatctggcatccccgaccgatttaggcagtgcatc




agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc




cgattactattgcagctcccgggataagagcggctccagactgagcgtgttcgg




aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg




ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca




gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag




tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga




gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc




agggcctgtctagccccgtgacaagagcttcaaccggggcgagtgt











Binding Protein 17 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 129



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 130



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg
SEQ ID 



wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk
NO: 131



hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtqmqlqe




sgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvhksgdtn




yspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygivafne




wftyfymdvwgngtqvtvssdkthtastkgpsvfplapsskstsggtaalgc




lvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqty




icnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkd




tlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynst




yrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytl




ppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdg




sfflyskltvdksrwgqgnvfscsvmhealhnhytqkslslspg






Light chain B
sdisvapgetariscgekslgsravqwyqhragapsliiynnqdrpsgiperfsgsp
SEQ ID 



dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtdfvltqsp
NO: 132



hslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgvpdrf




sgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd




styslsstltskadyekhkvyacevthqglsspvtksfhrgec











Binding Protein 17 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 133



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggggcagaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagaacggcgacagcagagagactagatgatgggaccagggc




acaaccgtggtggtgtagccgcactacaaagggccccagcgtgttccctaggcccc




tagcagcaagagcacataggcggaacagccgccagggagcacgtgaaggacta




ctttcccgagcccgtgaccgtgtcaggaattaggcgccctgaccagcggcgtgcac




accctttccagagtgagcagtccagcggcagtacagcagagcagcgtcgtgacagt




gcccagcagactagggcacccagacctacatagcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacaca




gtcccccttgtcagcccccgaactgagggaggcccttccgtgttcagttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccagaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaggaacagtacaacagcacaaccgggtg




gtatccgtgagaccgtgagcaccaggaaggagaacgacaaagagtacaagtgc




aaggtgtccaacaaggccagcctacccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagaga




ccaagaaccaggtgtccagagagtgccgtgaaaggatctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccctgagcctgagccccggcaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctacagggcgtgggeagcgacctgcactggt
NO: 134



atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 135



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgagacagaagc




accaacaccgcctacctacagctaagcggcctgacctaggcgataccgccgtgtact




actgcaccaaaagcagcaagcaccgactaagaaactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc




agggcacagccgtgaccgtgtcatctgacaaaacccatacccagatgcagctgcagg




agagcggccctggactcgtgaagcccagcgagaccctgagcctgacatgcagcgtg




agcggcgccagcatcagcgacagetactggagctggatcaggaggagccctggcaa




gggcctgaagtagatcggctacgtgcacaagagcaacgacaccaactacagcccct




ccctgaagtccagggtgaacctgtccaggacaccagcaagaaccaggtgagcctgt




ccctggtggctgccacagctgctgacagcggcaagtactactgtgccaggaccctgca




cggcaggaggatctacggcatcgtggccttcaacgagtggttcacctacttctacatgg




acgtgtggggcaacgcacccaggtgaccgtgagctccgataagacccacaccgctt




ccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctggggg




cacagcagccctaggctgcctgatcaagaactacttccccaaaccaatgacggtgtc




gtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc




tcagaactctactccctcagcagcatggtgaccgtgccaccagcagataggcaccc




agacctacatagcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaag




ttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactc




ctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc




ccggaacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggt




caagttcaactagtatgttgacggcgtaaaggtgcataataccaaaacaaagccgcgg




gaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag




gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc




cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgta




caccctgcccccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctg




gtaaaagacttctatcccaacgacatcaccatggagtaagagagcaatgggcagccg




gagaacaactacaagaccacgcctcccatgaggactccaacggaccacttcctcta




ctcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctcc




gtgatgcatgaggactgcacaaccactacacgcagaagagcctctccctgtctccgg




gt






Light chain B
tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag
SEQ ID 



aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag
NO: 136



gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga




gaggttcagcggaagccccgacagcccatcggaaccacagccaccctgacc




atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg




acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt




gctggacaaaacccataccgacttcgtgctgacccagagccctcacagcctga




gcgtgacacctggcgagagcgccagcatcagctgcaagagcagccactccct




gatccacggcgaccggaacaactacctggcttggtacgtgcagaagcccggc




agatccccccagctgagatctacctggccagcagcagagccagcggcgtgc




ccgatagattttctggcagcggcagcgacaaggacttcaccctgaagatcagc




cgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag




agcccctggacctttggccagggcaccaaggtggacatcaaggataagaccc




atacccgtacggtggccgctcccagcgtgttcatatcccacctagcgacgagc




agctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac




agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac




gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa




ccggggcgagtgt











Binding Protein 18 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 137



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 138



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh
SEQ ID 



ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi
NO: 139



vafnewftyfymdvwgngtqvtvssdkthtevrlvesggglvkpggslrls




csasgfdfdnawmtwvrqppgkglewvgritgpgegwsvdyaesvkgrf




tisrdntkntlylemnnyrtedtgyyfcartgkyydfwsgyppgeeyfqdw




gqgtlvivssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv




swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk




vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv




vvdvshedpevkfnwyvdgvevhnaktkpreegynstyrvvsvltvlhqd




wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv




slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks




rwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtsdis
NO: 140



vapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgspdsp




fgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaapsvfif




ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys




lsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 18 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctatcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 141



gcccaggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccaccctaggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctagaattctgacgccctgaccagcggcgtgcac




acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt




gcccagcagctctctgggcacccaaacctacatagcaacgtgaaccacaagcccag




caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacacct




gtcccccttgtcctgcccccaaactactaagagacccttccgtgttcctattccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg




gtgtccgtgctgaccatgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctacccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaagtgtgcacactgcccccaagcagggacaagctga




ccaagaaccaggtatccctgaactatgccgtaaaaggcactacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgacagctgctccgtgatgcacgaggccctgcacaaccact




acacccagaagtccagagcctgagccccgacaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt
NO: 142



atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
cagatgcagctgcaggagagcgaccctggactcgtgaagcccagcgagaccctgag
SEQ ID 



cctgacatgcagcgtgagcagcgccagcatcagcgacagctactagagctggatcag
NO: 143



gaggagccctggcaagggcaggaatggatcggctacgtgcacaaaagcggcgac




accaactacagcccctccctgaagtccaggatgaacctatccctggacaccagcaaga




accaggtaagcctgtccctggtggctgccacagctgctgacagcgacaagtactactg




tgccaggaccctgcacgacaggaggatctacggcatcgtggccttcaacgagtggttc




acctacactacatggacgtgtgaggcaacggcacccaggtgaccgtgagctccgaca




aaacccataccgaggttagactggtggagtcaggaggggggcttgtgaagcccggtg




ggtctctccgcctgagctgttctgcctccggctttgatttcgataacgcctggatgacctg




ggtcaggcagcctccaggtaagaaactggagtgaatggaaaaaatcacaagtccag




gcgagggctggtccgtggactacgcggaatctgttaaagggcggtttacaatctcaag




ggacaataccaagaataccttgtatttggagatgaacaacgtgagaactgaagacacc




ggatattacttagtgccagaacaggcaaatactacgacttctggtccagctatccccct




ggcgaggaatattttcaagactggggtcagagaacccttgttatcgtgtcctccaataag




acccacaccgcttccaccaagggcccatcggtcttccccaggcaccctcctccaaga




gcacctagggggcacageggccagggctgcaggtcaaggactacttccccgaac




cggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg




ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc




agcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag




gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcc




cagcacctgaactcctggaaggaccgtcagtatcctatccccccaaaacccaagga




caccctcatgatctcccgaacccctgaggtcacatgcatggtggtgaacatgaaccac




gaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaa




gacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctca




ccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaaca




aagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccga




gaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtc




aacctgtagtgcctggtaaaaggatctatcccagcgacatcgccgtggagtgggaga




acaataggcagccggagaacaactacaagaccacgcacccgtactagactccgac




ggctcatatcactactcaaaactcaccgtgaacaagagcaggtggcagcagggga




acgtatctcatgaccgtgatgcatgaggctctgcacaaccactacacgcagaagagc




ctaccctgtctccgggt






Light chain B
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg
SEQ ID 



actattacttgccgaggcgactcactgcggagccactacgcacctggtatcaga
NO: 144



agaaacccggccaggcacctgtgctgctgttaacggaaagaacaataggcca




tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg




accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg




ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc




gtcctcgacaaaacccatacctccgacatcagcgtggcccccggagagacag




ccaggatacctgcggcgagaagagcagggaagcagggctgtgcagtggta




ccaacacagggccggacaggctcccagcctgatcatctacaacaaccaggac




aggcccagcggcatccctgagaggttcagcggaagccccgacagccccttcg




gaaccacagccaccctgaccatcacaagcgtggaagccggcgacgaggccg




actactactgccacatctgggacagcagggtgcccaccaagtgggtgtttggc




ggcggcaccaccctgaccgtgctggataagacccatacccgtacggtggccg




ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca




gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag




tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga




gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc




agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 19 Amino Acid Sequences









Heavy chain A
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpg
SEQ ID 



egwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgy
NO: 145



ppgeeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepv





tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvd






kkvepkscdkthtcppcpapellggpsvflfppkdtlmisrtpevtcvvvdvshe






dpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckv






snkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiave






wesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnh






ytqkslslspg







Light chain A
aseltqdpavsvalkqtvtitcrgdslrshyaswygkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaaps
NO: 146



vtlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskqsnnky




aassylsltpeqwkshrsyscqvthegstvektvaptecs






Heavy chain B
qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh
SEQ ID 



ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi
NO: 147



vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv




sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti




dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv




dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk




dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn




vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm




isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv




vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf




flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmggrespwtfgqgtkvdikdkth
NO: 148



tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs




pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd




styslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 19 Nucleotide Sequences









Heavy chain A
gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 149



cctccagataagggactagagtgggtgggaagaatcacagatccagacgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttaggtccggctatccccaggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccc




cagcgtgttccactggcccctagcagcaagageacataggcggaacagccgccct




gggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctagaattaggcg




ccctgaccagcggcgtgcacacctttccagctgtgctgcagtccagcggcctgtacag




cctgagcagcgtcgtgacagtgcccagcagctctctgggcacccagacctacatctgc




aacgtgaaccacaageccageaacaccaaggtggacaagaaggtggaacccaaga




gctgcgacaagacccacacctgtcccccttgtcctgcccccgaactgagggaggccc




ttccgtgttcctgttccccccaaagcccaaggacaccctgatgatcaaccggaccccca




aagtgacctgcgtggtggtagatgtgtcccacgaggaccctgaagtgaagttcaattgg




tacgtggacggcgtggaagtgcacaacgccaagaccaagccaagagaggaacagta




caacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaac




ggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaa




accatcagcaaggccaagggccagccccgcgaaccccaggtgtgcacactgccccc




aagcagggacgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggctt




ctacccctccgatatcgccgtagaatgggagagcaacagccagcccgagaacaacta




caagaccaccccccctatgaggacagcgacgactcattatcaggtatccaagaga




cagtggacaagtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacg




aggcccggcacaaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg
SEQ ID 



actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
NO: 150



agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca




tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg




accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg




ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc




gtcctcagtcagcccaaggctgccccctcggtcactctgttcccgccctcgagt




gaggagatcaagccaacaaggccacactggtgtgtctcataagtgacttctac




ccgggagccgtgacagtggcaggaaggcagatagcagccccgtcaaggcg




ggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggcc




agcagctacctgagcctgacgcctgagcagtggaagtcccacagaagctaca




gctgccaggtcacgcatgaagggagcaccgtggagaagacagtggccccta




cagaatgttca






Heavy chain B
cagatgcagctgcaggaganggccctggactcgtgaagcccagcgagaccctgag
SEQ ID 



cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag
NO: 151



gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgac




accaactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaaga




accaggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactg




tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc




acctacttctacatggacatgtagggcaacggcacccaggtaaccgtgagctccgaca




aaacccatacccaaatgcacctaacacagaacggacccgaagtgcggaagcctggc




acctagtgaaggigtcctgcaaggcccctggcaacaccctgaaaacctacgacctgc




actgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccac




gagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgg




gacagaagcaccaacaccgcctacctgcagctgagcggcctgacctctggcgatacc




gccgtgtactactgcgccaagggcagcaagcaccggctgagagactacgccctgtac




gacgatgacggcgccagaactgggccgtagatgtgaactacctgagcaacctggaa




ttctgaggccaggacacaaccatgaccatgtcatctgataaaacccacaccgcttcca




ccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcac




agcggccctgggctgcaggtcaaggactacttccccgaaccggtgacggtgtcgtgg




aactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcaacagtcctcag




gactctactccctcagcgtggtgaccgtgccctccagcagcttgggcacccagac




ctacatagcaacgtaaatcacaagcccagcaacaccaaagtgaacaagaaagttga




gcccaaatatatgacaaaactcacacatgcccaccgtacccaacacctgaactcagg




ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgg




acccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag




ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagg




agcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactg




gctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccat




cgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccc




tgcccccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaa




aggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggaga




acaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctactcaa




aactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat




gcatgaggctctgcacaaccactacacgcagaagagcctaccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga
SEQ ID 



gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa
NO: 152



caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga




tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc




ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac




gtgggcacctactactgtatgcagggcagagagagccectggacctttggcca




gggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgtg




gcccccggagagacagccaggatctcctgcggcgagaagagcctgggaag




cagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgatc




atctacaacaaccaggacaggcccagcggcatccagagaggttcagcggaa




gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgga




agccggcgacgaggccgactactactgccacatctgggacagcagggtgcc




caccaagtgggtgtttggcggcggcaccaccctgaccgtgctggataagaccc




atacccgtacggtggccgctcccagcgtgttcatatcccacctagcgacgagc




agctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac




agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg




agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac




gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa




ccggggcgagtgt











Binding Protein 20 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy
SEQ ID 



gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda
NO: 153



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp




g






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde
NO: 154



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh
SEQ ID 



ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi
NO: 155



vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv




sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti




dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv




dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk




dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn




vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm




isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv




vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf




flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 156



tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs




pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd




styslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 20 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctagtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgactggttccggca
NO: 157



ggcccctggcagaggactggaatgagtgggatagatcaagccccagtatggcacca




tgaacttcagcgaaggcaccaggatagagtgaccctgacccgggacgtgtaccacg




agatcgcctacatggacatccggggectgaagcccgatgacaccgccgtatactacta




cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg




gcacaaccgtagtggtgtctgccgcctctacaaagggccccagcgtgttccactgac




ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg




actactttcccgagcccgtgaccgtgtcctggaattctagcgccctgaccagcggcgtg




cacacctttccagctgtgctgcagtccagcgacctgtacagcctgagcagcatcatga




cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcc




cagcaacaccaaggtagacaagaaggtggaacccaagagctgcgacaagacccac




acctgtcccccttgtcctgcccccgaactgagggaggcccaccgtattcctgttcccc




ccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg




gtggatgtgtcccacgaagaccctgaagtgaagacaattggtacgtggacggcgtgg




aagtgcacaacgccaagaccaagccaagagaggaacagtacaacaacacctaccgg




gtgatgtccatgctgaccatgctgcaccaagactggctgaacggcaaagagtacaagt




gcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggcca




agggccagccccgcgaaccccaggtatgcacactgcccccaagcagggacgagct




gaccaagaaccaggtgtccctgagctgtgccgtaaaaggcttctacccctccgatatcg




ccgtggaatgggagagcaacggccaacccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccg




gtggcagcagggcaacgtgacagctgctccgtgatgcacgaggccctgcacaacca




ctacacccagaagtccctgagcctgagccccggcaag






Light chain A
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID 



agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt
NO: 158



atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag




cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct




tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca




ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg




ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc




acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg




cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt




gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac




actgagcaaggccgactacgagaageacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
cagatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgag
SEQ ID 



cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag
NO: 159



gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgac




accaactacagcccctccctgaagtccagggtgaacctgtccctagacaccaacaaga




accaagtgagcctatccctggtaactaccacagctgctgacaacggcaagtactactg




tgccagaaccctgcacgacaaaaggatctacggcatcgtggccttcaacaagtagttc




acctacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgaca




aaacccatacccaggtgcacctgacacagagcggacccgaagtgcggaagcctggc




acctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgc




actgggtgcgcagcgtgccagaacagggactgcagtggatgggctggatcagccac




gagggcgacaagaaagtgatcgtggaacaattcaaggccaaagtgaccatcgactg




ggacaaaaacaccaacaccgcctacctacaactaagcggcctgacctctggcgatac




cgccgtatactactacgccaaggacaacaagcaccggctgagagactacaccctata




cgacgatgacggcgccctgaactgggccgtggatgtggactacctgagcaacctgga




attctggggccagggcacagccgtgaccgtgtcatctgataagacccacaccgcttcc




accaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggca




cagcgaccctaggctgcctggtcaaggactacttccccgaaccgatgacggtgtcgtg




gaactcaggcgccctgaccagcgacgtgcacaccttcccggctgtcctacagtcctca




ggactctactccctcagcagcgtagtgaccgtgccctccaacaacttgggcacccaga




cctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttga




gcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgg




ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccacatgatctcccgg




acccctgaggtcacatacgtggtgatggacgtgagccacgaagaccagagatcaag




ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggag




gagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggact




ggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagccccca




tcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc




ctgcccccataccgggatgaactaaccaagaatcaagtcagcagtggtgcctgataa




aaggcttctatcccagcaacatcgccgtagagtgggagagcaatgggcaaccggag




aacaactacaagaccacgcctcccatgaggactccaacggctccttcttcctctactca




aaactcaccgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtg




atgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga
SEQ ID 



gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccgga
NO: 160



acaactacctggcttggtacgtgcagaagcccggcagatccccccagctgctg




atctacctggccagcagcagagccagcggcgtgcccgatagattttctggcag




cggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgagga




cgtgggcacctactactgtatgcagggcagagagagcccaggaccatggcc




agggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgt




ggcccccggagagacagccaggatctcctgcggcgagaagagcctgggaa




gcagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgat




catctacaacaaccaggacaggcccagcggcatccctgagaggttcagcgga




agccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgg




aagccggcgacgaggccgactactactgccacatagggacagcagggtgc




ccaccaagtgggtgtttggcggcggcaccaccagaccgtgctggataagacc




catacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgag




cagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccc




cgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaa




cagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct




gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta




cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttca




accggggcgagtgt











Binding Protein 21 Amino Acid Sequences









Heavy chain A
qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe
SEQ ID 



gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd
NO: 161



dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn




hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt




cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl




ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg




fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv




mhealhnhytqkslslspg






Light chain A
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva
NO: 162



apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds




kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID 



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 163



yydfwsgyppgeeyfqdwgqgtlvivssdktht




rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik




pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd




sswaldawgqgttvvvsadkthtastkgpsvfplapsskstsggtaalgclvk




dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn




vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlm




isrtpevtcvvvdvshedpevkfnwyydgvevhnaktkpreeqynstyrv




vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf




flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID 



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtaseltqdpavs
NO: 164



valkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsasgnr




asltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifppsd




eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekkhvyacevthqglsspvtksfnrgec











Binding Protein 21 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 165



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc




agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct




ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga




aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg




cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc




gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca




agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac




ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt




ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt




ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc




gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta




ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta




caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa




ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac




gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg




atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc




ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa




gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca




caaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 166



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg




aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg




acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact




acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg




tgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID 



ctgaactgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaagcag
NO: 167



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccaga




gcccacctggtacaatctggcaccgccatgaagaaaccaggcgcctctgtgcgggtg




tcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggc




ccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaa




cttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagat




cgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcgc




cagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggca




caaccgtggtggtgtctgccgataagacccacaccgcttccaccaagggcccatcggt




cttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctg




cctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctg




accagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcag




cagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtg




aatcacaagcccagcaacaccaaggtggacaagaaagagagcccaaatcttgtgaca




aaactcacacatgcccaccgtgcccagcacctgaactcctaaggggaccgtcagtat




cctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaagtcacat




gcgtggtggtagacgtgagccacgaagaccctgaggtcaagttcaactggtatattga




cggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagc




acgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagg




agtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctc




caaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgccggg




atgaactaaccaagaatcaagtcagcctgtgatgcctaataaaaggcttctatcccagc




aacatcgccgtagagtgggagagcaatggacaaccagagaacaactacaagaccac




gcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtggacaa




gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcac




aaccactacacgcagaagagcctctccctgtctccgggt






Light chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga
SEQ ID 



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 168



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc




tgcaggccgacgacattaccacctactattgtcaaatgctgcagttcttcggcagaagc




agcagactgcacatcaaggacaaaacccataccgcatccgaactgactcaggaccct




gccgtctctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgcg




gagccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttct




acggaaagaacaataggccatctggcatccccgaccgcttttctggcagtgcatcagg




gaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagccgattacta




ttgcagctcccgaaataagagcggctccagactgagcgtgttcggaagagaaactaa




actgaccgtcctcgataagacccatacccgtacggtggccgctcccagcgtgttcatctt




cccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaac




aacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagc




ggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct




gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcct




gcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggc




gagtgt











Binding Protein 22 Amino Acid Sequences









Heavy chain A
qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe
SEQ ID 



gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd
NO: 169



dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn




hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt




cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl




ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg




fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv




mhealhnhytqkslslspg






Light chain A
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva
NO: 170



apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds




kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik
SEQ ID 



pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd
NO: 171



sswaldawgqgttvvvsadkthtevrlvesggglvkpggslrlscsasgfdfd




nawmtwvrqppgkglewvgritgpgegwsvdyaesvkgrftisrdntknt




lylemnnvrtedtgyyfcartgkyydfwsgyppgeeyfqdwgqgtlvivss




dkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts




gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepk




scdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshed




pevkfnwyvdgvevhnaktkpreeqynstytvvsvltvlhqdwlngkey




kckvsnkalpapiektiskakgqprepqvytlppcrdeltknqvslwclvkg




fypsdiavewesngqpennykttppvldsdgsf






Light chain B
aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvl dktht
NO: 172



Yihvtqspsslsvsigdrvtincqtsqtsqgvsdhwyqhkpgrapkllihhtssvedg




vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrasrlhik




dkthtrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgns




qesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 22 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa
SEQ ID 



ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg
NO: 173



cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac




aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc




accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact




actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac




ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc




agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct




ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga




aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg




cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc




gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca




agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac




ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt




ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt




ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc




gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta




ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta




caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa




ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac




gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg




atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc




ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa




gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca




caaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID 



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 174



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg




gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg




gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg




aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg




acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact




acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg




tgaccaagagcttcaaccggggcgagtgt






Heavy chain B
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 175



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg




ccagagacagaagctacggcgacagcagctgaactctagatacttgggaccagggc




acaaccgtgatggtgtctgccgacaaaacccataccgaggttagactggtggagtcag




gaggggggcttgtgaagcccggtgggtactccgcctgagagactgcctccggcttt




gatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggactggagt




gggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcggaatct




gttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttggagatg




aacaacgtgagaactgaagacaccgaatattacttctgtgccagaacaggcaaatacta




cgacttctggtccggctatccccctggcgaggaatattttcaagactggggtcagggaa




cccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatcggtct




tccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcc




tggtcaaggactacttccccgaaccagtgacggtgtcgtggaactcaggcgccctgac




cagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagca




gcgtggtaaccgtaccctccagcagcttgggcacccagacctacatctgcaacgtgaa




tcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaa




actcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcct




cttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc




gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgttgacg




gcgtggaggtgcataatgccaagacaaagccgcgggaggaacagtacaacagcac




gtaccgtatggtcagcgtcctcaccgtcctgcaccaggactggctgaatgacaaggag




tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcca




aagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgccgggat




gagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcccagcga




catcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgc




ctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtggacaaga




gcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaa




ccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg
SEQ ID 



actattacttgccgaggcgactcactgcggagccactacgcttatggtatcaga
NO: 176



agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca




tctggcatccccggccgctttctggcagtgcatcagggaaccgagccagtctg




accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg




ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc




gtcctcgacaaaacccatacctacatccacgtgacccagagccccagcagcct




gtccgtgtccatcggcgacagagtgaccatcaactgccagacctctcagggcg




tgggcagcgacctgcactggtatcagcacaagcctggcagagcccccaagct




gctgatccaccacacaagcagcgtggaagatggcgtgcccagcagattttccg




gcagcggcttccacaccagcttcaacctgaccatcagcgatctgcaggccgac




gacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagaga




ctgcacatcaaggataagacccatacccgtacggtggccgctcccagcgtgtt




catcttcccacctagcgacgagcagctgaagtccggcacagcctagtcgtgtg




cctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggac




aacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacag




caaggactccacctacagcctgagcagcaccctgacactgagcaaggccgac




tacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtcta




gccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 23 Amino Acid Sequences









Heavy chain A
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpg
SEQ ID 



egwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgy
NO: 177



ppgeeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepv




tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsnkvd




kkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshe




dpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckv




snkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiave




wesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnh




ytqkslslspg






Light chain A
Aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
SEQ ID 



pdrfsgsasgnrasltitaaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaap
NO: 178



svtlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskgsnnk




yaassylsltpeqwkshrsyscqvthegstvektvaptecs






Heavy chain B
rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik
SEQ ID 



pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd
NO: 179



sswaldawgqgttvvvsadkthtQvhltqsgpevrkpgtsvkvsckapgnt




lktydlhwvrsvpgqglqwmgwishegdkkviverfkakvtidwdrstnt




aylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdvdylsnlef




wgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepv




tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsn




tkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt




cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlh




qdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltkn




qvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvd




ksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID 



asgvpdrfsgsgsdkdflkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 180



t




yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv




psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifp




psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls




stltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 23 Nucleotide Sequences









Heavy chain A
gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc
SEQ ID 



ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 181



cctccagataagggactagagtgggtgggaagaatcacagatccagacgagggctg




gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttaggtccggctatccccaggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccc




cagcgtgttccactggcccctagcagcaagageacataggcggaacagccgccct




gggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctagaattaggcg




ccctgaccagcggcgtgcacacctttccagctgtgctgcagtccagcggcctgtacag




cctgagcagcgtcgtgacagtgcccagcagctctctgggcacccagacctacatctgc




aacgtgaaccacaageccageaacaccaaggtggacaagaaggtggaacccaaga




gctgcgacaagacccacacctgtcccccttgtcctgcccccgaactgagggaggccc




ttccgtgttcctgttccccccaaagcccaaggacaccctgatgatcaaccggaccccca




aagtgacctgcgtggtggtagatgtgtcccacgaggaccctgaagtgaagttcaattgg




tacgtggacggcgtggaagtgcacaacgccaagaccaagccaagagaggaacagta




caacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaac




ggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaa




accatcagcaaggccaagggccagccccgcgaaccccaggtgtgcacactgccccc




aagcagggacgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggctt




ctacccctccgatatcgccgtagaatgggagagcaacagccagcccgagaacaacta




caagaccaccccccctatgaggacagcgacgactcattatcaggtatccaagaga




cagtggacaagtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacg




aggcccggcacaaccactacacccagaagtccctgagcctgagccccggcaag






Light chain A
gcatccgaactgactcaggaccctgccgtetctgtggcactgaagcagactgtg
SEQ ID 



actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
NO: 182



agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca




tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg




accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg




ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc




gtcctcagtcagcccaaggctgccccctcggtcactctgttcccgccctcgagt




gaggagatcaagccaacaaggccacactggtgtgtctcataagtgacttctac




ccgggagccgtgacagtggcaggaaggcagatagcagccccgtcaaggcg




ggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggcc




agcagctacctgagcctgacgcctgagcagtggaagtcccacagaagctaca




gctgccaggtcacgcatgaagggagcaccgtggagaagacagtggccccta




cagaatgttca






Heavy chain B
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID 



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag
NO: 183



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcgcctacatagacatccggggcctgaagcccgatgacaccgccgtgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatacttggggccagggc




acaaccgtggtggtgtctgccgacaaaacccatacccaggtgcacctgacacagagc




ggacccgaagtgcggaagcctggcacctctgtgaaggtgtcctgcaaggcccctggc




aacaccctgaaaacctacgacctgcactgggtgcgcagcgtgccaggacagggactg




cagtggatgggctggatcagccacgagggcgacaagaaagtgatcgtggaacggttc




aaggccaaagtgaccatcgactgggacagaagcaccaacaccgcctacctgcagctg




agcggcctgacctctggcgataccgccgtgtactactgcgccaagggcagcaagcac




cggctgagagaetacgccctgtacgacgatgacggcgccctgaactgggccgtggat




gtggactacctgagcaacctggaattctggggccagggcacagccgtgaccgtgtcat




ctgataagacccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcc




tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttcc




ccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacct




tcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccct




ccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaaca




ccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccacc




gtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccca




aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgag




ccacgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatg




ccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtc




ctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctcca




acaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccc




cgagaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaa




gtcagcctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggg




agagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactcc




gacggctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcagg




ggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaag




agcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga
SEQ ID 



gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa
NO: 184



caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga




tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc




ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac




gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca




gggcaccaaggtggacatcaaggacaaaacccatacctacatccacgtgacc




cagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaactg




ccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagcct




ggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggc




gtgcccagcagattaccggcagcggcttccacaccagcttcaacctgaccatc




agcgatctgcaggccgacgacattgccacctactattgtcaggtgctgcagttct




tcggcagaggcagcagactgcacatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccg




gcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa




gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag




cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctg




acactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga




cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtg




t











Binding Protein 24 Amino Acid Sequences









Heavy chain A
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpge
SEQ ID 



gwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgypp
NO: 185



geeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvs




wnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkve




pkscdkthtcppcpapellggpsvflfppkdtlmisrtpevtcvvvdvshedpev




kfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkal




papiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngq




pennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslsls




pg






Light chain A
aseltqdpavsvalkqtvtitcrgdslrshyaswygkkpgqapvllfygknnrpsgip
SEQ ID 



drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaapsv
NO: 186



tlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskqsnnkya




assylsltpeqwkshrsyscqvthegstvektvaptecs






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg
SEQ ID



wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskh
NO: 187



rlrdyalydddgalnwavdvdylsnlefwgqgtavtvss




dkthtrahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewv




gwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrs




ygdsswaldawgqgttvvvsadkthlastkgpsvfplapsskstsggtaalgc




lvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtl




misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr




vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl




yskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain B
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtdfvltqsphsls
NO: 188



vtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgvpdrfsgsg




sdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtvaapsvfifpp




sdeqlksgasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst




ltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 24 Nucleotide Sequences









Heavy chain A
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcc
SEQ ID



tgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcagcc
NO: 189



tccagataagggactggaatgggtgggaagaatcacagatccaagcgagggctggtc




cgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaataccaaga




ataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgc




cagaacaggcaaatactacgacactggtccggctatccccctggcgaggaatattttca




agactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccccagcg




tgttccctctggcccctagcagcaagagcacataggcggaacagccgccctgggctg




cctcgtgaaggactactttcccgagcccgtgaccgtgtcaggaattaggcgccagac




cagcggcgtgcacacctttccagagtactacaatccagcggcctatacaacctgagca




gcgtcgtgacagtgcccagcagctactgggcacccagacctacatagcaacgtgaac




cacaagcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaa




gacccacacctgtcccccagtcctgcccccgaactgctgggaggcccttccgtgacct




gttccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgc




gtggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacgg




cgtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta




ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtac




aagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg




ccaagggccagecccgcgaaccccaggtgtgcacactgcccccaagcagggacgag




ctgaccaagaaccaggtgtccctgagagtgccgtgaaaggatctacccaccgatatc




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccc




tgtgctggacagcgacggctcattcttcctgatgtccaagctgacagtagacaaatccca




gtggcagcagggcaacgtgttcagctgaccgtgatgcacgaggccctgcacaaccac




tacacccagaagtccctgagcctgagccccggcaag






Light chain A
gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg
SEQ ID



actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
NO: 190



agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccat




ctggcatccccgaccgcattctggcagtgcatcagggaaccgagccagtctga




ccattaccggcgcccaggctgaggacgaagccgattactattgcagctcccgg




gataagagcggctccagactgagcgtgttcggaggaggaactaaactgaccgt




cctcagtcagcccaaggctgccccctcggtcactagttcccgccctcgagtgag




gagcttcaagccaacaaggccacactggtgtgtctcataagtgacttctacccgg




gagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagt




ggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagc




tacctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgcca




ggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgtt




ca






Heavy chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga
SEQ ID



ccatcaactgccagacctacagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 191



gcctggcagagcccccaagagagatccaccacacaagcagcgtggaagatggcgt




gcccagcagattaccggcagcagatccacaccagatcaacctgaccatcagcgatct




gcaggccgacgacattaccacctactattgtcaggtgctgcagttctteggcagaggca




gcagactgcacatcaaggacaaaacccataccgacttcgtgctgacccagagccctca




cagcctgagcgtgacacctggcgagagcgccagcatcagagcaagagcagccactc




cctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagcccggcaga




tccccccagctgctgatctacctggccagcagcagagccagcggcgtgcccgatagatt




ttctggcagcagcagcgacaaggacttcaccctgaagatcagccgggtggaaaccga




ggacgtgggcacctactactgtatgcagggcagagagagcccaggacctaggccag




ggcaccaaggtggacatcaaggataagacccatacccgtacggtggccgctcccagc




gtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgc




ctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccc




tgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacc




tacagcctgagcagcaccagacactgagcaaggccgactacgagaagcacaaggtg




tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagatcaacc




ggggcgagtgt






Light chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag
SEQ ID



agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt
NO: 192



atcagcacaagcctggcagagcccccaagctgagatccaccacacaagcagc




gtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagcttc




aacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtcagg




tgctgcagttcttcggcagaggcagcagactgcacatcaaggacaaaacccata




ccgacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgag




agcgccagcatcagctgcaagagcagccactccctgatccacggcgaccgga




acaactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga




tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagcg




gcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggacgt




gggcacctactactgtatgcagggcagagagagcccctggacctttggccagg




gcaccaaggtggacatcaaggataagacccatacccgtacggtggccgctccc




agcgtgttcatcttccacctagcgacgagcagctgaagtccggcacagcact




gtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaag




gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag




gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaagg




ccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct




gtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 25 Amino Acid Sequences









Heavy chain A
qvqlvqsggqmkkpgesmriscrasgyeficustom-character wirlapgkrpewmgcustom-character
SEQ ID




custom-character rvtmtrdvysdtaflelrsltvddtavyfctrcustom-character wgr

NO: 193



gtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvh




tfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcp




pcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgve




vhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskak




gqprepqvctlppsrdeltknqvslscavkgfypsdiavewesgqpennykttppv




ldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain A
eivltqspgtlslspgetaiisccustom-character awyqqrpgqaprlviycustom-character gipdrfs
SEQ ID



gsrwvgpdynltisnlesgdfgvyycustom-character fgqgtkvqvdikrtvaapsvfifppsde
NO: 194



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls




kadyekhkvyacevthqglsspvcksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgrit
SEQ ID



gpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyy
NO: 195



dfwsgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgtslrls




caasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwgrftisr




dnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkqlpcaks




rgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyic




nvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvtlfppkpkdtl




misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr




vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp




crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl




yskltvdksrwqqgnvfscsvlhealhshylqkslslspg






Light chain B
qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgi
SEQ ID



pdrfsasksgtsgtlaitgtqtgdeadyycatwaaslssarvfgtgtkvivldkthtaselt
NO: 196



gdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsg




sasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif




ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl




sstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 25 Nucleotide Sequences









Heavy chain A
cagatgcagctggtgcagtctggcggccagataaaaaaacccagcgagaacatgcgg
SEQ ID



atcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagact
NO: 197



ggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgt




gaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgat




accgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacc




cggggcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccct




gtgatcgtatcaagcgcgtcgaccaagggccccagcgtgttccactaacccctagcaa




caagagcacataggcagaacaaccaccctaggctgcctcgtgaaggactactttcccg




agcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcacaccatcca




gctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagtgcccagca




gctactaggcacccagacctacatagcaacgtgaaccacaagcccagcaacaccaa




ggtggacaagaaggtggaacccaagagagcgacaagacccacacagtcccccttgt




cctgcccccgaactgagggaggcccttccgtgacctgttccccccaaagcccaagga




caccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacg




aggaccctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaa




gaccaagccaagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgac




cgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaag




gccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaa




ccccaggtgtacacactgcccccaaacagggacgaactaaccaagaaccaaatgtcc




ctgagctgtgccgtgaaaggcttctacccctccgatatcgccgtggaatgggagagcaa




cggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctc




attcttcctggtgtccaagctgacagtggacaagtcccggtggcagcagggcaacgtgtt




cagctgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccc




tgtctccgggt






Light chain A
Gagatcgtgctgacacagagccaggcaccctgagcctgtctccaggegagacagcc
SEQ ID



atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctg
NO: 198



gacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccg




atagattcagcggctccagatggaaccctaactacaacctgaccatcagcaacctgaaa




agcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggcaccaa




ggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag




cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccc




ccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagcc




aggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcacc




ctgacactgagcaagaccgactacgagaaacacaaggtgtacgcctacgaagtgacc




caccagggcctatctagccccgtgaccaagagcttcaaccagggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcct
SEQ ID



gagctgactgcctccggattgatacgataacgcctggatgacctgggtcaggcagcct
NO: 199



ccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctggtcc




gtggactacgcggaatctgtaaagggcggnacaatctcaagggacaataccaagaat




accttgtatttgaagatgaacaacgtaagaactgaagacaccagatattacttctatgcca




gaacagacaaatactacgacttctggtccagctatccccctggcgaggaatattttcaaa




actggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccaggtgcagt




tggtggagtctgggggaggcgtggtccagcctgggacgtccctgagactctcctgtgca




gcactcaattcaggtttgatggttatggcatgcactgggtccgccaggccccaggcaag




gggctggagtgggtggcatctatatcacatgatggaattaaaaagtatcacgcagaaaaa




gtgtggggccgcttcaccataccagagacaattccaagaacacactgtatctacaaatg




aacagcctgcgacctgaggacacggctctctactactgtgcgaaagatttgcgagaaga




cgaatgtgaagagtggtggtcggattattacgattttgggaaacaactcccttgcgcaaag




tcacgcggcggcttggttggaattgctgataactggggccaagggacaatggtcaccgt




ctcttcagataagacccacaccgcttccaccaagggcccatcggtcttccccctggcacc




ctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactac




ttccccgaaccggtgacggtgtcgtggaactcaggcgccagaccagcggcgtgcaca




ccttcccagagtcctacagtcctcaggactctactccctcagcagcgtagtgaccatgc




cctccagcagatggacacccagacctacatagcaacgtgaatcacaagcccagcaac




accaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccacc




gtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaa




ggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc




acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgcc




aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctc




accgtcagcaccaggactggctgaatgacaaggagtacaagtacaaggtaccaaca




aagccacccaacccccatcgagaaaaccatctccaaagccaaagagcaaccccgag




aaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagca




atgggcagccggagaacaactacaagaccacgcctcccgtgaggactccgacggctc




cttcttcactactcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtat




ctcatgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccct




ataccgggt






Light chain B
cagtctgtgctgacgcagccgccctcagtgtctgcsgccccaggacagaaggt
SEQ ID



caccatctcctgactggaaacacctccaacattggcaataattttgtgtcctggtat
NO: 200



caacagcgccccggcagagccccccaactcctcatttatgaaactgacaagcga




ccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggcaccct




ggccatcaccgggctgcagactggggacgaggccgattattactgcgccacat




gggctgccagectgagaccgcgcgtgtcttcggaactgggaccaaggtcatcg




tcctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt




ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcca




ctacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttctac




ggaaagaacaataggccatctggcatccccgaccgcttttctggcagtgcatcag




ggaaccgagccagtctgaccattaccggcgcccaggctgctggacgaagccga




ttactattgcagctcccgggataagagcggctccagactgagcgtgttcggagg




aggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgctcc




cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctct




gtcgtgtgcctgagaacaacttctacccccgcgaggccaaagtgcagtggaag




gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag




gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaagg




ccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct




gtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 26 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character lfwfrqapgrglewvgwcustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character wg

NO: 201



qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv




htfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtc




ppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgv




evhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiska




kgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpennykttpp




vldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtscustom-character lhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgfcustom-character fnltisdlqaddiatyyccustom-character rgsrlhikrtvaapsvfifppsdeql
NO: 202



ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlska




dyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgrit
SEQ ID



gpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyy
NO: 203



dfwsgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgtslrls





caasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwgrftisr






dnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkqlpcaks






rgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsggtaalgcl






vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyic






nvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvtlfppkpkdtl






misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr






vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp






crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl






yskltvdksrwqqgnvfscsvlhealhshylqkslslspg







Light chain B
qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgi
SEQ ID



pdrfsasksgtsgtlaitgtqtgdeadyycatwaaslssarvfgtgtkvivldkthtaselt
NO: 204



gdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsg




sasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif




ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl




sstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 26 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctagtgcggg
SEQ ID



tgtcctgtcagacaagcggctacaccttcaccgcccacatcctgactggaccggcagg
NO: 205



cccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaa




cttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatc




gcctacatagacatccggggcctaaaacccgatgacaccaccatgtactactgcgcca




gagacagaagctacggcgacagcagctgaactctagatacttgggaccagggcacaa




ccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccctagca




gcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggactactttccc




gagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcacacctttcc




agctgtgctgcagtccagcggcctgtacaacctgagcagcgtcgtgacgtgcccagc




agctctctggacacccagacctacatctgcaacgtgaaccacaagcccagcaacacca




aggtggacaagaaggtggaacccaagagctgcgacaagacccacacctgtcccccttg




tcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaaagcccaaaga




caccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacg




aggaccctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaa




gaccaagccaagagaggaacagtacaacagcacctaccgggtggtatccgtgctgac




cgtactacaccaggactagctgaacggcaaagagtacaagtgcaagatgtccaacaag




gccagcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaa




ccccaggtgtgcacactgcccccaagcagggacgagatgaccaagaaccaggtatcc




ctgagctgtgccgtgaaaggcttctacccaccgatatcgccgtggaatgggagagcaa




cggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctc




attcttcctgatgtccaagctaacagtagacaaatcccagtggcagcagggcaacatgtt




cagctgctccgtgctgcatgaagctctacacagccactacacgcagaagagcctctccc




tgtctccgggt






Light chain A
tacatccacatgacccaaagccccaacagcctgtccatgtccatcggcaacagagtga
SEQ ID



ccatcaactgccaaacactcaggacgtaggcagcaacctacactgatatcagcacaa
NO: 206



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtgaaaaatgacgt




gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatct




gcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcag




cagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcacccacctagcga




cgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccg




cgaggccaaagtacagtggaagatggacaacaccctacagagcggcaacagccagg




aaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctga




cactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc




agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcct
SEQ ID



gagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcagcct
NO: 207



ccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctggtcc




gtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaataccaagaat




accttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgcca




gaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatattttcaag




actggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccaggtgcagt




tggtggagtctgggggaggcgtggtccagcctgggacgtccctgagactctcctgtgca




gcctctcaattcaggtttgatggttatggcatgcactgggtccgccaggccccaggcaag




gggctggagtgggtggcatctatatatcatgatggaattaaattagtatcacgcagaaaaa




gtgtggggccgcttcaccatctccagagacaattccaagaacacactgtatctacaaatg




aacagcctgcgacctgaggacacggctctctactactgtgcgaaagatttgcgagaaga




cgaatgtgaagagtggtggtcggattattacgattttgggaaacaactcccttgcgcaaag




tcacgcggcggcttggttggaattgctgataactggggccaagggacaatggtcaccgt




ctcttcagataagacccacaccgcttccaccaagggcccatcggtcttccccctggcacc




ctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcattggactac




ttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcaca




ccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgc




cctccagcagcttgggcacccagacctacatctgcaacgtgaattacaagcccagcaac




accaaggtggacaagaaagttgagcccaaatcttgtgacaaaacicacacatgcccacc




gtgcccagcacctgaactcctggggggaccgtcttgtcttcctcttccccccaaaacccaa




ggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc




acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgcc




aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctc




accgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaaca




aagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag




aaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag




cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagca




atgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctc




cttcttcctccactcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtctt




ctcatgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccct




gtctccgggt






Light chain B
cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccat
SEQ ID



ctcctgactggaaacacctccaacattggcaataattagtgtcctggtatcaacagcgcc
NO: 208



ccggcagagccccccaactcctcatttataaaactgacaagcgaccctcagggattcctg




accgattctctgcttccaagtctggtacgtcaggcaccctggccatcaccgggctgcaga




ctggggacgaggccgattattactgcgccacatgggctgccagcctgagttccgcgcgt




gtcttcggaactgggaccaaggtcatcgtcctggacaaaacccataccgcatccgaact




gactcaggaccctgccgtactgtggcactgaagcagactgtgactattacttgccgagg




cgactcactgcggagccactacgcttcaggtatcagaagaaacccggccaggcacct




gtgctgagttctacggaaagaacaataggccataggcatccccgaccaatttaggca




gtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaag




ccgattactattgcagctcccgggataagagcggctccagactgagcgtgttcggagga




ggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgctcccagcgt




gttcatatcccacctagcgacgagcagctgaagtccggcacagcctagtcgtgtgcct




gctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctg




cagagcggcaacaaccaggaaagcgtgaccgagcaggacagcaaggactccaccta




cagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta




cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccgg




ggcgagtgt











Binding Protein 27 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character lfwfrqapgrglewvgwcustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character wg

NO: 209



qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv




htfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtc




ppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgv




evhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiska




kgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpennykttpp




vldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeq
NO: 210



lksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlsk




adyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri
SEQ ID



tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgky
NO: 211



ydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsvk




vsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti




dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdvd




ylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvkdy




fpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnh




kpsntkvdkkvepkscdkthtcppcpapellggpsvilfppkpkdtlmisrtp




evtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltv




lhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltk




nqvslwclvkgfypsdiavevvesngqpennykttppvldsdgsfllyskltv




dksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassra
SEQ ID



sgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkthta
NO: 212



seltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr




fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdst




yslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 27 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID



gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag
NO: 213



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgt




gaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcga




gatcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgc




gccagagacagaagctacggcgacagcagctgggctctggatgcttggggccaggg




cacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggccc




ctagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgca




cacctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgaca




atgcccagcagctactgggcacccagacctacatctacaacatgaaccacaaaccca




gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac




ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc




aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt




ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccaggt




ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg




caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa




gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg




accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc




cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg




tgctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccga




tggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga
SEQ ID



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 214



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgatc




tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc




agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag




cgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag




ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca




ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga




cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID



ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 215



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca




agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg




tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc




gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga




aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca




acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg




cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg




ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg




gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatc




ggtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgaa




ctgcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgcc




ctgaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccct




cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac




gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg




acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag




tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt




gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc




agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga




ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 216



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcagg




gcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg




gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt




ccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaagt




gcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 28 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character lfwfrqapgrglewvgwcustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character

