[0001] This application claims the priority benefit of U.S. Provisional Application Serial No. 62/246,113, filed October 25, 2015, EP Application No. EP16305211.1, filed February 24, 2016, U.S. Provisional Application Serial No. 62/322,029, filed April 13, 2016, and U.S. Provisional Application Serial No.62/331,169, filed May 03, 2016, which are incorporated herein by reference in their entirety.

[0002] 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.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

[0003] 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: October 19, 2016, size: 1,064 KB).

FIELD OF THE INVENTION

[0004] 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

[0005] 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

[0006] 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:

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

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

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

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.

[0007] 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.

[0008] 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:

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

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

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

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.

[0009] 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.

[0010] 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, 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. 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).

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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).

[0016] 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:

V H1 -L 3 V H 2 -L 4 -C H1 [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.

[0017] 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:

V H1 -L 3 V H 2 -L 4 -C H1 [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.

[0018] 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

What is claimed is:

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:

V H1 - L 3 V H 2 - L 4 -C H1 [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.

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.

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 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.

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; 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.

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.

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];

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.

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.

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:

V H1 - L 3 V H 2 - L 4 -C H1 [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.

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.

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 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.

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; and

b) 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.