0001] This application claims priority to U.S. Provisional Application No. 62/831,415, filed April 9, 2019, and EP Application No. EP19306312.0, filed October 8, 2019, the disclosures of each of which are incorporated herein by reference in their entirety.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

[0002] 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: 183952031940SEQLIST.TXT, date recorded: March 25, 2020, size: 580 KB).

FIELD

[0003] 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. 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

[0004] Anti-retroviral therapy (ART) has been the standard of care for HIV/AIDS patients in the past decades. ART drugs target internal proteins such as reverse

transcriptase (RT), integrase (IN), and viral protease (PI) by inhibiting reverse transcription of HIV-1 genome, integration of HIV-1 genome, and proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles. Treatment using ART or combination of different classes of ART results in inhibition of HIV- 1 replication and subsequent reduction of viremia, often to undetectable level (aviremic status). Although ART greatly helps HIV patients in controlling their disease progression, and containing the global HIV epidemic, it does require patients taking daily medicines often following a strict regimen. About 10% patients fail therapy each year due to drug toxicity, suboptimal adherence and emerging drug resistance. As more HIV patients can live a normal life span (over 80 years), chronic complications are of particular concern, such as aging and drug-drug interaction, and cardiovascular/renal/bone toxicities. The economic burden treating HIV/AIDS has not subsided thus far.

[0005] HIV latently infects long-lived resting memory CD4+ T cells and others as a form of proviral DNA integrated into the host genome. The latently infected cells survive for decades and self-renew like stem cells via homeostatic proliferation, which is regarded as an HIV-1 reservoir. The HIV-1 reservoirs are neither affected by ART nor the host immune system as they do not express viral proteins. Yet, a small proportion of cells among the reservoirs are randomly reactivated by unknown mechanism(s), which are responsible for recurrence of viremia once ART is stopped.

[0006] Therefore, a need exists for developing HIV/AIDS treatments to target the HIV-1 reservoir(s), and ultimately eliminate them completely, achieving a cure, or long term remission of HIV without any further treatment. Any therapeutic strategy to eliminate the HIV-1 reservoir needs to activate the reservoir first, followed by elimination of the activated HIV-1 reservoir cells.

[0007] All references cited herein, including patent applications, patent publications, and UniProtKB/Swiss-Prot Accession numbers are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.

BRIEF SUMMARY

[0008] To meet these and other needs, provided herein are multispecific binding proteins ( e.g ., antibodies) that form three antigen binding sites. In some embodiments, the binding proteins bind one or more HIV target proteins and a CD3 polypeptide. In some embodiments, the binding proteins bind an HIV target protein, a CD28 polypeptide, and a CD3 polypeptide. The trispecific anti-HIV/CD28xCD3 T cell engager (TCE) concept disclosed herein is thought to be an effective eliminator of the HIV-1 reservoir through activation by anti-CD3, co-activation by anti-CD28, and subsequent killing of activated HIV-1 reservoir cells through anti-HIV/anti-CD28 by engaging activated CD8 T cells, providing a potential strategy for attacking the HIV-1 reservoir. In addition, anti-CD3 binding sites are described with high affinity binding to human CD3 polypeptides and potential manufacturing liabilities (e.g., deamidation sites) removed.

[0009] In some embodiments, provided herein are binding proteins comprising four polypeptide chains that form the 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 [P]

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;

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

wherein VH1 and VL1 form a first antigen binding site;

wherein VH2 and VL2 form a second antigen binding site that binds a CDS polypeptide, wherein the VH2 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:22), and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of

QSLVHX1NX2X3TY, wherein X1 is E or Q, X2 is A or L, and X3 is Q, R, or F (SEQ ID NO:293), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30); and

wherein VH3 and VL3 form a third antigen binding site that binds an HIV target protein.

[0010] In some embodiments, the first binding site binds a CD28 polypeptide ( e.g ., a human CD28 polypeptide). In some embodiments, the VH1 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:33), and the VL1 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of KAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO: 36). In some embodiments, the VH1 domain comprises the amino acid sequence of

QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGN VNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDV WGKGTTVTVSS (SEQ ID NO:59), and/or the VL1 domain comprises the amino acid sequence of

DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHT GVPSRF SGSGSGTDFTLTIS SLQPEDIAT YYCQQGQTYP YTF GQGTKLEIK (SEQ ID NO: 60).

[0011] In some embodiments, the CDR-L1 sequence of the VL2 domain comprises an amino acid sequence selected from the group consisting of QSLVHQNAQTY (SEQ ID NO:24), QSLVHENLQTY (SEQ ID NO:25), QSLVHENLFTY (SEQ ID NO:26), and QSLVHENLRTY (SEQ ID NO:27). In some embodiments, the VH2 domain comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:22); and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHQNAQTY (SEQ ID NO:24), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30). In some embodiments, the VH2 domain comprises: a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of

RGVYYALSPFDY (SEQ ID NO:22); and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLQTY (SEQ ID NO:25), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30). In some embodiments, the VH2 domain comprises: a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:22); and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLFTY (SEQ ID NO:26), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30). In some embodiments, the VH2 domain comprises: a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:22); and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHENLRTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30). In some embodiments, the VH2 domain comprises the amino acid sequence of

QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKD K SN S Y AT Y Y AD S VKGRFTI SRDD SKNTL YLQMN SLR AEDT A V Y Y CRGV Y Y AL SPF DYWGQGTLVTVSS (SEQ ID NO:52), and/or the VL2 domain comprises an amino acid sequence selected from the group consisting of

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHQNAQT YL S W YLQKPGQ SPQ SLI YK V S NRF SGVPDRF SGSGSGTDFTLKISRVEAED VGVYYCGQGTQ YPFTFGSGTKVEIK

(SEQ ID NO: 54),

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHENLQTYL S W YLQKPGQ SPQ SLI YK V S NRF SGVPDRF SGSGSGTDFTLKISRVEAED VGVYYCGQGTQYPFTFGSGTKVEIK

(SEQ ID NO: 55),

DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVS NRF SGVPDRF SGSGSGTDFTLKISRVEAED VGVYYCGQGTQYPFTFGSGTKVEIK

(SEQ ID NO:56), and

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHENLRTYL S WYLQKPGQ SPQ SLIYK V S NRF S GVPDRF S GS GS GTDF TLKI SRVE AED V GV Y Y CGQGT Q YPF TF GSGTK VEIK

(SEQ ID NO:57). In some embodiments, a binding protein of the present disclosure comprises an antigen binding site comprising: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:52, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:54. In some embodiments, a binding protein of the present disclosure comprises an antigen binding site comprising: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:52, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:55. In some embodiments, a binding protein of the present disclosure comprises an antigen binding site comprising: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:52, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:56. In some embodiments, a binding protein of the present disclosure comprises an antigen binding site comprising: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:52, and/or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:57.