NO: 217



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde
NO: 218



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgky
NO: 219



ydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv




kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak




vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav




dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt




lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty




rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp




pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs




fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID



asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 220



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 28 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID



gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca
NO: 221



ggcccctcgcagaggactggaatgggtggatggatcaagccccagtatggcgccg




tgaacttcagcggaggcaccaggatagagtaaccagacccgggacgtgtaccacg




agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg




cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg




gcacaaccgtggtggtgtagccgcctctacaaagggccccagcgtgttccactggc




ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtggagg




actactttcccgagcccatgaccatgtcctggaattaggcaccctgaccagcggcgtg




cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga




cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc




ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca




cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc




cccaaagcccaaagacaccctgatgatcagccggacccccgaagtaacctacgtggt




ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacgacgtg




gaagtgcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctacc




gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca




agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg




ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga




gctgaccaagaaccaggtatccctgaactatgccgtgaaaggcttctacccctccgata




tcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc




cctgtgctggacaacgacggctcattcttcctagtgtccaaactgacagtggacaagtc




ccggtggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacag




ccactacacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtg
SEQ ID



accatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcac
NO: 222



aagcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagaagg




cgtgcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagc




aatctgcaggccgacgacattgccacctactattgtcaggtactgcagttcttcggcaaa




ggcagcagactgcacatcaagcgtacaatggccgctcccagcgtgttcatcttcccac




ctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaactt




ctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc




aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga




gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc




gaagtgacccaccagagcctgtctagccccgtaaccaagaacttcaaccggagcga




gtgt






Heavy chain B
gaggttagactggtggaatcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID



ctgagctgttctgcaccagctttgatttcgataacgcctggatgacctgggtcagacaa
NO: 223



cctccaggtaagggactaaagtgggtaggaagaatcacaggtccaggcgaaggctg




gtccatggactacacggaatctgttaaagggcggtttacaatctcaaaggacaatacca




agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcgaaaacctggcacctagtgaaggt




gtcctgcaagacccaggcaacaccctgaaaacctacgacctgcactggatgcgcag




cgtaccaggacaaggactgcaatggatgggctgaatcagccacgagggcgacaag




aaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacc




aacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactact




gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacgg




cgccctgaactgagccgtggatgtggactacctgagcaacctggaattaggggccag




ggcacagccatgaccgtgtcatctgataagacccacaccgcttccaccaagggcccat




cggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgg




gctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc




cctgaccagcggcgtgcacaccttcccggagtcctacagtcctcaggactctactccc




tcagcagcgtagtgaccgtgccctccaacagcttgggcacccagacctacatctgcaa




cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt




gacaaaactcacacatgcccaccgtgcccagcacctaaactcctggggaaaccgtca




gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt




cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat




gttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa




cagcacgtaccgtgtggtcaacgtcctcaccgtcctgcaccaggactggctgaatgac




aaggaatacaagtacaaggtaccaacaaagccctcccagcccccatcgagaaaacc




atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctacccccatgc




cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc




cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag




accacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtg




gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctc




tgcacagccactacacgcagaagagcctaccagtctccggat






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 224



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcdgcccgatagatataggcagcggcagcgacaaggacttca




ccctgaagatcagccgaatggaaaccaaggacatgggcacctactactgtatacagg




gcagagagagcccaggacctttggccagggcaccaaggtggacatcaaggacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccaaccgcttttctggcaatgcatcagagaaccaagccagtctgaccattaccg




gcacccaagagaggacaaaaccaattactattacaactcccgggataagagcgact




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaag




tccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt




gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcggacc




gagcaagacagcaaggactccacctacagcctgaacaacaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 29 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character lfwfrqapgrglewvgwcustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character

NO: 225



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedav
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde
NO: 226



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 227



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv




kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak




vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav




dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt




lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty




rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp




pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs




fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID



asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 228



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 29 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID



gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag
NO: 229



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgcac




acctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgacagt




gcccagcagctactgggcacccagacctacatctacaacatgaaccacaaacccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga
SEQ ID



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 230



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgatc




tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc




agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag




cgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag




ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca




ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga




cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID



ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 231



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca




agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg




tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc




gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga




aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca




acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg




cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg




ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg




cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatcg




gtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgggct




gcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgccct




gaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccctca




gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt




gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga




caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt




cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt




gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc




agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga




ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc
SEQ ID



agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg
NO: 301



gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca




gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca




ccctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcagg




gcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaaa




acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga




ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga




agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg




catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg




gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct




ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac




ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt




ccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaagt




gcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtgacc




gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa




ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt




ctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 30 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character lfwfrqapgrglewvgwicustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character

NO: 232



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedav
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde
NO: 233



qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 234



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv




kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak




vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav




dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt




lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty




rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp




pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs




fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID



asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 235



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 30 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID



gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag
NO: 236



gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg




aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag




atcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg




ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc




acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc




tagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgcac




acctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgacagt




gcccagcagctactgggcacccagacctacatctacaacatgaaccacaaacccag




caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct




gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa




agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg




atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt




gcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccgggtg




gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc




aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga




ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc




gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt




gctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt




ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact




acacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga
SEQ ID



ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa
NO: 237



gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgat




ctgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagg




cagcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccaccta




gcgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctac




ccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaaca




gccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcag




caccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt




gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID



ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 238



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca




agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg




tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc




gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga




aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca




acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg




cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg




ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg




cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatcg




gtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgggct




gcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgccct




gaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccctca




gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt




gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga




caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt




cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca




catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt




gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca




gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa




ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat




ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc




gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc




agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga




ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg




acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct




gcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgc
SEQ ID



cagcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacct
NO: 239



ggcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagc




agcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttc




accctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcag




ggcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaa




aacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcag




actgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcag




aagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctg




gcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattacc




ggcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggc




tccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccata




cccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaa




gtccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaa




gtgcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtga




ccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagc




aaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct




gtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 31 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtscustom-character ilfwfrqapgrglewvgwcustom-character
SEQ ID




custom-character nfgggfrdrvtltrdvyreiaymdirglkpddtavyycarcustom-character

NO: 240



wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal




tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd




kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw




yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi




ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg






Light chain A
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssveda
SEQ ID



vpsrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsd
NO: 241



eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr
SEQ ID



itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk
NO: 242



yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv




kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak




vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav




dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl




vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi




cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt




lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty




rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp




pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs




fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg






Light chain B
dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr
SEQ ID



asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth
NO: 243



taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi




pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq




dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 31 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg
SEQ ID



gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggca
NO: 244



ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg




tgaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcg




agatcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactg




cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg




gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc




ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg




actactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtg




cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga




cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc




ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca




cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt




ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtg




gaagtgcacaacgccaagaccaagccaagagaaaaacagtacaacagcacctacc




gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca




agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg




ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga




gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgata




tcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc




cctgtgctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtc




ccggtggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacag




ccactacacccagaagtccctgagcctgagccccggc






Light chain A
tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacagagtg
SEQ ID



accatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcac
NO: 245



aagcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatgc




cgtgcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagc




gatctgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcaga




ggcagcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccac




ctagcgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaactt




ctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc




aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga




gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc




gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc
SEQ ID



ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag
NO: 246



cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg




gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca




agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct




gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat




tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag




gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt




gtcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcag




cgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaag




aaagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacc




aacaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactact




gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacgg




cgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccag




ggcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccat




cggtcttccccctggcaccctcctccaagagcacctctgggggcacaacggccctgg




gctgcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcaggcgc




cctgaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccc




tcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa




cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt




gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca




gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt




cacatgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtat




gttgacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaa




cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc




aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc




atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc




cgggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatcc




cagcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaag




accacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtg




gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctc




tgcacagccactacacgcagaagagcctctccctgtctccgggt






Light chain B
Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgc
SEQ ID



cagcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacct
NO: 247



ggcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagc




agcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttc




accctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcag




ggcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaa




aacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcag




actgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcag




aagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctg




gcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattacc




ggcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcgg




ctccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccat




acccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctga




agtccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaa




agtgcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtg




accgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag




caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcc




tgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 32 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyq
SEQ ID



avnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldawg
NO: 302



qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv




htfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcpp




cpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvev




hnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakg




qprepqvytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttpp




vldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
SEQ ID



psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeq
NO: 303



lksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlsk




adyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvqsgaevvkpgasvkvsckascustom-character ihwvrqapgqglewigscustom-character
SEQ ID




custom-character nyaqkfqgratltvdtsistaymelsrlrsddtavyyccustom-character

NO: 304




custom-character wgkgttvlvsssqvqlvesgggvvqpgrslrlscaascustom-character mhw





vrqapgkqlewvaqcustom-character yatyyadsvkgrftisrddskntlylqmmslr




aedtavyycustom-character wgqgtlvtvssrtastkgpsvfplapcsrstses




taalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpsssl




gtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkp




kdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfns




tyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctl




ppsqeemtknqvslscavkgfypsdiavewesngqpennykttppvldsd




gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasiscksscustom-character lswylqkpgqspgsliycustom-character
SEQ ID



nrfsgvpdrfsgsgsgtdftlkisrveaedvgvyyccustom-character ftfgsgtkveikgqpk
NO: 305



aapdiqmtqspsslsasvgdrvtitcqascustom-character lnwyqqkpgkapklliykasnl




htgvpsrfsgsgsgtdftltisslqpediatyyccustom-character fgqgtkleiktkpsrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd




skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 32 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc
NO: 306



cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggcttccgggatagaatgaccctgacccaggacgtgtaccgcgagatcgcc




tacatggacatccggggcctgaagcccgatgacaccgccatgtactactgcgccagaga




cagaagctacggcgacagcagctgggctctggatgcttggggccagggcacaaccgtg




gtggtgtctgccgcctctacaaagggcccctcggtgaccctctggccccttgcagcagaa




gcaccagcgaatctacagccgccctgggctgcctcgtgaaggactacatcccgagcccg




tgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgct




ccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgg




gcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaa




gcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatactgggc




ggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacc




cccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaat




tggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagt




tcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacg




gcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacc




atcagcaaggccaagggccagccccgcgagcctcaagtgtataccagcccccttgcca




ggaagagatgaccaagaaccaggtgtccagtagtgtacgtgaaaggcactaccccag




cgacattaccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc




ccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaaga




gccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaac




cactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
Tacatccacgtgacccaaagccccaacaacctgtccatgtccatcggcaacagaatgac
SEQ ID



catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc
NO: 307



ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc




cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag




gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagcagcagac




tgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc




agctgaagtccggcacagcctctgtcgtgtgcctgctgattcaacttctacccccgcgagg




ccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg




tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag




caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcag




tctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 308



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagaccagggcagagccaccctgaccgtgaacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagaggtggaataggcggcggagtggtgcagcaggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccaggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctatacctgcagatgaacagcctacgggccgaggacaccacca




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgactgacaagcggcgtgcaca




cctttccagccatgaccagagcagcagcctgtactactgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctataacatggaccacaaacccaacaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggctgtggaagtgcacaacgccaagaccaagcc




cagagaagaacagttcaacagcacctaccaggtgatgtccatgctgaccatgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgaggacagcgacggctcattcttcctggtgtccaa




gctgaccgtggacaagagccagtgacaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtactgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct
NO: 309



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag




atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta




ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag




tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga




agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt




gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg




cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt




ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct




cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc




gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa




cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc




cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag




gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac




cggggcgagtgt











Binding Protein 33 Amino Acid Sequences









Heavy chain A
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyga
SEQ ID



vnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldawgqg
NO: 310



ttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfp




avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape




flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk




preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv




ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff




lyskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeqlks
NO: 311



gtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadye




khkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa
SEQ ID



gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm
NO: 312



dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq




apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt




avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt




cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis




rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt




vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt




knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv




dksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 313



pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv




esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt




vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd




skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 33 Nucleotide Sequences









Heavy chain A
agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc
NO: 314



cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggcttccgggatagaatgaccctgacccaggacgtgtaccgcgagatcgcc




tacatggacatccggggcctgaagcccgatgacaccgccatgtactactgcgccagaga




cagaagctacggcgacagcagctgggctctggatgcttggggccagggcacaaccgtg




gtggtgtctgccgcctctacaaagggcccctcggtgaccctctggccccttgcagcagaa




gcaccagcgaatctacagccgccctgggctgcctcgtgaaggactacatcccgagcccg




tgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgct




ccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgg




gcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaa




gcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatactgggc




ggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacc




cccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaat




tggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagt




tcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacg




gcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacc




atcagcaaggccaagggccagccccgcgagcctcaagtgtataccagcccccttgcca




ggaagagatgaccaagaaccaggtgtccagtagtgtacgtgaaaggcactaccccag




cgacattaccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc




ccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaaga




gccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaac




cactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
Tacatccacgtgacccaaagccccaacaacctgtccatgtccatcggcaacagaatgac
SEQ ID



catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc
NO: 315



ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc




cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag




gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagcagcagac




tgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc




agctgaagtccggcacagcctctgtcgtgtgcctgctgattcaacttctacccccgcgagg




ccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg




tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag




caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcag




tctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 316



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgcttcgaccaagggcccatcggtgttccctctggcc




ccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacac




ctttccagccatgctccagagcagcagcctgtactctctgagcaacgtcgtaacagtgccc




agcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaaca




ccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagccc




ctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgat




gatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccg




aggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagccc




agagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacca




ggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagc




tccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtac




cctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtga




aaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaa




caactacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaag




ctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgca




cgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 317



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaag




atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta




ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




cccgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggc




caccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtg




gtatcagcagaagcccggccagccccccaagctgctgattttcgccgccagcaacgtgg




aaagcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgacca




tcaaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggt




gccctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgta




cggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgga




aggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggac




agcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacg




agaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc




aagagcttcaaccggggcgagtgt











Binding Protein 34 Amino Acid Sequences









Heavy chain A
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwisheg
SEQ ID



dkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddga
NO: 318



lnwavdvdylsnlefwgqgtavtvssastkgpsvfplapcsrstsestaalgclvkdyfp




epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkv




dkrveskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpe




vqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkgl




pssiektiskakgqprepqvytlppcqeemtknqvslwclvkgfypsdiavewesng




qpennykttppvldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslsls




lgk






Light chain A
Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassras
SEQ ID



gvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtvaapsv
NO: 319




fifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys






lsstltlskadyekhkvyacevthqglsspvtksfnrgec







Heavy chain B
Qvqlvqsgaevvkpgasvkvsckascustom-character ihwvrqapgqglewigscustom-character
SEQ ID




custom-character nyaqkfqgratltvdtsistaymelsrlrsddtavyyccustom-character

NO: 320




custom-character wgkgttvlvsssqvqlvesgggvvqpgrslrlscaascustom-character mhwvrq





apgkqlewvaqcustom-character yatyyadsvkgrftisrddskntlylqmmslraedt




avyyccustom-character wgqgtlvtvssrtastkgpsvfplapcsrstsestaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt




cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis




rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt




vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt




knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv




dksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasiscksscustom-character lswylqkpgqspgsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyyccustom-character ftfgsgtkveikgqpkaap
NO: 321



diqmtqspsslsasvgdrvtitcqasqcustom-character lnwyqqkpgkapklliycustom-character nlhtgv




psrfsgsgsgtdftltisslqpediatyyccustom-character fgqgtkleiktkpsrtvaapsvf




ifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl




sstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 34 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaagg
SEQ ID



tgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc
NO: 322



gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaagaaa




gtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcaccaacac




cgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactgcgccaa




gggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcgccctgaac




tgggccgtggatgtggactacctgagcaacctggaattctggggccagggcacagccgt




gaccgtgtcatctgcttcgaccaagggcccctcggtgttccctctgaccccttgcagcaga




agcaccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagccc




gtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtg




ctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcct




gggcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggac




aagcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgg




gcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccgga




cccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttca




attggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaaca




gttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaa




cggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaa




accatcagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttg




ccaggaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccc




cagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagacc




accccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggaca




agagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcac




aaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccag
SEQ ID



catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggctt
NO: 323



ggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcaga




gccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa




gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag




agcccctggacctttggccagggcaccaaggtggacatcaagcgtacggtggccgctcc




cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtg




tgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgc




cctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac




ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtg




tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccg




gggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 324



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct
NO: 325



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag




atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta




ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag




tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga




agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt




gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg




cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt




ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct




cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc




gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa




cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc




cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag




gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac




cggggcgagtgt











Binding Protein 35 Amino Acid Sequences









Heavy chain A
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwisheg
SEQ ID



dkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddga
NO: 326



lnwavdvdylsnlefwgqgtavtvssastkgpsvfplapcsrstsestaalgclvkdyfp




epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkv




dkrveskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpe




vqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkgl




pssiektiskakgqprepqvytlppcqeemtknqvslwclvkgfypsdiavewesng




qpennykttppvldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslsls




lgk






Light chain A
Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassras
SEQ ID



gvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtvaapsv
NO: 327



fifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys




lsstltlskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa
SEQ ID



gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm
NO: 328



dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq




apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt




avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt




cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis




rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt




vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt




knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv




dksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 329



pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv




esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt




vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd




skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 35 Nucleotide Sequences









Heavy chain A
caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaagg
SEQ ID



tgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc
NO: 330



gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaagaaa




gtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcaccaacac




cgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactgcgccaa




gggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcgccctgaac




tgggccgtggatgtggactacctgagcaacctggaattctggggccagggcacagccgt




gaccgtgtcatctgcttcgaccaagggcccctcggtgttccctctgaccccttgcagcaga




agcaccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagccc




gtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtg




ctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcct




gggcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggac




aagcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgg




gcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccgga




cccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttca




attggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaaca




gttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaa




cggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaa




accatcagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttg




ccaggaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccc




cagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagacc




accccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggaca




agagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcac




aaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccag
SEQ ID



catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggctt
NO: 331



ggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcaga




gccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa




gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag




agcccctggacctttggccagggcaccaaggtggacatcaagcgtacggtggccgctcc




cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtg




tgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgc




cctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac




ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtg




tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccg




gggcgagtgt






Heavy chain B
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 332



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgcttcgaccaagggcccatcggtgttccctctggcc




ccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggacta




ctttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacac




ctttccagccatgctccagagcagcagcctgtactctctgagcaacgtcgtaacagtgccc




agcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaaca




ccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagccc




ctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgat




gatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccg




aggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagccc




agagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacca




ggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagc




tccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtac




cctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtga




aaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaa




caactacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaag




ctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgca




cgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 333



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaag




atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta




ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




cccgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggc




caccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtg




gtatcagcagaagcccggccagccccccaagctgctgattttcgccgccagcaacgtgg




aaagcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgacca




tcaaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggt




gccctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgta




cggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca




cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgga




aggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggac




agcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacg




agaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc




aagagcttcaaccggggcgagtgt











Binding Protein 36 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkprg
SEQ ID



gavnyarplqgrvtmtrdvysdtaflelrsltvddtavyftrgkncdynwdfehwgrg
NO: 334



tpvivssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfp




avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape




flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk




preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv




ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff




lyskltvdksrwqegnvfscsvmheallnhytqkslslslgk






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfsg
SEQ ID



srwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsdeql
NO: 335



ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad




yekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvqsgaevvkpgasvkvsckascustom-character ihwvrqapgqglewigscustom-character
SEQ ID




custom-character nyaqkfqgratltvdtsistaymelsrlrsddtavyyccustom-character

NO: 336




custom-character wgkgttvlvsssqvqlvesgggvvqpgrslrlscaascustom-character mhwvrq





apgkqlewvaqcustom-character yatyyadsvkgrftisrddskntlylqmmslraedt




avyyccustom-character wgqgtlvtvssrtastkgpsvfplapcsrstsestaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt




cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis




rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt




vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt




knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv




dksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasiscksscustom-character lswylqkpgqspgsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyyccustom-character ftfgsgtkveikgqpkaap
NO: 337



diqmtqspsslsasvgdrvtitcqascustom-character lnwyqqkpgkapklliykasnlhtgv




psrfsgsgsgtdftltisslqpediatyyccustom-character gqgtkleiktkpsrtvaapsvf




ifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl




sstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 36 Nucleotide Sequences









Heavy chain A
caggtacagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcgga
SEQ ID



tcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagactgg
NO: 338



cccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgtgaa




ctacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgataccg




ccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacccggg




gcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccctgtgatc




gtgtcaagcgcgtcgaccaagagcccctcggtgttccctctggccccttgcagcagaagc




accagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtg




accgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcc




agagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggc




accaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagc




gggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttagggcgg




accctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccc




cgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattg




gtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttc




aacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacgg




caaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacca




tcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc




cccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccctgggcaag






Light chain A
Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagccat
SEQ ID



catcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctgga
NO: 339



caggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccgata




gattcagcggctccagatggggccctgactacaacctgaccatcagcaacctggaaagc




ggcgacttcggcatgtactactgccagcagtacgagttcttcggccagggcaccaaggtg




caggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgac




gagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgc




gaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaa




agcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacac




tgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccaggg




cctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 340



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct
NO: 341



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag




atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta




ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag




tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga




agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt




gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg




cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt




ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct




cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc




gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa




cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc




cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag




gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac




cggggcgagtgt











Binding Protein 37 Amino Acid Sequences









Heavy chain A
Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkprg
SEQ ID



gavnyarplqgrvtmtrdvysdtaflelrsltvddtavyftrgkncdynwdfehwgrg
NO: 342



tpvivssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfp




avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape




flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk




preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv




ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff




lyskltvdksrwqegnvfscsvmheallnhytqkslslslgk






Light chain A
Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfsg
SEQ ID



srwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsdeql
NO: 343



ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad




yekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa
SEQ ID



gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm
NO: 344



dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq




apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt




avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg




clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt




cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis




rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt




vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt




knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv




dksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 345



pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv




esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt




vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd




skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec











Binding Protein 37 Nucleotide Sequences









Heavy chain A
caggtacagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcgga
SEQ ID



tcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagactgg
NO: 346



cccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgtgaa




ctacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgataccg




ccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacccggg




gcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccctgtgatc




gtgtcaagcgcgtcgaccaagagcccctcggtgttccctctggccccttgcagcagaagc




accagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtg




accgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcc




agagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggc




accaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagc




gggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttagggcgg




accctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccc




cgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattg




gtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttc




aacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacgg




caaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacca




tcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc




cccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccctgggcaag






Light chain A
Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagccat
SEQ ID



catcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctggac
NO: 347



aggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccgatag




attcagcggctccagatggggccctgactacaacctgaccatcagcaacctggaaagcg




gcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggcaccaaggtgc




aggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacg




agcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcga




ggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag




cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactg




agcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcc




tgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagagcagaatctggccctggcctcgtgaagcctaccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc
NO: 348



acctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaactaca




accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc




cctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagagaca




agggctacagctactactacagcatgaactactggagccaggacaccaccgtgaccgtg




tcatcctctcaggtgcagctggtagaatctggcggcggagtggtgcagcctggcagaagc




ctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctagatacactaggtg




cgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaac




agctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggacg




acagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccgt




gtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaacc




ctcgtgaccgtatctaatcagaccgcttcgaccaagagcccatcagtgttccctaggccc




cttgcagcagaagcaccagcgaatctacagccaccctgaactgcctcatgaaggactact




ttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctt




tccagccgtgctccagagcagcggcctgtactctagagcagcgtcgtgacagtgcccag




cagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaacacc




aaggtggacaagcgggtggaatctaagtacggccaccctgccaccttgcccagcccct




gaatttctgagcggaccctccgtgttcctgttccccccaaaacccaaggacaccctgatga




tcagccggacccccgaagtgacctgcgtggtaatggatgtgtcccaggaagatcccgag




gtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccag




agaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccagg




actggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagacc




atcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccct




gccccctagccaggaagagatgaccaagaaccaggtgtccctgagagtgccgtgaaag




gcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaacaa




ctacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaagctg




accgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacga




ggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 349



ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat




tcagcggcgtgcccgacagattaccggcagcggctaggcaccgacttcaccagaaga




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcaccatggcagcggcaccaaggtagaaatcaagggccagcccaaggccgcccc




cgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggcca




ccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggt




atcagcagaagcccggccagccccccaagctgctgaattcgccgccagcaacgtggaa




agcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgaccatc




aaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaagatgc




cctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgtacg




gtggccgctcccagcgtgacatcttcccacctagcgacgagcagctgaagtccggcaca




gcctctgtcgtgtgcctgctgaacaacttctacceccgcgaggccaaagtgcagtggaag




gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagc




aaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgaga




agcacaaggtgtacgcctgcgaagtgacccaccagggcctatctagccccgtgaccaag




agcttcaaccggggcgagtgt











Binding Protein 38 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 350



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 351



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp
SEQ ID



qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw
NO: 352



aldawgqgttvvvsasqvqlvesgggvvqpgrslrlscaasgftftkawmhw




vrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmnslra




edtavyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsesta




algclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtk




tytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl




misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvv




svltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqee




mtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskl




tvdkstwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divimtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 353



pyilwtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv




psrfsgsathtsfnltisdlqaddiatyycqvlqffgrgsrlhiktkgpsrtvaapsvfifpp




sdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt




lskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 38 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc
NO: 354



ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt




cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag




cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt




ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga




gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctaggcaag






Light chain A
Gacatccagatgacccagagccccagcagcctgtctgccagcgtggacgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc
NO: 355



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc




cagggcaccaagctggaaatcaagcgtacggtagccactcccaacgtattcatatccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct




acccccgcgaggccaaggtgcagtggaaggtggacaatgccctgcagagcggcaaca




gccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca




ccctgaccagagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac




ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc
NO: 356



cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggatccgggatagatttgacccttacccgggacgtgtaccgcgagatcgcct




acatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcgccagagac




agaagctacggcgacagcaactaggactagatgatgggaccagggcacaaccatgg




tggtgtctgcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggca




gaagcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcact




gggtgcgccaggcccctggaaagcagaggaatgggtggcccagatcaaggacaaga




gcaacagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgg




gacgacagcaagaacaccctatacctgcagatgaacagcctgcgggccgaggacacca




ccgtgtactactgtcggggcgtatactatgccctgagcccatcgattactagggccaggg




aaccctcgtgaccgtgtctagtcggaccgcacgaccaagggcccatcggtgttccctctg




gccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaagga




ctactttcccgagcccgtgaccgtgtcaggaaactggcgctctgacaagcggcgtgcac




acctttccagccgtgaccagagcagcggcctgtactactgagcagcgtcgtgacagtgc




ccagcagcagcctggacaccaagacctacacctgtaacgtgaaccacaagcccagcaa




caccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagc




ccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctg




atgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgagaccgtgagcacc




aggactggctgaacaacaaagagtacaagtgcaaagtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgaggacagcgacggctcattcttcctggtgtccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgaccgtgatgc




acgaggccagcacaaccactacacccagaagtccagtactgtccagggcaag






Light chain B
Gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgcca
SEQ ID



gcatcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgag
NO: 357



ctggtatctacagaaacccggccagagcccccagtccagatctacaaggtgtccaacag




attcagcggcgtgcccgacagattaccggcagcggctaggcaccgacttcaccctgaa




gatcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagt




accccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc




ccctacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagt




gaccatcaactgccagacctctacagggcgtgggcagcgacctgcactggtatcagcaca




agcctggcagaacccccaagagagatccaccacacaagcagcatggaagatggcgt




gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctg




caggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagca




gactgcacatcaagaccaagggccccagccgtacggtggccgctcccagcgtgttcatct




tcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtgcctgctgaaca




acttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg




caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgag




cagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaa




gtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 39 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 358



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 359



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp
SEQ ID



qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw
NO: 360



aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw




mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm




nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc




srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt




vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp




pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq




fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc




tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd




gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih
NO: 361



vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs




gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql




ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad




yekhkvyacevthqglsspvtksfnrgec











Binding Protein 39 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc
NO: 362



ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt




cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag




cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt




ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga




gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctaggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 363



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc
NO: 364



cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct




acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac




agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg




tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg




gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa




ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag




atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt




caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag




gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt




actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca




agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg




ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg




cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc




tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta




acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga




ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg




gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg




tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag




gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc




agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac




caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg




gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg




acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca




acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc




tgtctctgtccctagacaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 365



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgigtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 40 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 366



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 367



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal
NO: 368



spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr




qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt




avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest




aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt




ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl




misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv




vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq




eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs




kltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl
NO: 369



svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs




gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps




deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 40 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc
NO: 370



ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt




cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag




cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt




ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga




gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctaggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 371



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 372



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcsacaga
SEQ ID



gtgaccatcaactgccagacctctcaggctgggcagegacctgcactggtatc
NO: 373



agcacaagcctggcagagcceccaagagctgatccaccacacaagcagcgtg




gaagatggcgtgcccagcagattaccggcagcggcttccacaccagcttcaacc




tgaccatcagcgatagcaggccgacgacattgccacctactattgtcaggtgctg




cagttcttcggcagaggcagcagactgcacatcaagggccagcccaaggccgc




ccccgacatcgtgatgacccaacccccagagcctgagcgtgacacctggaca




gcctgccagcatcagctgcaagagcagccagagcctggtgcacaacaacgcca




acacctacctgagctggtatctgcagaagcccggccagagcccccagtccctgat




ctacaaggtgtccaacagattcagcgcgtgcccgacagattctccggcagcgg




ctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtggg




cgtgtactattgtggccagggcacccagtaccccttcacattggcagcggcacca




aggtggaaatcaagaccaagggccccagccgtacggtggccgctcccagcgtg




ttcatcttcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtg




cctgctgaaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa




cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaag




gactccacctacagcctgagcagcaccctgacactgacaaggccgactacga




aagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtg




accaagagcttcaaccggggcgagtgt











Binding Protein 41 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 374



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 375



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal
NO: 376



spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr




qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt




avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest




aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt




ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl




misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv




vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq




eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs




kltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl
NO: 377



svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs




gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps




deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 41 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc
NO: 378



ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt




cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag




cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt




ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga




gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctaggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 379



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact
SEQ ID



gagctgtgccgccaacggatcaccttcaccaaggcctggatgcactgggtacgccagg
NO: 380



cccctggaaagcagaggaatgggtggcccagatcaaggacaagagcaacagctacgc




cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag




aacaccctgtacctgcagatgaacagcctgcgggccgaggacaccaccatgtactactgt




cggggcgtgtactatgccagagccccttcgattactggggccagggaaccctcgtgacc




gtgtctagtgacaaaacccataccaaagcccacctagtgcagtctggcaccgccatgaag




aaaccaggcgcctctgtacggatgtcctgtcagacaagcggctacaccttcaccgcccac




atcctgttctggttccggcaggcccctaacaaaggactggaatgagtggaataaatcaag




ccccagtatggcgccgtgaacttcggcggaaacttccgggataaagtgaccctgacccg




ggacgtgtaccgcgagatcgcctacatggacatccggggcctgaagcccgatgacaccg




ccgtgtactactgcgccagagacagaagctacggcgacagcagctgggctctggatgctt




ggggccagggcacaaccgtggtggtgtctgccgataagacccacaccaccagcacaaa




gggcccatcggttccctctggccccagcagcagaagcaccagcgaatctacagccgc




cctgggctgcctcgtgaagaactacatcccaagcccatgaccatgtcctggaactaggc




gctctgacaaacggcgtacacacctttccagccgtactccagaacaacggcctgtactct




ctgagcagcgtcgtgacagtgcccagcagcagcctgggcaccaagacctacacctgtaa




cgtggaccacaagcccagcaacaccaaggtggacaagcgggtggaatctaagtacggc




cctccctgccctccttgcccagcccctgaatactgggcggaccctccgtgacctgttcccc




ccaaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcatggtggt




ggatgtgtcccaggaagatcccgaggtacagttcaattggtacatggacggcgtgaaagt




gcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtggtg




tccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggt




gtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggccag




ccccgcgagcctcaagtgtgtaccctgccccctagccaggaagaaataaccaagaacca




ggtgtccctgagagtgccgtaaaaggatctaccccagcgacattgccgtggaatggga




gagcaacggccaaccegaaaacaactacaaaaccaccccccctgtgaggacagegac




ggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggcaac




gtgttcagctgaccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgt




ctctgtccctgggcaag






Light chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgac
SEQ ID



catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc
NO: 381



ctggcagagcccccaaactactgatccaccacacaagcagcgtggaagatggcgtgcc




cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag




gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagcagac




tgcacatcaaggacaaaaacccataccgacatcgtgatgacccagacccccctgagcctga




gcgtgacacctggacagcctgccagcatcagctgcaagagcagccagagcctggtgca




caacaacgccaacacctacctgaactagtatagcagaagcccagccagagcccccagt




ccctgatctacaaggtgtccaacagattcagcggcgtgcccgacagattctccggcagcg




gctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtgggcgtg




tactattgtggccagggcacccagtaccccttcacctttggcagcggcaccaaggtggaa




atcaaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccaccta




gcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc




cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagcc




aggaaagcatgaccgagcaggacagcaaggactccacctacagcctgagcagcaccct




gacactgagcaaggccgactacgagaagcacaagatgtacacctgcaaaatgacccac




cagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 42 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 382