[0012] In some embodiments, the third antigen binding site binds an HIV target protein selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160. In some embodiments, the VH3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of NCPIN (SEQ ID NO: l) a CDR-H2 sequence comprising the amino acid sequence of WMKPRHGAV S YARQLQG (SEQ ID NO:2), and a CDR-H3 sequence comprising the amino acid sequence of GKYCTARDYYNWDFEH (SEQ ID NO:3), and the VL3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of RTSQYGSLA (SEQ ID NO:4), a CDR-L2 sequence comprising the amino acid sequence of SGSTRAA (SEQ ID NO:5), and a CDR-L3 sequence comprising the amino acid sequence of QQYEF (SEQ ID NO:6). In some embodiments, the Vro domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTAHI (SEQ ID NO:7) a CDR-H2 sequence comprising the amino acid sequence of IKPQYGAV (SEQ ID NO:8) or IKPQYGAT (SEQ ID NO:9), and a CDR-H3 sequence comprising the amino acid sequence of DRSYGDSSWALDA (SEQ ID NO: 10), and the VL3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGVGSD (SEQ ID NO: 11), a CDR-L2 sequence comprising the amino acid sequence of HTS (SEQ ID NO: 12), and a

CDR-L3 sequence comprising the amino acid sequence of CQVLQF (SEQ ID NO: 13). In some embodiments, the VH3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of DCTLN (SEQ ID NO: 14) a CDR-H2 sequence comprising the amino acid sequence of WLKPRW GAVNY ARPLQG (SEQ ID NO: 15), and a CDR-H3 sequence comprising the amino acid sequence of GKNCDYNWDFEH (SEQ ID NO: 16), and the VL3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of

RTSQYGSLA (SEQ ID NO: 17), a CDR-L2 sequence comprising the amino acid sequence of SGSTRAA (SEQ ID NO: 18), and a CDR-L3 sequence comprising the amino acid sequence of QQYEF (SEQ ID NO: 19). In some embodiments, the VH3 domain comprises the amino acid sequence of

QVRLSQSGGQMKKPGDSMRISCRASGYEFINCPINWIRLAPGKRPEWMGWMKPRH GAVSYARQLQGRVTMTRDMYSETAFLELRSLTSDDTAVYFCTRGKYCTARDYYN WDFEHWGQGTPVTVSS (SEQ ID NO:43), and/or the VL3 domain comprises the amino acid sequence of

SLTQ SPGTL SL SPGET All S CRT S Q Y GSL AW Y QQRPGQ APRL VI Y S GSTRA AGIPDRF SGSRWGPDYNLTISNLESGDF GVYY CQQYEFF GQGTKVQVDIK (SEQ ID NO:45).

In some embodiments, the VH3 domain comprises the amino acid sequence of

QVRLSQSGGQMKKPGDSMRISCRASGYEFINCPINWIRLAPGKRPEWMGWMKPRH GAVSYARQLQGRVTMTRQLSQDPDDPDWGTAFLELRSLTSDDTAVYFCTRGKYC T ARD YYNWDFEHW GQGTP VT V S S (SEQ ID NO:44), and/or the VL3 domain comprises the amino acid sequence of

SLTQ SPGTL SL SPGET All S CRT S Q Y GSL AW Y QQRPGQ APRL VI Y S GSTRA AGIPDRF SGSRWGPDYNLTISNLESGDF GVYY CQQYEFF GQGTKVQVDIK (SEQ ID NO:45).

In some embodiments, the VH3 domain comprises the amino acid sequence of

RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQ

Y GAVNF GGGFRDRVTLTRD VYREIAYMDIRGLKPDDT AV YY C ARDRS Y GD S SW A LDAWGQGTTVVVSA (SEQ ID NO:46), and/or the VL3 domain comprises the amino acid sequence of

YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDG VP SRF SGSGFHT SFNLTISDLQ ADDIAT YY CQ VLQFF GRGSRLHIK (SEQ ID NO:49). In some embodiments, the VH3 domain comprises the amino acid sequence of

RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQ

Y GATNF GGGFRDRVTLTRD VYREI AYMDIRGLKPDDT AVYY C ARDRS Y GD S SWA

LDAWGQGTTVVVSA (SEQ ID NO:47), and/or the VL3 domain comprises the amino acid sequence of

YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDG VP SRF SGSGFHT SFNLTISDLQ ADDIAT YY CQ VLQFF GRGSRLHIK (SEQ ID NO:49). In some embodiments, the VH3 domain comprises the amino acid sequence of

RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQ

Y GA VNF GGGFRDR VTLTRQL S QDPDDPD W GI A YMDIRGLKPDDT A V Y Y C ARDRS

Y GD S S WALD AW GQGTT VVV S A (SEQ ID NO:48), and/or the VL3 domain comprises the amino acid sequence of

YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDG VP SRF SGSGFHT SFNLTISDLQ ADDIAT YY CQ VLQFF GRGSRLHIK (SEQ ID NO:49). In some embodiments, the VH3 domain comprises the amino acid sequence of

Q VQL VQ S GGQMKKP GE SMRI S CRA S GYEFID C TLNWIRL AP GKRPEWMGWLKPR WGAVNYARPLQGRVTMTRQLSQDPDDPDWGTAFLELRSLTVDDTAVYFCTRGKN CD YNWDFEHW GRGTP VI V S S (SEQ ID NO:50), and/or the VL3 domain comprises the amino acid sequence of

LTQSPGTLSLSPGETAIISCRTSQYGSLAWYQQRPGQAPRLVIYSGSTRAAGIPDRFS GSRWGPDYNLTISNLESGDFGVYYCQQYEFFGQGTKVQVDIK (SEQ ID NO:51).

[0013] In some embodiments that may be combined with any other embodiments described herein, at least one of L1, L2, L3 or L4 is independently 0 amino acids in length.

In some embodiments, L1, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:40), GGGGSGGGGSGGGGS (SEQ ID NO: 41), S, RT, TKGPS (SEQ ID NO: 39), GQPKAAP (SEQ ID NO: 38), and GGSGSSGSGG (SEQ ID NO: 42). In some embodiments, L1, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:40), GGGGSGGGGSGGGGS (SEQ ID NO:41), S, RT, TKGPS (SEQ ID NO:39), GQPKAAP (SEQ ID NO: 38), and

GGSGSSGSGG (SEQ ID NO:42). In some embodiments, L1 comprises the sequence GQPKAAP (SEQ ID NO: 38), L2 comprises the sequence TKGPS (SEQ ID NO:39), L3 comprises the sequence S, and L4 comprises the sequence RT. In some embodiments, at least one of L1, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO:37). In some embodiments, L1, L2, L3 and L4 comprise the sequence DKTHT (SEQ ID NO:37).

[0014] In some embodiments that may be combined with any other embodiments described herein, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. In some embodiments, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. In some embodiments, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. In some embodiments, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S. In some embodiments, the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

[0015] In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:62 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:62; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:63; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:64 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:64. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:69 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:69; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:70 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:70; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:71; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:72 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:72. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:77 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:77; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:78 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:78; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:79 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:79; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:80 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:80. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:85 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:85; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:86 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:86; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:87 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:87; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:88 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:88. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:93 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:93; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:94 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 94; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:95 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 95; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 96 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:96. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104. In some embodiments, the first 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; the second 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; the third 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; and the fourth polypeptide chain 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 109 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 109; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 110; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 111; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: l 13 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; the second 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; the third 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; and the fourth 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: l 16. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: l 17; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 120. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 136. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 141 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 142 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 143; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 144 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 144. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 152 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 168. In some embodiments, the first 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; the second 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; the third 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; and the fourth 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. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 176.

[0016] In some embodiments, provided herein are isolated nucleic acid molecules comprising a nucleotide sequence encoding the binding protein of any one of the above embodiments. In some embodiments, provided herein are expression vectors comprising the nucleic acid molecule of any one of the above embodiments. In some embodiments, provided herein are isolated host cells comprising the nucleic acid molecule of any one of the above embodiments or the expression vector of any one of the above embodiments. In some embodiments, the host cell is a mammalian or insect cell.

[0017] In some embodiments, provided herein are pharmaceutical compositions comprising the binding protein of any one of the above embodiments and a

pharmaceutically acceptable carrier.

[0018] In some embodiments, provided herein are methods 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 the above embodiments or the pharmaceutical composition of any one of the above embodiments. In some embodiments, the binding protein is co-administered with standard anti-retroviral therapy. In some embodiments, administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.

[0019] In some embodiments, the binding protein or pharmaceutical composition of any one of the above embodiments is provided for the prevention and/or treatment of HIV infection in a patient. In some embodiments, the binding protein is to be co-administered with standard anti-retroviral therapy. In some embodiments, the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.

[0020] In some embodiments, the binding protein or pharmaceutical composition of any one of the above embodiments is provided for use in the manufacture of a medicament for the prevention and/or treatment of HIV infection in a patient. In some embodiments, the binding protein is to be co-administered with standard anti-retroviral therapy. In some embodiments, the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.

[0021] In some embodiments, provided herein is 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 the above embodiments. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.

[0022] In some embodiments, provided herein are kits comprising one, two, three, or four polypeptide chains of a binding protein according to any one of the above

embodiments. In some embodiments, the kits further comprise instructions for using the polypeptide chain or binding protein according to any of the methods or uses described herein, e.g. , supra.

[0023] In some embodiments, provided herein are kits comprising one, two, three, or four polynucleotides according to any one of the above embodiments. In some

embodiments, provided herein are kits of polynucleotides comprising one, two, three, or four polynucleotides of a kit of polynucleotides comprising: (a) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 177, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 178, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 179, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 180; (b) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 181, a second polynucleotide

comprising the polynucleotide sequence of SEQ ID NO: 182, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 183, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 184; (c) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 185, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 186, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 187, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 188; (d) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 189, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 190, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 191, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 192; (e) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 195, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 196; (f) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 198, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 199, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:200; (g) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:201, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:202, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:203, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:204; (h) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:205, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:206, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:207, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:208; (i) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:209, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:210, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:211, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:212; (j) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:213, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:214, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:215, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:216; (k) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:217, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:218, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:219, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:220; (1) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:221, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:222, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:223, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:224; (m) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:225, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:226, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:227, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:228; (n) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:229, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:230, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:231, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:232; (o) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:233, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:234, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:235, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:236; (p) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:237, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:238, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:239, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:240; (q) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:241, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:242, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:243, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:244; (r) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:245, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:246, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:247, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:248; (s) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:249, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:250, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:251, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:252; (t) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:253, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:254, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:255, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:256; (u) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:257, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:258, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:259, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:260; (v) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:261, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:262, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:263, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:264; (w) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:265, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:266, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:267, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:268; (x) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:269, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:270, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:271, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:272; (y) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:273, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:274, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:275, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:276; (z) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:277, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:278, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:279, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:280; (aa) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:281, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:282, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:283, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:284; (bb) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:285, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:286, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:287, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:288; or (cc) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:289, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:290, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:291, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:292. In some embodiments, the first, second, third, and fourth polynucleotides are present on one or more expression vectors, e.g ., one, two, three, or four expression vectors.