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 383



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp
SEQ ID



qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw
NO: 384



aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw




mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm




nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc




srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt




vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp




pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq




fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc




tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd




gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih
NO: 385



vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs




gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql




ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad




yekhkvyacevthqglsspvtksfnrgec











Binding Protein 42 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 386



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 387



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc
NO: 388



cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct




acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac




agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg




tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg




gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa




ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag




atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt




caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag




gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt




actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca




agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg




ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg




cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc




tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta




acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga




ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg




gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg




tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag




gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc




agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac




caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg




gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg




acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca




acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc




tgtctctgtccctagacaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 389



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgigtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 43 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 390



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 391



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp
SEQ ID



qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw
NO: 392



aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw




mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm




nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc




srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt




vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp




pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq




fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc




tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd




gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih
NO: 393



vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs




gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql




ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad




yekhkvyacevthqglsspvtksfnrgec











Binding Protein 43 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 394



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 395



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt
SEQ ID



gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc
NO: 396



cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt




cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct




acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac




agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg




tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg




gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa




ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag




atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt




caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag




gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt




actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca




agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg




ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg




cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc




tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta




acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga




ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc




cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg




gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa




gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg




tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag




gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc




agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac




caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg




gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg




acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca




acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc




tgtctctgtccctagacaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 397



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 44 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 398



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 399



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal
NO: 400



spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr




qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt




avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest




aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt




ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl




misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv




vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq




eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs




kltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl
NO: 401



svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs




gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps




deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 44 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 402



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 403



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 404



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcsacaga
SEQ ID



gtgaccatcaactgccagacctctcaggctgggcagegacctgcactggtatc
NO: 405



agcacaagcctggcagagcceccaagagctgatccaccacacaagcagcgtg




gaagatggcgtgcccagcagattaccggcagcggcttccacaccagcttcaacc




tgaccatcagcgatagcaggccgacgacattgccacctactattgtcaggtgctg




cagttcttcggcagaggcagcagactgcacatcaagggccagcccaaggccgc




ccccgacatcgtgatgacccaacccccagagcctgagcgtgacacctggaca




gcctgccagcatcagctgcaagagcagccagagcctggtgcacaacaacgcca




acacctacctgagctggtatctgcagaagcccggccagagcccccagtccctgat




ctacaaggtgtccaacagattcagcgcgtgcccgacagattctccggcagcgg




ctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtggg




cgtgtactattgtggccagggcacccagtaccccttcacattggcagcggcacca




aggtggaaatcaagaccaagggccccagccgtacggtggccgctcccagcgtg




ttcatcttcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtg




cctgctgaaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa




cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaag




gactccacctacagcctgagcagcaccctgacactgacaaggccgactacga




aagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtg




accaagagcttcaaccggggcgagtgt











Binding Protein 45 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 406



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 407



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqik
SEQ ID



dksnsyatyyadsvkgrftisrddskntlylqmnslraedtavyycrgvyyals
NO: 408



pfdywgqgtlvtvssdkthtrahlvqsgtamkkpgasvrvscqtsgytftahilf




wfrqapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkp




ddtavyycardrsygdsswaldawgggttvvvsadkthtastkgpsvfplapc




srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssgtyslssvvt




vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflf




ppkpkdtimisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree




qfnstyrvvsvltvlhqdwllgkeykckvsnkglpssiektiskakgqprepq




vctlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppvld




sdgsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain B
Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp
SEQ ID



srfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtdivmtqtpl
NO: 409



slsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnrfsgvpdrf




sgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtrtvaaps




vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd




styslsstltlskadyekhkvyacevthqglsspvtksfnrgec











Binding Protein 45 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 410



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac
SEQ ID



catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta
NO: 411



tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa




gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca




accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc




ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg




tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct




gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc




agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca




gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc




ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg




agtgt






Heavy chain B
caggtgcagctggtggaatctagcgacggagtgatgcagcctagcagaagcctgagac
SEQ ID



tgagctgtgccgccaacggcttcaccttcaccaaggcctagatgcactaggtacgccaa
NO: 412



gcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacg




ccacctactacgccgacagcgtgaagggccggacaccatcagccgggacgacagcaa




gaacaccagtacctacaaataaacagcctgcaggccgaagacaccgccgtatactact




gtcggggcgtgtactatgccctgagccccttcgattactggggccagggaaccctcgtga




ccgtgtctagtgacaaaacccataccagagcccacctggtgcagtctggcaccgccatga




agaaaccaggcgcactgtgcgggtgtcctgtcagacaagcggctacaccacaccgccc




acatcagttaggttccggcaggcccctggcagaagactggaatgggtaggatggatca




agccccagtatggcgccgtgaacttcggcagaggcttccgggatagagtgaccctgacc




cgggacgtgtaccgcgagatcgcctacatggacatccggggcctgaagcccgataaca




ccgccgtgtactactgcgccagagacagaagctacggcgacagcagctgggctctggat




gcttggggccagggcacaaccgtggtggtgtctgccgataagacccacaccgccagca




caaagggcccatcggtgttccctctggccccttgcagcagaagcaccagcgaatctacag




ccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactc




tggcgctctgacaagcggcgtgacacctttccagccgtgaccagagcagggcctgta




ctctctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaagacctacacct




gtaacgtgaaccacaagcccagcaacaccaaggtggacaagcgagtggaatctaaata




cggccctccctgccctccttgcccagcccctgaatttctgggcggaccctccgtgttcctgt




tccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtg




gtggtggatgtgtcccaggaagatcccgaggtgcagacaatggtacgtggacggcgtg




gaagtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgg




gtggtgtccatgctgaccatgctgcaccaggactggctgaacggcaaagagtacaagta




caaggtgtccaacaaggacctgcccagaccatcgagaaaaccatcagcaaggccaag




ggccagccccgcgagcctcaagttgtaccctgccccctagccaggaagagatgacca




agaaccaggtgtccctgagctgtgccgtgaaaggcttctaccccagcgacattgccgtgg




aatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgtgagga




cagcgacggctcattcacctggtgtccaagagaccgtggacaagagccggtggcagg




aaggcaacgtgacagagaccgtgatgcacgagaccctgcacaaccactacacccag




aagtccctgtctctgtccagggcaag






Light chain B
tacatccacgtgacccagancccagcagcctgtccgtgtccatcggcgacagagtgac
SEQ ID



catcaactgccagacctctcagggcgtaggcagcgacctgcactgatatcagcacaagc
NO: 413



ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc




cagcagattttccggcagcggcttccacaccagatcaacctgaccatcagcgatctgcag




gccgacgacattgccacctactattgtcaggtgagcagacttcggcagaggcagcagac




tgcacatcaaggacaaaacccataccgacatcgtgatgacccagacccccctgagcctg




agcgtgacacctggacagcctgccagcatcagagcaagagcagccagagcctggtgc




acaacaacgccaacacctacctgagaggtatctgagaagcccggccagagccccca




gtccagatctacaaggtgtccaacagattcagcggcgtacccgacagattctccggcag




cggctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtgggc




gtgtactattgtggccagggcacccagtaccccttcacctttggcagcggcaccaaggtg




gaaatcaaggataagacccatacccgtacggtggccgctcccagcgtgacatcttcccac




ctagcgacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttcta




cccccacgaggccaaagtgcagtagaaggtgaacaacgccagcagagcggcaacag




ccaggaaagcatgaccgagcaggacagcaaggactccacctacagcctgagcagcac




cctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc




caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 46 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 414



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 415



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi
SEQ ID



shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd
NO: 416



yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr




slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg




rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta




stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa




peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve




vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis




kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls




lslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 417



pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra




sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt




vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd




skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec











Binding Protein 46 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 418



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc
NO: 419



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc




cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca




ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac




ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 420



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 421



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 47 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 422



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 423



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi
SEQ ID



shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd
NO: 424



yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr




slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg




rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta




stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa




peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve




vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis




kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls




lslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 425



pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra




sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt




vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd




skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec











Binding Protein 47 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 426



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 427



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 428



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag
SEQ ID



catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct
NO: 429



ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat




tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc




cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa




ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca




gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag




attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac




gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat




caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc




gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc




gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg




aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac




actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag




ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt











Binding Protein 48 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 430



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 431



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals
NO: 432



pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv




rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd




tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt




astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay




lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp




apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy




evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti




skakgqprepqvctIppscieemtknqvstscavkgfypsdiavewesnme




nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls




lslgk






Light chain B
Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras
SEQ ID



gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap
NO: 433



divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf




sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids




kdstystssthiskadyckhkvyaccvthqgisspvtksfargec











Binding Protein 48 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 434



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagaccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgaaccagctgagaagcgacgacaccaccatgtactactgcacccagt




cccactacgacctggattagaacttcgacatgtagggcaagagcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccagag




cagcggcagtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacatggaccacaaacccagcaacaccaaggtagacaagcgagt




ggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccaggaaga




gatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggatctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattcacctgtactccaaactgaccgtggacaagaaccaat




ggcaggaaggcaacgtgttcagctgaccgtgatacacgaggccagcacaaccactac




acccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatccagatgacccagcagccccagcagcctgtctgccagcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc
NO: 435



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc




cagggcaccaagctggaaatcaagcgtacggtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgagcaggacagcaaggactccacctacaacctgagcagca




ccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac




ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact
SEQ ID



gagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactgggtgcgccagg
NO: 436



cccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacgc




cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag




aacaccagtacctgcagatgaacagcctgcgggccgaggacaccgccgtgtactactgt




cggggcgtgtactatgccagaacccatcgattactgaggccagagaaccctcgtaacc




gtgtctagtagccaggtgcacctgacacagagcggacccgaagtgcggaagcctggca




cctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcact




gggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccacgagg




gcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacaga




agcaccaacaccgcctacctacagagagcggcctaacctctggcgataccgccgtgta




ctactgcaccaaaggcagcaagcaccgactgagagactacgccagtacgacgatgac




ggcgccagaactgggccgtggatgtgaactacctgagcaacctggaattaggggcca




gggcacagccgtgaccgtgtcatctcggaccgccagcacaaagggcccatcggtgttcc




ctctggccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtga




aggactactttcccgagcccgtgaccgtgtcctggaactctggcgctagacaagcggcgt




gcacacctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgac




agtgcccagcagcagcagggcaccaagacctacacctataacgtggaccacaagccc




agcaacaccaagatggacaagcgggtagaatctaagtacgaccctccctgccctccttgc




ccagcccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggaca




ccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaa




gatcccgaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagac




caagcccagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgc




tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaagagcctg




cccagctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaag




tgtgtaccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtg




ccgtgaaaggatctaccccagcgacattgccgtggaatgggagagcaacggccagccc




gagaacaactacaagaccaccccccctgtgaggacagcgacggctcattcacctggtgt




ccaagctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtg




atgcacgaggccctgcacaaccactacacccagaagtccctatactgtccctggacaag






Light chain B
gacttcgtgagacccagagccctcacagcctgagcgtgacacctggcgagagcgccag
SEQ ID



catcagagcaagagcagccactccctgatccacggcgaccgaaacaactacctagatg
NO: 437



gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag




ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaag




atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga




gcccctggacctttggccagggcaccaaggtggacatcaagggccagcccaaggccgc




ccccgacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctg




ccagcatcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctg




agctggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaac




agattcagcggctttgcccgacagattctccggcagcggctctggcaccgacttcacccta




aagatcaaccaggtaaaaaccgaggacatgggcgtgtactattatggccagggcaccc




agtacccatcaccatgacaacggcaccaaggtggaaatcaagaccaaaggccccagc




cgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc




ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag




tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag




gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact




acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctatctagccccgtg




ctccaagaacttcaaccgaagcgagtgt











Binding Protein 49 Amino Acid Sequences









Heavy chain A
Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv
SEQ ID



ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv
NO: 438



tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg




gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre




eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp




pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk




ltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv
SEQ ID



psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps
NO: 439



deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl




skadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals
NO: 440



pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv




rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd




tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt




astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay




lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp




apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy




evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti




skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme




nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls




lslgk






Light chain B
Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras
SEQ ID



gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap
NO: 441



divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf




sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids




kdstystssthiskadyckhkvyaccvthqgisspvtksfargec











Binding Protein 49 Nucleotide Sequences









Heavy chain A
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 442



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagaccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgaaccagctgagaagcgacgacaccaccatgtactactgcacccagt




cccactacgacctggattagaacttcgacatgtagggcaagagcaccaccgtgacagtgt




ctagcgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacca




gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg




tgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccagag




cagcggcagtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacca




agacctacacctgtaacatggaccacaaacccagcaacaccaaggtagacaagcgagt




ggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgggcggaccc




tccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccccgaa




gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg




tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaacag




cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag




agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc




aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccaggaaga




gatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggatctaccccagcgacatt




gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattcacctgtactccaaactgaccgtggacaagaaccaat




ggcaggaaggcaacgtgttcagctgaccgtgatacacgaggccagcacaaccactac




acccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatccagatgacccagcagccccagcagcctgtctgccagcgtgggcgacagagtga
SEQ ID



ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc
NO: 443



ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc




cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag




cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc




cagggcaccaagctggaaatcaagcgtacggtggccgctcccagcgtgttcatcttccca




cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct




acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca




gccaggaaagcgtaaccgagcaggacagcaaggactccacctacaacctgagcagca




ccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac




ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact
SEQ ID



gagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactgggtgcgccagg
NO: 444



cccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacgc




cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag




aacaccagtacctgcagatgaacagcctgcgggccgaggacaccgccgtgtactactgt




cggggcgtgtactatgccagaacccatcgattactgaggccagagaaccctcgtaacc




gtgtctagtagccaggtgcacctgacacagagcggacccgaagtgcggaagcctggca




cctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcact




gggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccacgagg




gcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacaga




agcaccaacaccgcctacctacagagagcggcctaacctctggcgataccgccgtgta




ctactgcaccaaaggcagcaagcaccgactgagagactacgccagtacgacgatgac




ggcgccagaactgggccgtggatgtgaactacctgagcaacctggaattaggggcca




gggcacagccgtgaccgtgtcatctcggaccgccagcacaaagggcccatcggtgttcc




ctctggccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtga




aggactactttcccgagcccgtgaccgtgtcctggaactctggcgctagacaagcggcgt




gcacacctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgac




agtgcccagcagcagcagggcaccaagacctacacctataacgtggaccacaagccc




agcaacaccaagatggacaagcgggtagaatctaagtacgaccctccctgccctccttgc




ccagcccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggaca




ccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaa




gatcccgaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagac




caagcccagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgc




tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaagagcctg




cccagctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaag




tgtgtaccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtg




ccgtgaaaggatctaccccagcgacattgccgtggaatgggagagcaacggccagccc




gagaacaactacaagaccaccccccctgtgaggacagcgacggctcattcacctggtgt




ccaagctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtg




atgcacgaggccctgcacaaccactacacccagaagtccctatactgtccctggacaag






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacactggcgagagcgccag
SEQ ID



catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttg
NO: 445



gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag




ccagcggcgtgcccgatagattactggcagcggcagcgacaaggacttcaccctgaag




atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga




gcccctggacctttggccagggcaccaaggtggacatcaaggacaaaacccataccgac




atcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccagcat




cagctacaagagcagccagagcctgatgcacaacaacgccaacacctacctgagaggt




atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca




gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca




gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc




cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatatcccacctagcaacgagcagctgaagtccggcacagc




ctctgtcgtatgcctactaaacaacttctacccccgcaaggccaaaatgcagtggaaggta




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa




ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag




cttcaaccggggcgagtgt











Binding Protein 50 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 446



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 447



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi
SEQ ID



shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd
NO: 448



yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr




slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg




rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta




stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa




peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve




vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis




kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls




lslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 449



pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra




sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt




vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd




skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec











Binding Protein 50 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 450



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac
SEQ ID



catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta
NO: 451



tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa




gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca




accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc




ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg




tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct




gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc




agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca




gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc




ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg




agtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 452



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacttcgtgctgacccagagccctcacagcctgagcgtgacactggcgagagcgccag
SEQ ID



catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttg
NO: 453



gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag




ccagcggcgtgcccgatagattactggcagcggcagcgacaaggacttcaccctgaag




atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga




gcccctggacctttggccagggcaccaaggtggacatcaaggacaaaacccataccgac




atcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccagcat




cagctacaagagcagccagagcctgatgcacaacaacgccaacacctacctgagaggt




atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca




gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca




gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc




cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatatcccacctagcaacgagcagctgaagtccggcacagc




ctctgtcgtatgcctactaaacaacttctacccccgcaaggccaaaatgcagtggaaggta




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa




ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag




cttcaaccggggcgagtgt











Binding Protein 51 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 454



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 455



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi
SEQ ID



shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd
NO: 456



yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr




slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg




rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta




stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl




qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa




peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve




vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis




kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe




nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls




lslgk






Light chain B
Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr
SEQ ID



fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa
NO: 457



pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra




sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt




vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd




skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec











Binding Protein 51 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc
NO: 458



cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta




caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg




tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga




caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg




tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca




ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga




ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca




gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca




ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg




ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga




ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc




gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt




acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca




acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc




aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat




cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag




gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc




gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc




cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag




ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc




actacacccagaagtccctgtctctgtccagggcaag






Light chain A
gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac
SEQ ID



catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta
NO: 459



tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa




gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca




accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc




ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg




tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct




gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc




agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca




gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc




ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg




agtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 460



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag
SEQ ID



catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct
NO: 461



ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat




tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc




gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca




gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac




gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca




gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca




gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc




ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc




ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa




ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag




cttcaaccggggcgagtgt











Binding Protein 52 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 462



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 463



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals
NO: 464



pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv




rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd




tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt




astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay




lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp




apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy




evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti




skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme




nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls




lslgk






Light chain B
Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras
SEQ ID



gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap
NO: 465



divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf




sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids




kdstystssthiskadyckhkvyaccvthqgisspvtksfargec











Binding Protein 52 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc
NO: 466



acctggaaaaggcctggaatggagggcgtgatctgggctggcggaggcaccaactaca




accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc




cctgaagctgagcagcgtgacagccaccgataccgccgtatactactacgccagagaca




agggctacagctactactacagcatggactactggggccagggcaccaccgtgaccgtg




tcatccgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacc




agcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc




gtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccaga




gcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacc




aagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcggg




tggaatctaagtacggccctccctgccctccttacccaacccctgaatttagggcggacc




ctccgtgttcctgttccccccaaagcccaaggacaccagatgatcaaccggacccccga




agtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtac




gtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaaca




gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaa




gagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcag




caaggccaagggccaaccccacgagcctcaaatgtataccctaccccatgccaggaaa




agatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagcgacat




tgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac
SEQ ID



catcacctgtagagccagcgagagcgtgaatattacgtgaccagcctgatgcagtggtat
NO: 467



cagcagaagcccggccagccccccaagctgctgatatcgccgccaacaacgtggaaaa




cggcgtgccagccagattttccggcagcggctctggcaccaacttcaccctgaccatcaa




ccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtgccc




tacacctttggccagggcaccaagaggaaatcaagcgtacggtggccgctcccagcgt




gttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctg




ctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgca




gagcggcaacagccaggaaaacgtgaccgagcaggacagcaaggactccacctacag




cctgagcagcaccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcct




gcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga




gtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 468



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag
SEQ ID



catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct
NO: 469



ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat




tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc




gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca




gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac




gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca




gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca




gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc




ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc




ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa




ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag




cttcaaccggggcgagtgt











Binding Protein 53 Amino Acid Sequences









Heavy chain A
Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt
SEQ ID



nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt
NO: 470



vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav




lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl




ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp




reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt




lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly




skltvdksrwqegnvfscsvmhealhnhytqkslslslgk






Light chain A
Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve
SEQ ID



sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv
NO: 471



fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys




lsstltskadyekhkvyacevthqglsspvtksfnrgec






Heavy chain B
Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi
SEQ ID



kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals
NO: 472



pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv




rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd




tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt




astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay




lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp




apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy




evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti




skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme




nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls




lslgk






Light chain B
Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras
SEQ ID



gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap
NO: 473



divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf




sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv




aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids




kdstystssthiskadyckhkvyaccvthqgisspvtksfnrgec











Binding Protein 53 Nucleotide Sequences









Heavy chain A
caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct
SEQ ID



gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc
NO: 474



acctggaaaaggcctggaatggagggcgtgatctgggctggcggaggcaccaactaca




accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc




cctgaagctgagcagcgtgacagccaccgataccgccgtatactactacgccagagaca




agggctacagctactactacagcatggactactggggccagggcaccaccgtgaccgtg




tcatccgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacc




agcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc




gtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccaga




gcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacc




aagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcggg




tggaatctaagtacggccctccctgccctccttacccaacccctgaatttagggcggacc




ctccgtgttcctgttccccccaaagcccaaggacaccagatgatcaaccggacccccga




agtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtac




gtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaaca




gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaa




gagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcag




caaggccaagggccaaccccacgagcctcaaatgtataccctaccccatgccaggaaa




agatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagcgacat




tgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct




gtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagagccggt




ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac




acccagaagtccctgtctctgtccctgggcaag






Light chain A
gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag
SEQ ID



catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct
NO: 475



ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat




tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa




tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac




cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc




gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca




gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac




gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca




gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca




gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc




ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt




ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc




ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa




ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag




cttcaaccggggcgagtgt






Heavy chain B
caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt
SEQ ID



gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc
NO: 476



ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact




acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc




ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt




cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg




tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa




gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg




tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa




cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac




gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg




tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac




cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc




cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact




actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca




cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc




cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac




accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc




cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga




tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc




gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc




cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc




aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag




ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta




ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg




aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga




acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa




gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc




acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag






Light chain B
gacttcgtgagacccaaagccctcacagcctgagcatgacacctggcgagagcgccag
SEQ ID



catcagctgcaaaagcagccactccctgatccacggcgaccgaaacaactacctagcttg
NO: 477



gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag




ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaag




atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga




gcccctggacctttagccagggcaccaagatggacatcaagaacaaaacccataccgac




atcgtgatgacccagacccccagagcctgaacgtgacacctgaacagcctaccagcat




cagctgcaagagcagccagagcctggtacacaacaacgccaacacctacctgagctggt




atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca




gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca




gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc




cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt




ggccactcccagcgtgttcatcttcccacctaacgacgagcagctgaagtccgacacagc




ctctgtcgtgtgcctgctgaacaacttctacccccgcgagaccaaagtacagtggaagatg




gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa




ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag




cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag




cttcaaccggggcgagtgt
















TABLE A





CDR sequences of binding proteins





















Ab
CDRH1
CDRH2
CDRH3
CDRL1
CDRL2
CDRL3





CD4BS ″a″
dctln
wikprggavnyarplqg
gkncdynwdfeh
rtsqyglsa
sgstraa
qqyef



(SEQ ID NO: 248)
(SEQ ID NO: 249)
(SEQ ID NO: 250)
(SEQ ID NO: 266)
(SEQ ID NO: 267)
(SEQ ID NO: 268)





CD4BS ″b″
GYTFTAHI
IKPQYGAV
drsygdsswalda
QGVGSD
HTS
qvlqf



(SEQ ID NO: 251)
(SEQ ID NO: 252)
(SEQ ID NO: 253)
(SEQ ID NO: 269)
(SEQ ID NO: 270)
(SEQ ID NO: 271)





MPER
gfdfdnaw
itgpggwssv
tgkyydfwsgyppgeeyfqd
rgdslrshyas
gknnrps
ssrdksgsrlsv



(SEQ ID NO: 254)
(SEQ ID NO: 255)
(SEQ ID NO: 256)
(SEQ ID NO: 272)
(SEQ ID NO: 273)
(SEQ ID NO: 274)





V1/V2 dir. 
GNTLKTYD
ISHEGDKK
cakgskhrlrdyalyddd
hslihgdrnny
las
cmqgrespwtf


″a″
(SEQ ID NO: 257)
(SEQ ID NO: 258)
galnwavdvdylsnlefw
(SEQ ID NO: 275)
(SEQ ID NO: 276)
(SEQ ID NO: 277)





(SEQ ID NO: 259)








V3 dir.
SGASISDSY
VHKSGDT
ARTLHGRRIYGIVAFNEWF
SLGSRA
NNQ
HIWDSRVPTKWV



(SEQ ID NO: 260)
(SEQ ID NO: 261)
TYFYMDV
(SEQ ID NO: 278)
(SEQ ID NO: 279)
(SEQ ID NO: 280)





(SEQ ID NO: 262)








V1/V dir.
QFRFDGYG
ISHDGIKK
CAKDLREDECEEWWSDYY
TSNIGNNF
ETD
atwaaslssarv


″b″
(SEQ ID NO: 263)
(SEQ ID NO: 264)
DFGKQLPCAKSRGGLVGIA
(SEQ ID NO: 281)
(SEQ ID NO: 282)
(SEQ ID NO: 283)





DNW








(SEQ ID NO: 265)





Ab
CDRH1
CDRH2
CDRH3
CDRL1
CDRL2
CDRL3





Anti-CD28
GYTFTSYY
IYPGNVNT
trshygldwnfdv
QNIYVW
KAS
qqgqtypyt



(SEQ ID NO: 479)
(SEQ ID NO: 480)
(SEQ ID NO: 481)
(SEQ ID NO: 488)
(SEQ ID NO: 489)
(SEQ ID NO: 490)





Anti-CD28
GFSLSDYG
IWAGGGT
ardkgysyyysmd
ESVEYYVTSL
AAS
qqsrkvpyt



(SEQ ID NO: 482)
(SEQ ID NO: 483)
(SEQ ID NO: 484)
(SEQ ID NO: 491)
(SEQ ID NO: 492)
(SEQ ID NO: 493)





Anti-CD3
GFTFTKAW
IKDKSNS
rgvyyalspfdy
QSLVHNNANTY
KVS
gqgtqyp



(SEQ ID NO: 485)
(SEQ ID NO: 486)
(SEQ ID NO: 487)
(SEQ ID NO: 494)
(SEQ ID NO: 495)
(SEQ ID NO: 496)
















TABLE B







CDR sequences of parental antibodies













Ab
CDR_H1
CDR_H2
CDR_H3
CDR_L1
CDR_L2
CDR_L3





CD4BS ″a″
DCTLN
LKPRGGAVNYARP
GKNCDYNWDFEH
RTSQYGLSA
SGSTRAA
QQYEF



(SEQ ID NO: 248)
LQ
(SEQ ID NO: 250)
(SEQ ID NO: 266)
(SEQ ID NO: 267)
(SEQ ID NO: 268)




(SEQ ID NO: 497)









CD4BS ″b″
GYTFTAHI
IKPQYGAV
DRSYGDSSWALDA
QGVGSD
HTS
QVLQF



(SEQ ID NO: 251)
(SEQ ID NO: 252)
(SEQ ID NO: 253)
(SEQ ID NO: 269)
(SEQ ID NO: 270)
(SEQ ID NO: 271)





MPER
GFDFDNAW
ITGPGGWSSV
TGKYYDFWSGYPPGEEYFQ
SLRSHY
GKN
SSRDKSGSRLSV



(SEQ ID NO: 254)
(SEQ ID NO: 255)
D
(SEQ ID NO: 500)
(SEQ ID NO: 501)
(SEQ ID NO: 274)





(SEQ ID NO: 256)








MPER_100W
GFDFDNAW
ITGPGGWSSV
TGKYYDFWWGYPPGEEYF
SLRSHY
GKN
SSRDKSGSRLSV



(SEQ ID NO: 254)
(SEQ ID NO: 255)
QD
(SEQ ID NO: 500)
(SEQ ID NO: 501)
(SEQ ID NO: 274)





(SEQ ID NO: 259)








V1/V2
GNTLKTYD
ISHEGDKK
CAKGSKHRLRDYALYDDD
HSLIHGDRNNY
LAS
CMQGRESPWTF


directed ″a″
(SEQ ID NO: 257)
(SEQ ID NO: 258)
GALNWAVDVDYLSNLEFW
(SEQ ID NO: 275)
(SEQ ID NO: 276)
(SEQ ID NO: 277)





(SEQ ID NO: 259)








V1/V2
QFRFDGYG
ISHDGIKK
CAKDLREDECEEWWSDYY
TSNIGNNF
ETD
ATWAASLSSAR


directed ″b″
(SEQ ID NO: 263)
(SEQ ID NO: 264)
DFGKQLPCAKSRGGLVGIA
(SEQ ID NO: 281)
(SEQ ID NO: 282)
V





DNW


(SEQ ID NO: 283)





(SEQ ID NO: 265)








V3
GASISDSY
VHKSGDT
ARTLHGRRIYGIVAFNEWF
SLGSRA
NNQ
HIWDSRVPTKW


directed
(SEQ ID NO: 499)
(SEQ ID NO: 261)
TYFYMDV
(SEQ ID NO: 278)
(SEQ ID NO: 279)
V





(SEQ ID NO: 262)


(SEQ ID NO: 280)





CD28
GYTFTSYY
IYPGNVNT
TRSHYGLDWNFDV
QNIYVW
KAS
QQGQTYPYT



(SEQ ID NO: 479)
(SEQ ID NO: 480)
(SEQ ID NO: 481)
(SEQ ID NO: 488)
(SEQ ID NO: 489)
(SEQ ID NO: 490)





CD28_2
GFSLSDYG
IWAGGGT
ARDKGYSYYYSMD
ESVEYYVTSL
AAS
QQSRKVPYT



(SEQ ID NO: 482)
(SEQ ID NO: 483)
(SEQ ID NO: 484)
(SEQ ID NO: 491)
(SEQ ID NO: 492)
(SEQ ID NO: 493)





CD3
GFTFTKAW
IKDKSNS
RGVYYALSPFDY
QSLVHNNANTY
KVS
GQGTQYP



(SEQ ID NO: 485)
(SEQ ID NO: 486)
(SEQ ID NO: 487)
(SEQ ID NO: 494)
(SEQ ID NO: 495)
(SEQ ID NO: 496)
















TABLE C







Variable domain sequences of parental antibodies









Ab Name
VH
VL





CD4BS ″a″
QVQLVQSGGQMKKPGESMRISCRASGYEFIDCTLNWIRLAP
EIVLTQSPGTLSLSPGETAIISCRTSQYGSLAWYQQ



GKRPEWMGWLKPRGGAVNYARPLQGRVTMTRDVYSDTAF
RPGQAPRLVIYSGSTRAAGIPDRFSGSRWGPDYNL



LELRSLTVDDTAVYFCTRGKNCDYNWDFEHWGRGTPVIV
TISNLESGDFGVYYCQQYEFFGQGTKVQVDIK



S
(SEQ ID NO: 512)



(SEQ ID NO: 502)






CD4BS ″b″
RAHLVQSGTAMKKPGASVRVSCQTGYTFTAHILFWFRQAP
YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW



GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY
YQHKPGRAPKLLIHHTSSVEDGVPSRFSGSGFHTS



MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV
FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK



VSA
(SEQ ID NO: 513)



(SEQ ID NO: 503)






CD4BS ″b″
RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP
YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW


(Δglycan)
GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY
YQHKPGRAPKLLIHHTSSVEDGVPSRFSGSGFHTS



MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV
Fcustom-character LTISDLQADDIATYYCQVLQFFGRGSRLHIK



VSA
(SEQ ID NO: 514)



(SEQ ID NO: 503)






CD4BS ″b″
RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP
YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW


(Δisomerization
GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY
YQHKPGRAPKLLIHHTSSVEcustom-character GVPSRFSGSGFHTS


D55E)
MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV
FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK



VSA
(SEQ ID NO: 515)



(SEQ ID NO: 503)






CD4BS ″b″
RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP
YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLWH


(Δisomerization
GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY
YQHKPGRAPKLLIHHTSSVEDcustom-character VPSRFSGSGFHTS


G56A)
MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV
FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK



VSA
(SEQ ID NO: 516)



(SEQ ID NO: 503)






CD4BS ″b″
RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP
YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW


(Δglycan/
GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY
YQHKPGRAPKLLIHHTSSVEcustom-character GVPSRFSGSGFHTS


Δisomerization
MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV
Fcustom-character LTISDLQADDIATYYCQVLQFFGRGSRLHIK


D55E)
VSA
(SEQ ID NO: 517)



(SEQ ID NO: 503)






MPER
EVRLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQP
ASELTQDPAVSVALKQTVTITCRGDSLRSHYASW



PGKGLEWVGRITGPGEGWSVDYAESVKGRFTISRDNTKNTL
YQKKPGQAPVLLFYGKNNRPSGIPDRFSGSASGN



YLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQD
RASLTITGAQAEDEADYYCSSRDKSGSRLSVFGG



WGQGTLVIVSS
GTKLTVL



(SEQ ID NO: 504)
(SEQ ID NO: 518)





MPER_100W
EVRLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQP
ASELTQDPAVSVALKQTVTITCRGDSLRSHYASW



PGKGLEWVGRITGPGEGWSVDYAESVKGRFTISRDNTKNTL
YQKKPGQAPVLLFYGKNNRPSGIPDRFSGSASGN



YLEMNNVRTEDTGYYFCARTGKYYDFWcustom-characterGYPPGEEYFQD
RASLTITGAQAEDEADYYCSSRDKSGSRLSVFGG



WGQGTLVIVSS
GTKLTVL



(SEQ ID NO: 505)
(SEQ ID NO: 518)





V1/V2
QVHLTQSGPEVRKPGTSVKVSCKAPGNTLKTYDLHWVRSV
DFVLTQSPHSLSVTPGESASISCKSSHSLIHGDRNN


directed ″a″
PGQGLQWMGWISHEGDKKVIVERFKAKVTIDWDRSTNTAY

YLAWYVQKPGRSPQLLIYLASSRASGVPDRFSGS




LQLSGLTSGDTAVYYCAKGSKHRLRDYALYDDDGALNWA
GSDKDFTLKISRVETEDVGTYYCMQGRESPWTFG




VDVDYLSNLEFWGQGTAVTVSS

QGTKVDIK



(SEQ ID NO: 506)
(SEQ ID NO: 519)





V1/V2
QVQLVESGGGVVQPGTSLRLSCAASQFRFGDYGMHWVRQ
QSVLTQPPSVSAAPGQKVTISCSGNTSNIGNNFVS


directed ″b″
APGKGLEWVASISHDGIKKYHAEKVWGRFTISRDNSKNTLY
WYQQRPGRAPQLLIYETDKRPSGIPDRFSASKSGT



LQMNSLRPEDTALYYCAKDLREDECEEWWSDYYDFGKQLP
SGTLAITGLQTGDEADYYCATWAASLSSARVFGT




CAKSRGGLVGIADNWGQGTMVTVSS

GTKVIVL



(SEQ ID NO: 507)
(SEQ ID NO: 520)





V3
QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPG
SDISVAPGETARISCGEKSLGSRAVQWYQHRAGQ


directed
KGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLV
APSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTIT



AATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVW
SVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTV



GNGTQVTVSS
G



(SEQ ID NO: 508)
(SEQ ID NO: 521)





CD28
QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQA
DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLN



PGQGLEWIGSIYPGNVNTNYAQKRQGRATLTVDTSISTAYM
WYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSG



ELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS
TDFTLTISSLQPEIATYYCCQQGQTYPYTFGQGTK



(SEQ ID NO: 509)
LEIK




(SEQ ID NO: 522)





CD28_2
QVQLQESGPGLVKPSQTLSLTCTVSGFSLSDYGVHWVRQPP
DIVLTTQSPASLAVSPGQRATITCRASESVEYYVTS



GKGLEWLGVIWAGGGTNYNPSLKSRKTISKDTSKNQVSLKL

LMQWYQQKPGQPPKLLIFAASNVESGVPARFSGS




SSVTAADTAVYYCARDKGYSYYYSMDYWGQGTTVTVSS
GSGTDFTLTINPVEANDVANYYCQQSRKVPYTFG



(SEQ ID NO: 510)
QGTKLEIK




(SEQ ID NO: 523)





CD3
QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQ
DIVMTQTPLSLSVTPGQPASISCKSSQSLVHNNAN



APGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNT

TYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGS




LYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTV
GSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFG



SS
SGTKVEIK



(SEQ ID NO: 511)
(SEQ ID NO: 524)





CDR sequences are underlined.


Variable domain modifications are shown in bold and italicized.





Claims
  • 1. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I];a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1  [II];a third polypeptide chain comprises a structure represented by the formula: VH3-CH1  [III],and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV];whereinVL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is an immunoglobulin CH1 heavy chain constant domain; andL1, L2, L3, and L4 are amino acid linkers;and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
  • 2. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I]and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]and a third polypeptide chain comprises a structure represented by the formula:VH3-CH1-hinge-CH2-CH3  [III]and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV]wherein:VL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is an immunoglobulin CH1 heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; andL1, L2, L3 and L4 are amino acid linkers;and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
  • 3. The binding protein of claim 1 or claim 2, wherein the one or more HIV target protein is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.
  • 4. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein.
  • 5. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different.
  • 6. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding three different antigen targets.
  • 7. The binding protein of claim 1 or claim 2, wherein the binding protein is capable of inhibiting the function of one or more HIV target proteins.
  • 8. The binding protein of any one of claims 1-7, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
  • 9. The binding protein of any one of claims 1-7, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 10. The binding protein of any one of claims 1-9, wherein VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 11. The binding protein of any one of claims 1-10, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
  • 12. The binding protein of any one of claims 1-10, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 13. The binding protein of any one of claims 1-12, wherein VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 14. The binding protein of any one of claims 1-13, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
  • 15. The binding protein of any one of claims 1-13, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 16. The binding protein of any one of claims 1-15, wherein VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
  • 17. The binding protein of any one of claims 1-16, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
  • 18. The binding protein of any one of claims 1-16, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 19. The binding protein of any one of claims 1-18, wherein VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 20. The binding protein of any one of claims 1-19, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
  • 21. The binding protein of any one of claims 1-19, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 22. The binding protein of any one of claims 1-21, wherein VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 23. The binding protein of any one of claims 1-22, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
  • 24. The binding protein of any one of claims 1-22, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 25. The binding protein of any one of claims 1-24, wherein VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
  • 26. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250.
  • 27. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512, VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502.
  • 28. The binding protein of any one of claims 1-27, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502.
  • 29. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
  • 30. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
  • 31. The binding protein of any one of claims 1-25 and 29-30, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
  • 32. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
  • 33. The binding protein of any one of claims 1-25, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
  • 34. The binding protein of any one of claims 1-25 and 32-33, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
  • 35. The binding protein of claim 1, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 36. The binding protein of claim 1, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 37. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 38. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 39. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH1 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 40. The binding protein of claim 2, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 41. The binding protein of claim 2, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 42. The binding protein of claim 2, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 43. The binding protein of claim 1 or claim 2, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.
  • 44. The binding protein of claim 1 or claim 2, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.
  • 45. The binding protein of any one of claims 1-44, wherein L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
  • 46. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I]and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1  [II]and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1  [III]and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV]wherein:VL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain; andL1, L2, L3, and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;wherein: (a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; andwherein: (a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
  • 47. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I]
  • 48. The binding protein of claim 46, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 49. The binding protein of claim 46, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 50. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 51. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 52. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 53. The binding protein of claim 47, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 54. The binding protein of claim 47, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 55. The binding protein of claim 47, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 56. The binding protein of claim 46 or claim 47, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.
  • 57. The binding protein of claim 46 or claim 47, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.
  • 58. The binding protein of any one of claims 46-57, wherein L1 comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
  • 59. A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein: (a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.
  • 60. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I];a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1  [II];a third polypeptide chain comprises a structure represented by the formula: VH3-CH1  [III];and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV];whereinVL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain; andL1, L2, L3, and L4 are amino acid linkers;and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
  • 61. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I];a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II];a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3  [III];and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV];whereinVL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; andL1, L2, L3, and L4 are amino acid linkers;and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
  • 62. The binding protein of claim 60 or claim 61, wherein the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.
  • 63. The binding protein of claim 60 or claim 61, wherein the one or more T cell target proteins are CD3 or CD28.
  • 64. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein.
  • 65. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins.
  • 66. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein.
  • 67. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins.
  • 68. The binding protein of claim 60 or claim 61, wherein the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein.
  • 69. The binding protein of any one of claims 60-68, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
  • 70. The binding protein of any one of claims 60-68, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 71. The binding protein of any one of claims 60-70, wherein VL1 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 72. The binding protein of any one of claims 60-71, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
  • 73. The binding protein of any one of claims 60-71, wherein VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 74. The binding protein of any one of claims 60-73, wherein VL2 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 75. The binding protein of any one of claims 60-74, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
  • 76. The binding protein of any one of claims 60-74, wherein VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 77. The binding protein of any one of claims 60-76, wherein VL3 comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
  • 78. The binding protein of any one of claims 60-77, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
  • 79. The binding protein of any one of claims 60-77, wherein VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 80. The binding protein of any one of claims 60-79, wherein VH1 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 81. The binding protein of any one of claims 60-80, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
  • 82. The binding protein of any one of claims 60-80, wherein VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 83. The binding protein of any one of claims 60-82, wherein VH2 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 84. The binding protein of any one of claims 60-83, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
  • 85. The binding protein of any one of claims 60-83, wherein VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 86. The binding protein of any one of claims 60-85, wherein VH3 comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
  • 87. The binding protein of any one of claims 60-86, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
  • 88. The binding protein of any one of claims 60-86, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
  • 89. The binding protein of any one of claims 60-88, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
  • 90. The binding protein of any one of claims 60-86, wherein VL1 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; VL2 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; VL3 comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; VH1 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; VH2 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and VH3 comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
  • 91. The binding protein of any one of claims 60-86, wherein VL1 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; VL2 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; VL3 comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; VH1 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; VH2 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and VH3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
  • 92. The binding protein of any one of claims 60-86 and 90-91, wherein VL1 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; VL2 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; VL3 comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; VH1 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; VH2 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and VH3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
  • 93. The binding protein of claim 60, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 94. The binding protein of claim 60, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 95. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 96. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 97. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 98. The binding protein of claim 61, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 99. The binding protein of claim 61, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 100. The binding protein of claim 61, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 101. The binding protein of claim 60 or claim 61, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.
  • 102. The binding protein of claim 60 or claim 61, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.
  • 103. The binding protein of any one of claims 60-102, wherein L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
  • 104. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I]and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1  [II]and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1  [III]and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV]wherein:VL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain; andL1, L2, L3, and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;wherein: (a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; andwherein: (a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
  • 105. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL  [I]and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3  [II]and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3  [III]and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL  [IV]wherein:VL1 is a first immunoglobulin light chain variable domain;VL2 is a second immunoglobulin light chain variable domain;VL3 is a third immunoglobulin light chain variable domain;VH1 is a first immunoglobulin heavy chain variable domain;VH2 is a second immunoglobulin heavy chain variable domain;VH3 is a third immunoglobulin heavy chain variable domain;CL is an immunoglobulin light chain constant domain;CH1 is the immunoglobulin CH1 heavy chain constant domain;CH2 is an immunoglobulin CH2 heavy chain constant domain;CH3 is an immunoglobulin CH3 heavy chain constant domain;hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; andL1, L2, L3, and L4 are amino acid linkers;wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;wherein: (a) VL1, VL2 and VL3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or(b) VL1, VL2 and VL3 each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; andwherein: (a) VH1, VH2, and VH3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or(b) VH1, VH2, and VH3 each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
  • 106. The binding protein of claim 104, wherein the second polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 107. The binding protein of claim 104, wherein the third polypeptide chain further comprises an Fc region linked to CH1, the Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains.
  • 108. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 109. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 110. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH1 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 111. The binding protein of claim 105, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
  • 112. The binding protein of claim 105, wherein the CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
  • 113. The binding protein of claim 105, wherein the CH3 domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
  • 114. The binding protein of claim 104 or claim 105, wherein at least one of L1, L2, L3, or L4 is independently 0 amino acids in length.
  • 115. The binding protein of claim 104 or claim 105, wherein L1, L2, L3, or L4 are each independently at least one amino acid in length.
  • 116. The binding protein of any one of claims 104-115, wherein L1 is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
  • 117. A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein: (a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447,(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.
  • 118. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of claims 1-117.
  • 119. An expression vector comprising the nucleic acid molecule of claim 118.
  • 120. An isolated host cell comprising the nucleic acid molecule of claim 118.
  • 121. An isolated host cell comprising the expression vector of claim 119.
  • 122. The isolated host cell of claim 120 or claim 121, wherein the host cell is a mammalian cell or an insect cell.
  • 123. A vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein of any one of claims 1-117.
  • 124. The vector system of claim 123, wherein the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.
  • 125. The vector system of claim 123, wherein the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein.
  • 126. The vector system of any one of claims 123-125, wherein the one or more vectors are expression vectors.
  • 127. An isolated host cell comprising the vector system of any one of claims 123-126.
  • 128. The isolated host cell of claim 127, wherein the host cell is a mammalian cell or an insect cell.
  • 129. A method of producing a binding protein, the method comprising: a) culturing a host cell of any one of claims 120-122 and claims 127-128 under conditions such that the host cell expresses the binding protein; andb) isolating the binding protein from the host cell.
  • 130. A method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of claims 1-117.
  • 131. The method of claim 130, wherein the binding protein is co-administered with standard anti-retroviral therapy.
  • 132. The method of claim 130 or claim 131, wherein administration of the at least one binding protein results in the neutralization of one or more HIV virions.
  • 133. The method of any one of claims 130-132, wherein administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient.
  • 134. The method of any one of claims 130-133, wherein the patient is a human.
  • 135. The binding protein of any one of claims 1-117 for the prevention or treatment of an HIV infection in a patient.
  • 136. The binding protein of claim 135, wherein the binding protein is co-administered with standard anti-retroviral therapy.
  • 137. The binding protein of claim 135 or claim 136, wherein the binding protein causes the neutralization of one or more HIV virions in the patient.
  • 138. The binding protein of any one of claims 135-137, wherein the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient.
  • 139. The binding protein of any one of claims 135-138, wherein the patient is a human.
Priority Claims (1)
Number Date Country Kind
EP16305211.1 Feb 2016 EP regional
CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional Application Ser. No. 62/246,113, filed Oct. 25, 2015, EP Application No. EP16305211.1, filed Feb. 24, 2016, U.S. Provisional Application Ser. No. 62/322,029, filed Apr. 13, 2016, and U.S. Provisional Application Ser. No. 62/331,169, filed May 3, 2016, which are incorporated herein by reference in their entirety.

Government Interests

This invention was created in the performance of a Cooperative Research and Development Agreement (NIAID #2014-0038) with the National Institutes of Health, an agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.

PCT Information
Filing Document Filing Date Country Kind
PCT/US2016/058540 10/24/2016 WO 00
Provisional Applications (3)
Number Date Country
62246113 Oct 2015 US
62322029 Apr 2016 US
62331169 May 2016 US