[0024] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 provides a schematic representation of a trispecific binding protein comprising four polypeptide chains that form three antigen binding sites that binds three target proteins: CD28, CD3, and HIV Env. A first pair of polypeptides possess dual variable domains having a cross-over orientation (VH1-VH2 and VL2-VL1) forming two antigen binding sites (VH1 and VL1; VH2 and VL2) that recognize CD28 and CD3, resepectively, and a second pair of polypeptides possess a single variable domain (VH3 and VL3) forming a single antigen binding site that recognizes HIV Env. The trispecific binding protein shown in FIG. 1 uses a constant region with a“knobs-into-holes” mutation, where the knob is on the second pair of polypeptides with a single variable domain.

[0026] FIG. 2 shows a schematic representation of a trispecific T cell Engager (TCE) strategy for using the anti-HIV trispecific binding protein shown in FIG. 1 to target and eliminate the HIV reservoir.

DETAILED DESCRIPTION

[0027] The present disclosure provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind to one or more human immunodeficiency virus (HIV) target proteins and/or one or more T-cell receptor target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation, and wherein a second pair of polypeptides possess a single variable domain.

[0028] The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

Definitions

[0029] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0030] It is understood that aspects and embodiments of the disclosure described herein include“comprising,”“consisting,” and“consisting essentially of’ aspects and

embodiments.

[0031] The term "polynucleotide" as used herein refers to single-stranded or double-stranded nucleic acid polymers of at least 10 nucleotides in length. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or

deoxyribonucleotides or a modified form of either type of nucleotide. Such modifications include base modifications such as bromuridine, ribose modifications such as arabinoside and 2',3'-dideoxyribose, and internucleotide linkage modifications such as

phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term

"polynucleotide" specifically includes single-stranded and double-stranded forms of DNA.

[0032] An "isolated polynucleotide" is a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence.

[0033] An "isolated polypeptide" is one that: (1) is free of at least some other polypeptides with which it would normally be found, (2) is essentially free of other polypeptides from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or noncovalent interaction) with portions of a polypeptide with which the "isolated polypeptide" is associated in nature, (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated polypeptide can be encoded by genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free from polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).

[0034] Naturally occurring antibodies typically comprise a tetramer. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full-length "light" chain (typically having a molecular weight of about 25 kDa) and one full-length "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain" as used herein refer to any

immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (VH) and three constant domains (CH1, CH2, and CH3 ), wherein the VH domain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VL domain is at the amino-terminus of the polypeptide and the CL domain is at the carboxyl-terminus.

[0035] Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses including, but not limited to, IgM1 and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See , e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light/heavy chain pair typically form an antigen binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0036] The term "CDR set" refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Rabat (Rabat et al. , SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Rabat CDRs. Chothia and coworkers (Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-17; Chothia et al ., 1989, Nature 342: 877-83) found that certain sub-portions within Rabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as LI,

L2, and L3 or HI, H2, and H3 where the "L" and the "H" designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Rabat CDRs. Other boundaries defining CDRs overlapping with the Rabat CDRs have been described by Padlan, 1995, FASEB J. 9: 133-39; MacCallum, 1996, J. Mol. Biol. 262(5): 732-45; and Lefranc, 2003, Dev. Comp.

Immunol. 27: 55-77. Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Rabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Rabat or Chothia defined CDRs. Identification of predicted CDRs using the amino acid sequence is well known in the field, such as in Martin, A.C. "Protein sequence and structure analysis of antibody variable domains," In Antibody Engineering, Vol. 2. Kontermann R., Diibel S., eds. Springer-Verlag, Berlin, p. 33-51 (2010). The amino acid sequence of the heavy and/or light chain variable domain may be also inspected to identify the sequences of the CDRs by other conventional methods, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. The numbered sequences may be aligned by eye, or by employing an alignment program such as one of the CLUSTAL suite of programs, as described in Thompson, 1994, Nucleic Acids Res. 22: 4673-80. Molecular models are conventionally used to correctly delineate framework and CDR regions and thus correct the sequence-based assignments.

[0037] The term "Fc" as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins, although IgG1 and IgG2 are preferred. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent ( i.e ., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgAl, and IgGA2). One example of a Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term " Fc" as used herein is generic to the monomeric, dimeric, and multimeric forms.

[0038] A F(ab) fragment typically includes one light chain and the VH and CH1 domains of one heavy chain, wherein the VH-CH1 heavy chain portion of the F(ab) fragment cannot form a disulfide bond with another heavy chain polypeptide. As used herein, a F(ab) fragment can also include one light chain containing two variable domains separated by an amino acid linker and one heavy chain containing two variable domains separated by an amino acid linker and a CH1 domain.

[0039] A F(ab') fragment typically includes one light chain and a portion of one heavy chain that contains more of the constant region (between the CH1 and CH2 domains), such that an interchain disulfide bond can be formed between two heavy chains to form a F(ab')2 molecule.

[0040] The term "binding protein" as used herein refers to a non-naturally occurring (or recombinant or engineered) molecule that specifically binds to at least one target antigen.

A trispecific binding protein of the present disclosure, unless otherwise specified, typically comprises four polypeptide chains that form at least three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:

VL2- L1-VL1- L2-CL [I]

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

VH1-L3- VH2-L4-CH1-hinge-CH2-CH3 [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

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

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.

[0041] A "recombinant" molecule is one that has been prepared, expressed, created, or isolated by recombinant means.

[0042] One embodiment of the disclosure provides binding proteins having biological and immunological specificity to between one and three target antigens. Another

embodiment of the disclosure provides nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Another embodiment of the disclosure provides expression vectors comprising nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Yet another embodiment of the disclosure provides host cells that express such binding proteins (i.e., comprising nucleic acid molecules or vectors encoding polypeptide chains that form such binding proteins).

[0043] The term "swapability" as used herein refers to the interchangeability of variable domains within the binding protein format and with retention of folding and ultimate binding affinity. "Full swapability" refers to the ability to swap the order of both VH1 and VH2 domains, and therefore the order of VL1 and VL2 domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) while

maintaining full functionality of the binding protein as evidenced by the retention of binding affinity. Furthermore, it should be noted that the designations VH and VL refer only to the domain's location on a particular protein chain in the final format. For example, VH1 and VH2 could be derived from VL1 and VL2 domains in parent antibodies and placed into the VH1 and VH2 positions in the binding protein. Likewise, VL1 and VL2 could be derived from VH1 and VH2 domains in parent antibodies and placed in the VH1 and VH2 positions in the binding protein. Thus, the VH and VL designations refer to the present location and not the original location in a parent antibody. VH and VL domains are therefore "swappable." [0044] The term "antigen" or "target antigen" or "antigen target" as used herein refers to a molecule or a portion of a molecule that is capable of being bound by a binding protein, and additionally is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes.

With respect to each target antigen recognized by a binding protein, the binding protein is capable of competing with an intact antibody that recognizes the target antigen.

[0045] The term "HIV" as used herein means Human Immunodeficiency Virus. As used herein, the term“HIV infection” generally encompasses infection of a host, particularly a human host, by the human immunodeficiency virus (HIV) family of retroviruses including, but not limited to, HIV I, HIV II, HIV III (also known as HTLV-II, LAV-1, LAV-2). HIV can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV family. Thus, treating HIV infection will encompass the treatment of a person who is a carrier of any of the HIV family of retroviruses or a person who is

diagnosed with active AIDS, as well as the treatment or prophylaxis of the AIDS-related conditions in such persons.

[0046] The term "AIDS" as used herein means Acquired Immunodeficiency Syndrome. AIDS is caused by HIV.

[0047] The terms "CD4bs" or "CD4 binding site" refer to the binding site for CD4 (cluster of differentiation 4), which is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.

[0048] The term "CD3" is cluster of differentiation factor 3 polypeptide and is a T-cell surface protein that is typically part of the T cell receptor (TCR) complex.

[0049] "CD28" is cluster of differentiation 28 polypeptide and is a T-cell surface protein that provides co-stimulatory signals for T-cell activation and survival.

[0050] The term "glycoprotein 160" or "gpl60 protein" refers to the envelope glycoprotein complex of HIV and which is a homotrimer that is cleaved into gpl20 and gp41 subunits.

[0051] The term "MPER" refers to the membrane-proximal external region of glycoprotein 41 (gp41), which is a subunit of the envelope protein complex of retroviruses, including HIV.

[0052] The term "glycan" refers to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan. In the disclosed binding proteins, glycan refers to the HIV-1 envelope glycoprotein gpl20.

[0053] The term "T-cell engager" refers to binding proteins directed to a host's immune system, more specifically the T cells' cytotoxic activity as well as directed to a HIV target protein.

[0054] The term "trimer apex" refers to apex of HIV-1 envelope glycoprotein gpl20.

[0055] The term "monospecific binding protein" refers to a binding protein that specifically binds to one antigen target.

[0056] The term "monovalent binding protein" refers to a binding protein that has one antigen binding site.

[0057] The term "bispecific binding protein" refers to a binding protein that specifically binds to two different antigen targets.

[0058] The term "bivalent binding protein" refers to a binding protein that has two binding sites.

[0059] The term "trispecific binding protein" refers to a binding protein that specifically binds to three different antigen targets.

[0060] The term "trivalent binding protein" refers to a binding protein that has three binding sites. In particular embodiments the trivalent binding protein can bind to one antigen target. In other embodiments, the trivalent binding protein can bind to two antigen targets. In other embodiments, the trivalent binding protein can bind to three antigen targets.

[0061] An "isolated" binding protein is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the binding protein, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the binding protein will be purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated binding proteins include the binding protein in situ within recombinant cells since at least one component of the binding protein's natural environment will not be present.

[0062] The terms "substantially pure" or "substantially purified" as used herein refer to a compound or species that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In some

embodiments, a substantially purified fraction is a composition wherein the species comprises at least about 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition. In still other embodiments, the species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.

[0063] A "neutralizing" binding protein as used herein refers to a molecule that is able to block or substantially reduce an effector function of a target antigen to which it binds.

As used herein, "substantially reduce" means at least about 60%, preferably at least about 70%, more preferably at least about 75%, even more preferably at least about 80%, still more preferably at least about 85%, most preferably at least about 90% reduction of an effector function of the target antigen.

[0064] The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and/or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody or binding protein. In certain embodiments, a binding protein is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In some embodiments, a binding protein is said to specifically bind an antigen when the equilibrium dissociation constant is £ 10-8 M, more preferably when the equilibrium dissociation constant is £ 10-9 M, and most preferably when the dissociation constant is £ 10-10 M.

[0065] The dissociation constant (KD) of a binding protein can be determined, for example, by surface plasmon resonance. Generally, surface plasmon resonance analysis measures real-time binding interactions between ligand (a target antigen on a biosensor matrix) and analyte (a binding protein in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor; Piscataway, NJ). Surface plasmon analysis can also be performed by immobilizing the analyte (binding protein on a biosensor matrix) and presenting the ligand (target antigen). The term "KD, " as used herein refers to the dissociation constant of the interaction between a particular binding protein and a target antigen.

[0066] The term "specifically binds" as used herein refers to the ability of a binding protein or an antigen-binding fragment thereof to bind to an antigen containing an epitope with an Kd of at least about 1 x 10-6 M, 1 x 10-7 M, 1 x 10-8 M, 1 x 10-9 M, 1 x 10-10 M, 1 x 10-11 M, 1 x 10-12 M, or more, and/or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen.

[0067] The term "linker" as used herein refers to one or more amino acid residues inserted between immunoglobulin domains to provide sufficient mobility for the domains of the light and heavy chains to fold into cross over dual variable region immunoglobulins. A linker is inserted at the transition between variable domains or between variable and constant domains, respectively, at the sequence level. The transition between domains can be identified because the approximate size of the immunoglobulin domains are well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modeling or secondary structure prediction. The linkers described herein are referred to as L1, which is located on the light chain between the C-terminus of the VL2 and the N-terminus of the VL1 domain; and L2, which is located on the light chain between the C-terminus of the VL1 and the N-terminus of the CL domain. The heavy chain linkers are known as L3, which is located between the C-terminus of the VH1 and the N-terminus of the VH2 domain; and L4, which is located between the C-terminus of the VH2 and the N-terminus of the CH1 domain.

[0068] The term "vector" as used herein refers to any molecule ( e.g ., nucleic acid, plasmid, or virus) that is used to transfer coding information to a host cell. The term "vector" includes a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA molecule into which additional DNA segments may be inserted. Another type of vector is a viral vector, wherein additional DNA segments may be inserted into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms "plasmid" and "vector" may be used interchangeably herein, as a plasmid is the most commonly used form of vector.

However, the disclosure is intended to include other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.

[0069] The phrase "recombinant host cell" (or "host cell") as used herein refers to a cell into which a recombinant expression vector has been introduced. A recombinant host cell or host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term "host cell" as used herein. A wide variety of host cell expression systems can be used to express the binding proteins, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. To express a binding protein recombinantly, a host cell is transformed or transfected with one or more recombinant expression vectors carrying DNA fragments encoding the polypeptide chains of the binding protein such that the polypeptide chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the binding protein can be recovered.

[0070] The term "transformation" as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transformation, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. The term "transfection" as used herein refers to the uptake of foreign or exogenous DNA by a cell, and a cell has been "transfected" when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into suitable host cells.

[0071] The term "naturally occurring" as used herein and applied to an object refers to the fact that the object can be found in nature and has not been manipulated by man. For example, a polynucleotide or polypeptide that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man is naturally-occurring. Similarly, "non-naturally occurring" as used herein refers to an object that is not found in nature or that has been structurally modified or synthesized by man.

[0072] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. Stereoisomers ( e.g ., D-amino acids) of the twenty conventional amino acids; unnatural amino acids and analogs such as a-, a-di substituted amino acids, N- alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for the polypeptide chains of the binding proteins. Examples of

unconventional amino acids include: 4-hydroxyproline, g-carboxyglutamate, e-N,N,N-trimethyllysine, e-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, s-N-methylarginine, and other similar amino acids and imino acids ( e.g ., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxyl-terminal direction, in accordance with standard usage and convention.

[0073] Naturally occurring residues may be divided into classes based on common side chain properties:

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

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

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

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

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

(6) acidic: Asp, Glu;

(7) basic: His, Lys, Arg;

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

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

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

[0074] Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class.

[0075] A skilled artisan will be able to determine suitable variants of the polypeptide chains of the binding proteins using well-known techniques. For example, one skilled in the art may identify suitable areas of a polypeptide chain that may be changed without destroying activity by targeting regions not believed to be important for activity.

Alternatively, one skilled in the art can identify residues and portions of the molecules that are conserved among similar polypeptides. In addition, even areas that may be important for biological activity or for structure may be subject to conservative amino acid

substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0076] The term "patient" as used herein includes human and animal subjects.

[0077] The terms "treatment" or "treat" as used herein refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having the disorder as well as those prone to have a disorder or those in which the disorder is to be prevented. In particular embodiments, binding proteins can be used to treat humans infected with HIV, or humans susceptible to HIV infection, or ameliorate HIV infection in a human subject infected with HIV. The binding proteins can also be used to prevent HIV in a human patient.

[0078] It should be understood as that treating humans infected with HIV include those subjects who are at any one of the several stages of HIV infection progression, which, for example, include acute primary infection syndrome (which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache), asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4+T cells), and AIDS (which is defined by more serious AIDS-defming illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function). In addition, treating or preventing HIV infection will also encompass treating suspected infection by HIV after suspected past exposure to HIV by e.g., contact with HIV-contaminated blood, blood transfusion, exchange of body fluids,“unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.

[0079] The terms "pharmaceutical composition" or "therapeutic composition" as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.

[0080] The term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" as used herein refers to one or more formulation materials suitable for

accomplishing or enhancing the delivery of a binding protein.

What is claimed is:

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

VL2- L1-VL1-L2-CL [I]

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

VH1-L3-VH2-L4-CH1-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 Cm 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; and

wherein VH1 and VL1 form a first antigen binding site;

wherein VH2 and VL2 form a second antigen binding site that binds a CD3 polypeptide, wherein the VH2 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:20), a CDR-H2 sequence comprising the amino acid sequence of

IKDKSNSYAT (SEQ ID NO:21), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:22), and the VL2 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein Xi is E or Q, X2 is A or L, and X3 is Q, R, or F (SEQ ID NO:293), a CDR-L2 sequence comprising the amino acid sequence of KVS (SEQ ID NO:29), and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:30); and

wherein VH3 and VL3 form a third antigen binding site that binds an HIV target protein.

2. The binding protein of claim 1, wherein the first binding site binds a CD28 polypeptide.

3. The binding protein of claim 2, wherein the VH1 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:33), and the VL1 domain comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of KAS (SEQ ID NO:35), and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:36).

4. The binding protein of claim 3, wherein the VH1 domain comprises the amino acid sequence of

QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNV NTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWG KGTTVTVSS (SEQ ID NO:59), and/or the VL1 domain comprises the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTG VPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 60).

5. The binding protein of any one of claims 1-4, wherein the CDR-L1 sequence of the VL2 domain comprises an amino acid sequence selected from the group consisting of Q SLVHQNAQT Y (SEQ ID NO:24), QSLVHENLQTY (SEQ ID NO:25), QSLVHENLFTY (SEQ ID NO:26), and QSLVHENLRTY (SEQ ID NO:27).

6. The binding protein of claim 5, wherein the VH2 domain comprises the amino acid sequence of

QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKS N S YAT YY AD S VKGRFTISRDD SKNTLYLQMN SLRAEDT AVYY CRGVYY AL SPFD Y WGQGTLVTVSS (SEQ ID NO:52), and/or the VL2 domain comprises an amino acid sequence selected from the group consisting of

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHQNAQT YL S WYLQKPGQ SPQ SLIYK V SN RFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 54),

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHENLQTYL S WYLQKPGQ SPQ SLIYK V SN RFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO:55),

DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNR F SGVPDRF SGS GS GTDFTLKI SRVE AED V GV Y Y C GQGT Q YPF TFGS GTK VEIK (SEQ ID NO:56), and

DIVMTQTPLSL S VTPGQP ASISCKS SQ SLVHENLRTYL S WYLQKPGQ SPQ SLIYK V SN RF SGVPDRF SGSGSGTDFTLKISRVE AED VGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO:57).

7. The binding protein of any one of claims 1-6, wherein the third antigen binding site binds an HIV target protein selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.

8. The binding protein of claim 7, wherein:

(a) the VH3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of NCPIN (SEQ ID NO: l) a CDR-H2 sequence comprising the amino acid sequence of WMKPRHGAVSYARQLQG (SEQ ID NO:2), and a CDR-H3 sequence comprising the amino acid sequence of GKYCTARDYYNWDFEH (SEQ ID NO:3), and the VL3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of RTSQYGSLA (SEQ ID NO:4), a CDR-L2 sequence comprising the amino acid sequence of SGSTRAA (SEQ ID NO:5), and a CDR-L3 sequence comprising the amino acid sequence of QQYEF (SEQ ID NO: 6);

(b) the VH3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTAHI (SEQ ID NO:7) a CDR-H2 sequence comprising the amino acid sequence of IKPQYGAV (SEQ ID NO: 8) or IKPQYGAT (SEQ ID NO: 9), and a CDR-H3 sequence comprising the amino acid sequence of DRSYGDSSWALDA (SEQ ID NO: 10), and the VL3

domain comprises a CDR-L1 sequence comprising the amino acid sequence of QGVGSD (SEQ ID NO: 1 1), a CDR-L2 sequence comprising the amino acid sequence of HTS (SEQ ID NO: 12), and a CDR-L3 sequence comprising the amino acid sequence of CQVLQF (SEQ ID NO: 13); or

(c) the VH3 domain comprises a CDR-H1 sequence comprising the amino acid sequence of DCTLN (SEQ ID NO: 14) a CDR-H2 sequence comprising the amino acid sequence of WLKPRW GAVNY ARPLQG (SEQ ID NO: 15), and a CDR-H3 sequence comprising the amino acid sequence of GKNCDYNWDFEH (SEQ ID NO: 16), and the VL3 domain comprises a CDR-L1 sequence comprising the amino acid sequence of RTSQYGSLA (SEQ ID NO: 17), a CDR-L2 sequence comprising the amino acid sequence of SGSTRAA (SEQ ID NO: 18), and a CDR-L3 sequence comprising the amino acid sequence of QQYEF (SEQ ID NO: 19).

9. The binding protein of claim 8, wherein:

(a) the VH3 domain comprises the amino acid sequence of

QVRLSQSGGQMKKPGDSMRISCRASGYEFINCPINWIRLAPGKRPEWMGWMKPRHG AVSYARQLQGRVTMTRDMYSETAFLELRSLTSDDTAVYFCTRGKYCTARDYYNWD FEHWGQGTPVTVSS (SEQ ID NO:43), and/or the VL3 domain comprises the amino acid sequence of

SLTQ SPGTL SL SPGET All S CRT S Q Y GSL AW Y QQRPGQ APRL VI Y S GSTRA AGIPDRF S GSRWGPDYNLTISNLESGDF GVYY CQQYEFF GQGTKVQVDIK (SEQ ID NO:45);

(b) the VH3 domain comprises the amino acid sequence of

QVRLSQSGGQMKKPGDSMRISCRASGYEFINCPINWIRLAPGKRPEWMGWMKPRHG AV S YARQLQGRVTMTRQL SQDPDDPDW GT AFLELRSLT SDDT AVYF CTRGK Y CT A RD YYNWDFEHW GQGTP VT V S S (SEQ ID NO:44), and/or the VL3 domain comprises the amino acid sequence of

SLTQ SPGTL SL SPGET All S CRT S Q Y GSL AW Y QQRPGQ APRL VI Y S GSTRA AGIPDRF S GSRWGPDYNLTISNLESGDF GVYY CQQYEFF GQGTKVQVDIK (SEQ ID NO:45);

(c) the VH3 domain comprises the amino acid sequence of RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQY GAVNF GGGFRDRVTLTRD VYREIAYMDIRGLKPDDTAVYY C ARDRS Y GDS SWALD AWGQGTTVVVSA (SEQ ID NO:46), and/or the VL3 domain comprises the amino acid

sequence of

YfflVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDGV P SRF S GS GFHT SFNLTISDLQ ADDI AT Y Y C Q VLQFF GRGSRLHIK (SEQ ID NO:49);

(d) the VH3 domain comprises the amino acid sequence of

RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQY GATNF GGGFRDRVTLTRD VYREI AYMDIRGLKPDDT AVYY C ARDRS Y GD S S WALD AWGQGTTVVVSA (SEQ ID NO:47), and/or the VL3 domain comprises the amino acid sequence of

YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDGV P SRF S GS GFHT SFNLTISDLQ ADDI AT YY C Q VLQFF GRGSRLHIK (SEQ ID NO:49);

(e) the VH3 domain comprises the amino acid sequence of

RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAPGRGLEWVGWIKPQY GAVNFGGGFRDRVTLTRQLSQDPDDPDWGIAYMDIRGLKPDDTAVYYCARDRSYG D S S WALD AW GQGTT VVV S A (SEQ ID NO:48), and/or the VL3 domain comprises the amino acid sequence of

YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHWYQHKPGRAPKLLIHHTSSVEDGV P SRF S GS GFHT SFNLTISDLQ ADDI AT YY C Q VLQFF GRGSRLHIK (SEQ ID NO:49); or

(f) the VH3 domain comprises the amino acid sequence of

Q VQL VQ S GGQMKKP GE SMRI S CRA S GYEFID C TLNWIRL AP GKRPEWMGWLKPRW GAVNYARPLQGRVTMTRQLSQDPDDPDWGTAFLELRSLTVDDTAVYFCTRGKNCD YNWDFEHWGRGTPVIVSS (SEQ ID NO:50), and/or the VL3 domain comprises the amino acid sequence of

LTQSPGTLSLSPGETAIISCRTSQYGSLAWYQQRPGQAPRLVIYSGSTRAAGIPDRFSG SRWGPD YNLTISNLESGDF GVYY CQQYEFF GQGTKVQVDIK (SEQ ID NO:51).

10. The binding protein of any one of claims 1-9, wherein at least one of L1, L2, L3 or L4 is independently 0 amino acids in length.

11. The binding protein of any one of claims 1-9, wherein (a) L1, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:40), GGGGS GGGGS GGGGS (SEQ ID NO: 41), S, RT, TKGPS (SEQ ID NO: 39), GQPKAAP (SEQ ID NO: 38), and GGSGSSGSGG (SEQ

ID NO: 42); or (b) L1, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:40), GGGGS GGGGS GGGGS (SEQ ID NO:41), S, RT, TKGPS (SEQ ID NO:39), GQPKAAP (SEQ ID NO: 38), and GGSGSSGSGG (SEQ ID NO:42).

12. The binding protein of any one of claims 1-9, wherein L1 comprises the sequence GQPKAAP (SEQ ID NO: 38), L2 comprises the sequence TKGPS (SEQ ID NO:39), L3 comprises the sequence S, and L4 comprises the sequence RT.

13. The binding protein of any one of claims 1-9, wherein at least one of L1, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO:37).

14. The binding protein of claim 13, wherein L1, L2, L3 and L4 comprise the sequence DKTHT (SEQ ID NO:37).

15. The binding protein of any one of claims 1-14, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A.

16. The binding protein of any one of claims 1-14, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236.

17. The binding protein of any one of claims 1-16, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K.

18. The binding protein of any one of claims 1-14, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions

corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A.

19. The binding protein of any one of claims 1-14, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S.

20. The binding protein of any one of claims 1-19, wherein the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

21. The binding protein of any one of claims 1-19, wherein the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

22. The binding protein of claim 1, wherein:

(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:62 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:62; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:63 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:63; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:64 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 64;

(b) the first 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; the second 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; the third 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; and the fourth 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;

(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:69; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:70 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:70; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:71; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:72 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 72;

(d) the first 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; the second 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; the third 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; and the fourth 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;

(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:77 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:77; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:78 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:78; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:79 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:79; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:80 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:80;

(f) the first 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; the second 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; the third 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; and the fourth 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;

(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:85 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:85; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:86 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:86; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:87 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:87; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:88 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:88;

(h) the first 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; the second 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; the third 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; and the fourth 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;

(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:93 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:93; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:94 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:94; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:95 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:95; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:96 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:96;

(j) the first 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; the second 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; the third 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; and the fourth 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;

(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104;

(l) the first 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; the second 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; the third 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; and the fourth polypeptide chain 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;

(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 109 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 109; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 110 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 110; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 111 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 111; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112;

(n) the first 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; the second 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; the third 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; and the fourth 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;

(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 117; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 120;

(p) the first 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; the second 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; the third 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; and the fourth 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;

(q) the first 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; the second 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; the third 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; and the fourth 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;

(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID

NO: 136 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 136;

(s) the first 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; the second 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; the third 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; and the fourth 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;

(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 141 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 142 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 143 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 143; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 144 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 144;

(u) the first 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; the second 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; the third 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; and the fourth 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;

(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 152 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152;

(x) the first 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; the second 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; the third 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; and the fourth 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;

(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160;

(z) the first 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; the second 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; the third 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; and the fourth 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;

(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 168;

(bb) the first 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; the second 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; the third 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; and the fourth 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; or

(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 176.

23. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of claims 1-22.

24. An expression vector comprising the nucleic acid molecule of claim 23.

25. An isolated host cell comprising the nucleic acid molecule of claim 23 or the expression vector of claim 24.

26. The isolated host cell of claim 25, wherein the host cell is a mammalian or insect cell.

27. A pharmaceutical composition comprising the binding protein of any one of claims 1-22 and a pharmaceutically acceptable carrier.

28. 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 1-22 or the pharmaceutical composition of claim 27.

29. The method of claim 28, wherein the binding protein is co-administered with standard anti-retroviral therapy.

30. The method of claim 28 or claim 29, 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.

31. The method of any one of claims 28-30, wherein the patient is a human.

32. The binding protein of any one of claims 1-22 or the pharmaceutical composition of claim 27 for the prevention and/or treatment of HIV infection in a patient.

33. The binding protein for use of claim 32, wherein the binding protein is to be co-administered with standard anti -retroviral therapy.

34. The binding protein for use of claim 32 or claim 33, wherein the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient.

35. The binding protein for use of any one of claims 32-34, wherein the patient is a human.

36. 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 1-22.

37. The vector system of claim 36, 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.

38. A kit of polynucleotides, comprising:

(a) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 177, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 178, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 179, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 180;

(b) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 181, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 182, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 183, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 184;

(c) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 185, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 186, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 187, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 188;

(d) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 189, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 190, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 191, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 192;

(e) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 195, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 196;

(f) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 198, a third

polynucleotide comprising the polynucleotide sequence of SEQ ID NO: 199, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:200;

(g) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:201, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:202, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:203, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:204;

(h) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:205, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:206, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:207, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:208;

(i) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:209, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:210, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:211, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:212;

(j) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:213, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:214, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:215, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:216;

(k) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:217, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:218, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:219, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:220;

(l) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:221, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:222, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:223, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:224;

(m) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:225, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:226, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:227, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:228;

(n) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:229, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:230, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:231, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:232;

(o) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:233, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:234, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:235, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:236;

(p) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:237, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:238, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:239, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:240;

(q) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:241, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:242, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:243, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:244;

(r) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:245, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:246, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:247, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:248;

(s) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:249, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:250, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:251, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:252;

(t) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:253, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:254, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:255, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:256;

(u) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:257, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:258, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:259, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:260;

(v) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:261, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:262, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:263, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:264;

(w) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:265, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:266, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:267, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:268;

(x) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:269, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:270, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:271, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:272;

(y) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:273, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:274, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:275, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:276;

(z) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:277, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:278, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:279, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:280;

(aa) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:281, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:282, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:283, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:284;

(bb) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:285, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:286, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:287, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:288; or

(cc) a first polynucleotide comprising the polynucleotide sequence of SEQ ID NO:289, a second polynucleotide comprising the polynucleotide sequence of SEQ ID NO:290, a third polynucleotide comprising the polynucleotide sequence of SEQ ID NO:291, and a fourth polynucleotide comprising the polynucleotide sequence of SEQ ID NO:292.

39. The kit of claim 38, wherein the first, second, third, and fourth polynucleotides are present on one or more expression vectors.